An Isoxazole Strategy for the Synthesis of 2,2'-Bipyridine Ligands

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An Isoxazole Strategy for the Synthesis of 2,2’-Bipyridine Ligands: Symmetrical and Unsymmetrical 6,6’-Binicotinates, 2,2’-Bipyridine-5-carboxylates, and Their Metal Complexes Ekaterina E. Galenko, Mikhail Sergeevich Novikov, Firuza M. Shakirova, Julia R. Shakirova, Ilya V. Kornyakov, Vladimir A. Bodunov, and Alexander F. Khlebnikov J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00115 • Publication Date (Web): 27 Feb 2019 Downloaded from http://pubs.acs.org on February 28, 2019

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The Journal of Organic Chemistry

An Isoxazole Strategy for the Synthesis of 2,2’-Bipyridine Ligands: Symmetrical and Unsymmetrical 6,6’-Binicotinates, 2,2’-Bipyridine-5-carboxylates, and Their Metal Complexes Ekaterina E. Galenko, Mikhail S. Novikov, Firuza M. Shakirova, Julia R. Shakirova, Ilya V. Kornyakov, Vladimir A. Bodunov, Alexander F. Khlebnikov* Institute of Chemistry, Saint-Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Russia

ABSTRACT: An effective strategy was developed for the synthesis of new 2,2’-bipyridine ligands, symmetrical and unsymmetrical 6,6’-binicotinates, and 2,2’-bipyridine-5-carboxylates, from 4propargylisoxazoles. The synthesis of symmetrical 2,2’-disubstituted 6,6’-binicotinates was achieved using the Eglinton reaction of 5-methoxy-4-(prop-2-yn-1-yl)isoxazoles with Cu(OAc)2, followed by Fe(NTf2)2/Au(NTf2)tBuXPhos-catalysed isomerization of the so formed mixture of isoxazole/azirinesubstituted biacetylenic intermediates. Unsymmetrical 2,2’-disubstituted 6,6’-binicotinates were prepared via

a

copper-free

Sonogashira

coupling

of

5-methoxy-4-(prop-2-yn-1-yl)isoxazoles

with

6-

bromonicotinates to give methyl 6-(3-(5-methoxyisoxazol-4-yl)prop-1-ynyl)pyridine-3-carboxylates, 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

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followed by a transformation of the propargylisoxazole moiety of the adduct into the pyridine fragment under Fe(II)/Au(I) relay catalysis conditions. 6-(Pyrid-2-yl)nicotinates were synthesized by a Stille-type coupling of 2-(tributylstannyl)pyridine with 6-bromonicotinates. Several cyclopalladated complexes of a new series of 6,6’-binicotinates and 2,2’-bipyridine-5-carboxylates and homoleptic Cu(I) complex were synthesized in high yields.

INTRODUCTION 2,2’-Bipyridines are widely used in modern science, industry and medicine as ligands in metal complexes which are catalysts, substructures in supramolecular and macromolecular chemistry, photosensitizers, optical device materials, and medicines. A large number of synthetic procedures for the preparation of these sought-after compounds have been developed.1 Of particular interest is the specific class of 2,2’bipyridine derivatives, 2,2’-bipyridyl-5,5’-dicarboxylates or 6,6'-binicotinates (Bpydc), which have found application in the design of Metal-Organic Frameworks (MOFs) for various purposes, and especially in catalysis.2 Recently MOFs with a Bpydc linker were used as a fluorescent probe for pH measurement,3 for ratiometric temperature sensing,4 for designing hybrid membranes for efficient molecular separation,5 for photocatalytic CO2 conversion,6 for the detection of p-aminophenol, (the biomarker of aniline in the human urine),7 for highly selective sensing of Cu2+ in aqueous media,8 for highly selectively sensing of organic small molecules,9 and for many other applications10 Unexpectedly we found that the structural diversity of 6,6'-binicotinates is represented by only 7 structures where the main skeletons, 6,6'-binicotinic acids, are limited to the symmetrical ones (Scheme 1). 6,6'-Binicotinic acids can be prepared by the oxidation of 5,5′-dimethyl-2,2′-bipyridine,11 cross-coupling reactions of 6-halo-6,6'-binicotinic esters12-15 or the corresponding boronates, usually in low yields.16 The nitro-derivative 1g (R = Et) was synthesized by nitration of 1a (R = Et).17 One of the possible reasons for the low diversity of 6,6'-binicotinic derivatives is the lack of a general method for their preparation. 2 ACS Paragon Plus Environment

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Scheme 1. Synthesis of symmetrical substituted derivatives of 6,6'-binicotinic acid R2

1a, R1 = R2 = H; 1b, R1 = Me, R2 = H; 1c, R1 = H, R2 = Me; 1d, R1 = R2 = Me; 1e, R1 = H, R2 = CO2H; 1f, R1 = MeO, R2 = H; 1g, R1 = NO2, R2 = H

R2

RO2C

CO2R N

N

R1

R1

R = H, Alk, Ar KMnO4, H2O

. 1a, R = H, 70%, ref 11

N

N R2

CO2R

Cl

NiCl2 6H2O, LiCl, Zn AcOH, I2, DMF

N

. 1b, R = Et, 65%, ref 12 . , , , = 1c R Me 30% ref 12

R1 R2 Pd/C CO2R N

. . 1b, R = Me, 1 5%, ref 13 . , , , = re 1d R Et 9% f 14

R1 CO2Et Br

CO2Et PdCl (PPh ) 2 3 2

N O B O 1a =Et R ) (

Sn2Bu6

N

. 1e, R = Et, 44%, ref 15

Pd2(dba)3 CO2Me Josiphos OMe

HNO3 H2SO4

. 1f, R = Me, 14%, ref 16

. 1g, R= Et, ref 17

RESULTS AND DISCUSSION In the search for a general strategy which would enable preparation of structurally diverse 2,2’bi(pyridinecarboxylates), we took into consideration the recently discovered Fe(II)/Au(I) relay catalyzed18 isomerization of propargylisoxazoles to nicotinates.19 Three different approaches leading both to symmetrical (Scheme 2, approaches I and II) and unsymmetrical 6,6’-binicotinates (approach III), as well as unsymmetrical 2,2’-bipyridine-5-carboxylates can be designed using this transformation.

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Scheme 2. Retrosynthetic schemes for three possible propargylisoxazole approaches to 6,6'bicycotinic acid derivatives

MeO2C

CO2Me N R1

R1 = R2 O

N

R1 = R2 CO2Me

R1

OMe

R2

1

CO2Me

R1

N

N N MeO

R1

Br

R1

N

O

MeO

O

MeO

O

R1 N MeO

R1 MeO

O

N

R2

OMe

N

N

approach I (to symmetrical structures)

O

R1

Br R1

N

MeO2C

+

O

R2

N

Br

approach III (to unsymmetrical structures)

approach II o t ( symmetrical structures)

When considering approach I, we hypothesized that dimethyl (2,2'-bipyridine)-5,5'-dicarboxylates 1 could result from a Fe(II)/Au(I) relay catalyzed 1,6-bis(5-methoxyisoxazol-4-yl)hexa-2,4-diyne isomerization. The diynes, in turn, could potentially be prepared by Glaser/Eglinton coupling20 of 5-methoxy-4-(prop-2yn-1-yl)isoxazoles. In order to check the feasibility of this sequence propargylisoxazol 2a was synthesized according to known procedures.19 Glaser reaction of 2a with CuI yielded, according to 1H NMR, a complex mixture of compounds X. However, dimethyl 6,6'-diphenyl-[2,2'-bipyridine]-5,5'-dicarboxylate 1h could be isolated in 38% yield, when this mixture X was further reacted with Fe(NTf2)2/Au(NTf2)PPh3 catalyst under the reaction conditions used for the transformation of 4-propargylisoxazoles into nicotinates (Scheme 3).19


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Scheme 3. Two step transformation of isoxazole 2a into binicotinate 1h Ph N MeO

CuI, Et3N

O 2a O

[X]

OMe

MeO2C

Fe(NTf 2)2 Au(NTf 2)PPh3

CO2Me N Ph

Ph

O

N

OMe

Ph

N

N N MeO

Ph

O

MeO2C

Ph

3a

X=

Ph MeO2C N

3c

N

3b

e N CO2M Ph

Ph

1h

O

OMe

Ph C

N

N

C Ph

et c

3d

MeO

O

This meant that the mixture X contained at least one of the compounds 3a-d, which could be precursors of the binicotinate 1h, according to the reaction mechanism for the formation of nicotinates from 4propargylisoxazoles.19 This mechanism involves the isomerization of 5-alkoxy-4-propargylisoxazoles to the corresponding alkyl 2-propargyl-2H-azirine-2-carboxylates under Fe(II)-catalysis followed by Au(I)catalyzed propargylazirine-pyridine isomerization. It is known that 2H-azirine derivatives (3b, c) from isoxazole derivatives (2a, 3a, b) can also be formed in the presence of copper salts.21 The intense signal of ion [C26H20N2NaO4+Na]+ ([M+Na]+) was detected in the mass-spectrum of the mixture X (see the Supporting information), confirming the formation of one or more isomers of dimer 3 during the first stage of the reaction. In addition, copper salts can promote the formation of non-cyclic products from isoxazole and azirine derivatives.21 The non-cyclic products will not form binicotinates 1 at the next stage of the process, thereby reducing the yield of the target product. Further, we tried to optimize the first stage of the synthetic scheme using the Cu(OAc)2-mediated Eglinton coupling. It was also found that the use of Au(NTf2)tBuXPhos as one of the catalysts for the second stage of the process instead of Au(NTf2)PPh3 can accelerate the reaction. This modification of the process permitted the preparation of 1h in 52%



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overall yield over two stages. The series of symmetrically substituted binicotinates 1h-p were prepared using the above conditions (Table 1). The structure of binicotinate 1o was confirmed by X-ray analysis.

Table 1. Synthesis of symmetrical substituted binicotinates 1h-p a-c R o

N MeO

O 2a-i

1) Cu(OAc)2 H2O, Et3N, K2CO3, MeCN, 60 C o

CO2Me

CO2Me MeO2C

MeO2C

MeO2C

F

CO2Me

N

N

N

N

b (1k, 60% from 2d)

Cl

Cl

N

N

OMe

1m, 21%a from 2f Br b (1m, 37% from 2f) CO2Me N

N

S a

1n, 52% from 2g

Br

N

CO2Me MeO2C

MeO2C

N

a

CO2Me N

1l 62%a from 2e

S MeO

CO2Me N

1j, 40%a from 2c b (1j, 53% from 2c)

1i, 59% from 2b CO2Me

R

1h-p

N

a

1h, 52% from 2a

F

N

N

a

MeO2C

R

N

CO2Me MeO2C

MeO2C

N

N

N

2) Fe(NTf2)2, Au(NTf2)tBuXPhos, DCE, 60 C

MeO2C N

CO2Me

MeO2C

1o 36% from 2h b (1o 48% from 2h)

1p, 14%a from 2i b (1p, 53% from 2i)

______________ a

The overall isolated yield for two stage synthesis. b The overall isolated yield for three stage synthesis (Scheme 4). c Up to 2 mmol scale reactions.

The three substrates 2d, f, i (containing 4-fluorophenyl, 4-bromophenyl and cyclopropyl substituents) gave rather low yields of the binicotinate. We decided to try another scheme for the conversion of isoxazoles 2c, d, f, h, i into binicotinates 1: a) bromination of 4-propargylisoxazole 2 to give 4-(3bromopropargyl)isoxazole 4, isomerization of 4 to give 6-bromonicotinate 5,19 and Stille-type coupling22 6 ACS Paragon Plus Environment

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of 6-bromonicotinate 5 to give binicotinates 1 (Scheme 4). The use of the three-step synthesis scheme below for binicotinates 1j, k, m, o, p led, in some cases, to an increase in the yields of the target compounds (see Table 1). Scheme 4. Three step transformation of isoxazoles 2 into binicotinates 1 Br

2c, d, f, h, i

NBS, AgNO3

MeO

acetone, 25 oC

Fe(NTf2)2 Au(NTf2)PPh3 o

CO2Me Sn2Bu6, CuI, Pd(PPh3)4 1j, k, m, o, p o 105 C xylene, R

DCE, 85 C Br N R 5a-e N 4a-e Up to 0.8 mmol scale 4a, 5a, R = 4-tBuC6H4; 4b, 5b, R = 4-FC6H4; 4c, 5c, R = 4-BrC6H4; 4d, 5d, R = 2-Thienyl; 4e, 5e, R = c-Pr O

For obvious reasons, the direct Stille-type coupling of two different 6-bromonicotinates 5 cannot be used for an effective preparation of unsymmetrical binicotinates. We hypothesized that a simple approach to such compounds could be implemented via a copper-free Sonogashira coupling reaction of isoxazole 2 with nicotinate 5 to give adduct 6, followed by transformation of the substituted propargylisoxazole moiety to the pyridine fragment in binicotinate 7 under Fe(II)/Au(I) relay catalysis conditions (see Scheme in Table 2). In fact adducts 6a-f were formed in good isolated yields by heating a mixture of isoxazoles 2e, f, i and nicotinates 5a-d, f, g in the presence of diisopropylamine and Pd(PPh3)4 catalyst in refluxing benzene. Treatment of 6a-f with Fe(NTf2)2/Au(NTf2)tBuXPhos catalysts in DCE at 85 °C provided the target unsymmetrical binicotinates 7a-f in good to excellent yields (Table 2). This synthetic scheme is inapplicable for the preparation of 6-(pyrid-2-yl)nicotinates 8 since 2bromopyridine does not react with 5-methoxy-4-propargylisoxazoles under Sonogashira coupling reaction conditions. These compounds could be easily prepared by Stille-type coupling of 2-(tributylstannyl)pyridine 9 with 6-bromonicotinates 5 (Table 3). The reaction provided good yields of 6-pyrid-2ylnicotinates 8 for various substituted 6-bromonicotinates 5, prepared from the corresponding 4-(3bromopropargyl)isoxazoles 4, excluding nicotinate 5c with a 2-(4-bromophenyl)-substituent. Only a 50% yield of compound 8f was obtained when 1.3 equiv of stannane 9 was used, due to formation of the double 7 ACS Paragon Plus Environment


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cross-coupling by-product 8i (5%). The latter became the main product, albeit with a yield of only 37%, when a 3.6-fold excess of stannane 9 was used in the reaction. Table 2. Synthesis of unsymmetrical substituted binicotinates 7a-fa R1 N O MeO , , 2e f i + MeO2C

R1

N O Pd(PPh3)4 iPr2NH

CO2Me R1 N Fe(NTf2)2, Au(NTf2)tBuXPhos o DCE, 85 C N mmol scale to Up 0.6 R2

MeO

PhH, 80 oC

N

R2

Br N 5a-d, f, g 5f R = 4-MeOC6H4; 5g R = 4-MeC6H4

R2

Cl

Cl

Cl

N O

N

N O

N

6a, 84%, from 2e+5a

Br CO2Me

CO2Me N O

N OMe 6d, 65%, from 2e+5f

CO2Me

MeO2C N

Cl

MeO2C

N S

MeO

CO2Me

N

MeO 6f, 82%, from 2i+5g

CO2Me N

N

7b, 95% from 6b

F

Cl

N

7c, 79% from 6c

CO2Me MeO2C

MeO2C N

N

N O

CO2Me MeO2C N

Cl

CO2Me

6e, 81%, from 2f+5d

MeO2C

N

7a, 76% from 6a

N

Br 6c, 93%, from 2e+5c

6b, 73%, from 2e+5b

Cl

MeO

N

F MeO

MeO

MeO

N O

CO2Me

CO2Me

CO2Me N O

CO2Me 7a-f

CO2Me 6a-f

N

F

CO2Me N

N

S Cl

7d, 95% from 6d

OMe

Br

7e, 87% from 6e

7f, 70% from 6f

__________________ a The isolated yield. 8 ACS Paragon Plus Environment

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Table 3. Synthesis of bipyridylcarboxylates 8a-ia, b SnBu3 + N

CO2Me

Br

9

N

Pd(PPh3)4, CuI o xylene, 105 C

R

CO2Me N

N

8a-i

5a-d, f-i (5h R = Ph, 5i R = 4-ClC6H5) CO2Me

CO2Me

CO2Me

N

N

N

N

N 8a, 88% from 5h

N

8b, 81% from 5g

CO2Me

8c, 91% from 5a

CO2Me

N

CO2Me

N

N

F

8d, 90% from 5b

N

N

N

Cl

8e, 84% from 5i

CO2Me

Br

8f, 50% from 5c CO2Me

CO2Me

N N

N

N OMe

8g, 77% from 5f

R

N

S

8h, 80% from 5d

N 8i, 37% from 5c

N

____________________ a

The isolated yield. b Up to 1.2 mmol scale reactions.

Bipyridyl esters 1, 7, 8 can be easily hydrolyzed to the corresponding acids 10, which could be used for the preparation of new MOFs. Thus, refluxing of 1l,p, 7e, 8g in a mixture of MeOH/15% aq KOH gave inner salts 10a-d in high yields (Scheme 5). Scheme 5. Hydrolysis of bipyridyl esters 1l,p, 7e, 8g to inner salts 10a-d

KOH R3 CO2H H2O/MeOH N N R2 R1 reflux 10a-d mmol scale to 0.22 Up 10a, R1 = R2 = 4-ClC6H4, R3 = CO2H, 87% from 1l; 10b, R1 = R2 = c-Pr, R3 = CO2H, 91% from 1p; 10c, R1 = 2-thienyl, R2 = 4-BrC6H4, R3 = CO2H, 96% from 7e; 10d, R1 = 4-MeOC6H4, R2 = R3 = H, 87% from 8g 1l, p, 7e, 8g



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6-Aryl/hetaryl-2,2'-bipyridines form cyclopalladated complexes, which have been shown to possess useful photochemical, photophysical, photoelectrochemical and biological

properties.23 However, no

cyclopalladated complexes of derivatives of 6,6'-binicotinic and even pyridylnicotinic acid have been prepared so far. Having in our hands a general approach to symmetrical and unsymmetrical 6,6’binicotinates and 2,2’-bipyridine-5-carboxylates we synthesized several cyclopalladated complexes of these series (Table 4) and characterized them by NMR and HRMS. The structures of complexes 11b, c were determined by X-ray analysis. Table 4. Synthesis of cyclopalladated complexes 8a-f a CO2Me X

N

R'

CO2Me

Pd(MeCN)2Cl2 o

MeOH, 60 C

N

R'

R

N

1h,j,l,n,o; 8b

Pd

MeO2C

N

Pd

MeO2C

Pd

11b, 76% from 1j

Cl

11c, 85% from 1l CO2Me

CO2Me

N N Pd

OMe

Cl

MeO2C

N S

OMe 11d, 86% from 1n

Cl

Cl

CO2Me

a

N

Cl

11a, 83% from 1h

MeO2C

CO2Me

N N

Cl

N

11a-f

CO2Me

N MeO2C

X

Pd Cl

CO2Me

N

R

N

S

Pd Cl

N N

Pd Cl

11f, 92% from 8b

11e, 87% from 1o

Up to 0.1 mmol scale reactions.


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Homoleptic Cu(I) complex 12 was also synthesized by reaction of binicotinate ligand 7b with Cu(MeCN)4BF4 in high yield. (Scheme 6). Scheme 6. NN-Cu complex 12 CO2Me

MeO2C N

N 7b

Cu(MeCN)4BF4

R

o

R

DCM, MeCN, 20 C R = 4-FC6H4

R

Cu N

R

BF4

-

N CO2Me

MeO2C 12, 90%

In conclusion, a method was developed for the synthesis of symmetrical 2,2’-disubstituted 6,6’binicotinates using the Eglinton reaction of 5-methoxy-4-(prop-2-yn-1-yl)isoxazoles with Cu(OAc)2, followed by Fe(NTf2)2/Au(NTf2)tBuXPhos-catalyzed isomerization of the so formed mixture of isoxazole/azirine-substituted

biacetylenic

intermediates.

Unsymmetrical

2,2’-disubstituted

6,6’-

binicotinates were prepared via a copper-free Sonogashira coupling of 5-methoxy-4-(prop-2-yn-1yl)isoxazoles with 6-bromonicotinates to give methyl 6-(3-(5-methoxyisoxazol-4-yl)prop-1-ynyl)pyridine3-carboxylates, followed by a transformation of the propargylisoxazole moiety of the adduct into the pyridine fragment under Fe(II)/Au(I) relay catalysis conditions. 6-(Pyrid-2-yl)nicotinates were synthesized by a Stille-type coupling of 2-(tributylstannyl)pyridine with 6-bromonicotinates. Bipyridyl esters can be easily hydrolyzed to the corresponding acids, which could be used for the preparation of new MOFs. Several cyclopalladated complexes of a new series of 6,6’-binicotinates and 2,2’-bipyridine-5carboxylates and homoleptic Cu(I) complex were synthesized in high yields.



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EXPERIMENTAL SECTION General Information and Methods Melting points were determined on a capillary melting point apparatus. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a NMR spectrometer in CDCl3 or DMSO-d6. Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane (TMS δ = 0.00). 1H NMR spectra were calibrated according to the residual peak of CDCl3 (7.25 ppm) or DMSO-d6 (2.50 ppm). 13C{1H} and 13C DEPT135 spectra were calibrated according to the peak of CDCl3 (77.00 ppm) or DMSO-d6 (39.51 ppm). 19

F spectra were calibrated according to a CFCl3 external standard (δ = 0). Electrospray ionization (ESI)

mass spectra were recorded on a mass spectrometer, HRMS-ESI-QTOF, electrospray ionization, positive mode. Thin-layer chromatography (TLC) was conducted on aluminum sheets with 0.2 mm silica gel (fluorescent indicator) and Silica 60 M was used for column chromatography. All solvents were distilled and dried prior to use. Crystallographic data for the structures 1o, 11b, c have been deposited with the Cambridge Crystallographic Data Centre (CCDC 1o 1883739, 11b 1883747, 11c 1883740).

General Procedure A for the Synthesis of 4-Propargylisoxazolones. 4-Propargylisoxazolones 13 were synthesized according to published procedure.19 Alkyl 3-aryl-3oxopropanoate (10 mmol) and propargylbromide (11.5 mmol, 80% solution in toluene) were dissolved in dry acetone (50 mL), anhydrous potassium carbonate (15 mmol) and anhydrous sodium iodide (2-3 mmol) were then added and the mixture was stirred at rt until complete consumption of the starting ester (1.5-2 weeks, monitored by TLC). The mixture was diluted with water, extracted with ether, the organic phase was washed with brine, dried over sodium sulfate and all volatiles were removed in vacuo. Crude alkyl 2aroyl/alkylpent-4-ynoate (10 mmol) was dissolved in ethanol (35 mL) and hydroxylamine hydrochloride was then added (25 mmol). The mixture was stirred at rt for several days until TLC showed absence either of the starting ester or of any further changes (1-1.5 weeks). The mixture was diluted with water and 12 ACS Paragon Plus Environment

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portioned between water and ether, the layers were separated and the aqueous one was extracted with ether. The combined organic phases were washed with water and extracted with 5% aqueous potassium hydroxide solution and the combined basic extracts were washed with small portion of ether prior to acidification with concentrated hydrochloric acid. If the product solidified it was separated by filtration, washed with water and dried in air, otherwise it was extracted with ether. The ether solution was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. Spectral data of 3-phenyl-4(prop-2-yn-1-yl)isoxazole-5(4H)-one 13a, 4-(prop-2-yn-1-yl)-3-(4-tolyl)isoxazol-5(4H)-one 13b, 3-(4chlorophenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 13e, 3-(4-bromophenyl)-4-(prop-2-yn-1-yl)isoxazol5(4H)-one 13f, 3-(4-methoxyphenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 13g were in agreement with previously reported values.19

3-(4-(tert-Butyl)phenyl)-4-(prop-2-yn-1-yl)isoxazole-5(4H)-one/3-(4-tert-butyl)phenyl)-4(prop-2-yn-1-yl)isoxazol-5-ol (13c). Compound 13c was prepared following the general procedure A from ethyl 3-(4-(tert-butyl)phenyl)-3-oxopropanoate (6.39 g, 25.7 mmol), propargylbromide (4.40 g, 29.6 mmol), K2CO3 (5.33 g, 38.6 mmol), NaI (0.77 g, 5.1 mmol) and NH2OH·HCl (4.5 g, 64 mmol) in 4.84 g (74%) yield as a brown semisolid. 1Н NMR (DMSO-d6, 400 MHz, 23 °C): δ = 1.32 (s, 9H), 2.89 (t, J = 2.7 Hz, 1H), 3.23 (d, J = 2.7 Hz, 2H), 7.56-7.71 (m, 4H), 12.43 (br. s., 1H).

13

C NMR (DMSO-d6, 100

MHz, 23 °C): δ = 11.8 (CH2), 30.8 (CH3), 34.7 (C), 71.2 (CH), 81.5 (C), 93.4 (br s, C), 124.3 (C), 126.1 (CH), 127.2 (CH), 154.2 (C), 161.2 (C), 171.5 (C). ESI/HRMS (m/z): 256.1332 calcd. for C16H18NO2+ [M+H]+, found 256.1346.

3-(4-Fluorophenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one/3-(4-fluorophenyl)-4-(prop-2yn-1-yl)isoxazol-5-ol (13d). Compound 13d was prepared following the general procedure A from ethyl 3-(4-fluorophenyl)-3-oxopropanoate (6.05 g, 28.8 mmol), propargylbromide (4.92 g, 33.1 mmol), K2CO3 (5.97 g, 43.2 mmol), NaI (0.86 g, 5.8 mmol) and NH2OH·HCl (5.04 g, 72.5 mmol) in 4.69 g (75%) 13 ACS Paragon Plus Environment


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yield as a colorless solid, mp 109-110 °C (water). 1Н NMR (DMSO-d6, 400 MHz, 23 °C): δ = 2.87 (d, J = 2.7 Hz, 1H), 3.25 (d, J = 2.7 Hz, 2H), 7.43-7.47 (m, 2H), 7.74-7.78 (m, 2H), 12.53 (br. s. 1H). 13C NMR (DMSO-d6, 100 MHz, 23 °C): δ = 11.6 (CH2), 71.4 (CH), 81.3 (C), 92.7 (br. s., C), 116.4 (d, J = 22.1 Hz, CH), 123.9 (br. s., C), 130.0 (d, J = 8.7 Hz, CH), 160.4 (C), 163.6 (d, J = 249.9 Hz, C), 171.3 (C). ESI/HRMS (m/z): 240.0431 calcd. for C12H8FNNaO2+ [M+Na]+, found 240.0438.

4-(Prop-2-yn-1-yl)-3-(thiophen-2-yl)isoxazol-5(4H)-one/4-(prop-2-yl-1-yl)-3-(thiophen-2yl)isoxazol-5-ol (13h). Compound 13h was prepared following the general procedure A from methyl 3-oxo-3-(thiopen-2-yl)propanoate (10.73 g, 58.3 mmol), propargylbromide (9.96 g, 67.0 mmol), K2CO3 (11.55 g, 87.4 mmol), NaI (1.75 g, 11.7 mmol) and NH2OH·HCl (12.5 g, 180.0 mmol) in 3.59 g (32%) yield as a brown solid, mp 69-70 °C (water). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 2.09 (t, J = 2.6 Hz, 1H), 2.97 (ddd, J = 17.2, 5.3, 2.6 Hz, 1H), 3.05 (ddd, J = 17.2, 4.5, 2.6 Hz, 1H), 3.91 (t, J = 4.9 Hz, 1H), 7.17 (dd, J = 5.0, 3.8 Hz, 1H), 7.45 (dd. J = 3.7, 0.8 Hz, 1H), 7.58 (dd, J = 5.0, 8.0 Hz, 1H).

13

C NMR

(CDCl3, 100 MHz, 23 °C): δ 19.6 (CH2), 45.0 (CH), 72.9 (CH), 76.2 (C), 128.0 (CH), 130.0 (CH), 130.60 (CH), 130.64 (C), 160.2 (C), 176.0 (C). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ 2.06 (t, J = 2.7 Hz, 1H), 3.39 (d, J = 2.7 Hz, 2H), 3.72 (s, 1H) (only well resolved characteristic signals are given). ESI/HRMS (m/z): 206.0270 calcd. for C10H8NO2S+ [M+H]+, found 206.0273.

3-Cyclopropyl-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one/3-cyclopropyl-4-(prop-2-yn-1yl)isoxazol-5-ol (13i). Compound 13i was prepared following the slightly modified procedure A from ethyl 3-cyclopropyl-3-oxopropanoate (10.02 g, 64.1 mmol), propargylbromide (11.00 g, 79.8 mmol), K2CO3 (13.30 g, 96.2 mmol), NaI (1.90 g, 12.8 mmol) and NH2OH·HCl (13.34 g, 192.0 mmol) in 7.71 g (76%) yield as a dark orange oil. Crude ethyl 2-(cyclopropanecarbonyl)pent-4-ynoate was added to NH2OH prepared from hydrochloride by basification with 20% aq KOH (pH 7-8).1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 0.98-1.21 (m, 4H), 1.63-1.70 (m, 1H), 2.14 (t, J = 2.7 Hz, 1H), 2.86-2.88 (m, 2H), 3.54 14 ACS Paragon Plus Environment

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(t, J = 5.4 Hz, 1H) . 13C NMR (CDCl3, 100 MHz): δ δ 6.9 (CH2), 8.5 (CH), 8.7 (CH2), 17.8 (CH2), 46.5 (CH), 72.3 (CH), 77.2 (C), 169.8 (C), 176.6 (C). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 2.05 (t, J = 2.7 Hz, 1H), 3.25 (d, J = 2.7 Hz, 2H), 3.28 (s, 1H) (only well resolved characteristic signals are given). ESI/HRMS (m/z): 186.0525 calcd. for C9H9NNaO2+ [M+Na]+, found 186.0526.

General Procedure B for the Synthesis of 5-Methoxy-4-propargylisoxazoles 2. 3-Substituted 4-(prop-2-yn-1-yl)isoxazol-5(4H)-ones 13 (1 mmol) were dissolved in THF and slowly added to excess of freshly prepared ethereal diazomethane solution (2.6 mmol). 3-Substituted 5-methoxy4-(prop-2-yn-1-yl)isoxazoles 2 formed were isolated by chromatography according to the previously reported procedure.18 Spectral data of 5-methoxy-3-phenyl-4-(prop-2-yn-1-yl)isoxazole 2a, 5-methoxy-3(4-methylphenyl)-4-(prop-2-yn-1-yl)isoxazole yl)isoxazole

2e,

2b,

3-(4-chlorophenyl)-5-methoxy-4-(prop-2-yn-1-

3-(4-bromophenyl)-5-methoxy-4-(prop-2-yn-1-yl)isoxazole

2f,

5-methoxy-3-(4-

methoxyphenyl)-4-(prop-2-yn-1-yl)isoxazole 2g, 3-cyclopropyl-5-methoxy-4-(prop-2-yn-1-yl)isoxazole 2i were in agreement with previously reported values. 19

3-(4-(tert-Butyl)phenyl)-5-methoxy-4-(prop-2-yn-1-yl)isoxazole (2c). Compound 2c was prepared following the general procedure B from isoxazolone 13c (2.38 g, 9.31 mmol) in 2.19 g (87%) yield as a light brown oil. 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.36 (s, 9H), 2.06 (d, J = 2.6 Hz, 1H), 3.26 (d, J = 2.6 Hz, 2H), 4.16 (s, 3H), 7.50 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H).

13

C NMR

(CDCl3, 100 MHz, 23 °C): δ = 11.6 (CH2), 31.2 (CH3), 34.8, 58.0 (CH3), 68.8 (CH), 81.4 (C), 86.8 (C), 125.8 (CH), 126.5 (C), 127.7 (CH), 153.0 (C), 164.2 (C), 169.6 (C). ESI/HRMS (m/z): 270.1489 calcd. for C17H20NO2+ [M+H]+, found 270.1494.

3-(4-Fluorophenyl)-5-methoxy-4-(prop-2-yn-1-yl)isoxazole (2d). Compound 2d was prepared following the general procedure B from isoxazolone 13d (1.20 g, 4.7 mmol) in 0.84 g (76%) yield as a colorless solid, mp 103-104 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 15 ACS Paragon Plus Environment


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2.04 (t, J = 2.7 Hz, 1H), 3.24 (d, J = 2.7 Hz, 2H), 4.16 (s, 3H), 7.14-7.19 (m, 2H), 7.72-7.75 (m, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 11.5 (CH2), 58.0 (CH3), 69.0 (CH), 81.1 (C), 86.8 (C), 115.9 (d, J = 21.8 Hz, CH), 125.6 (d, J = 3.5 Hz, C), 130.0 (d, J = 8.5 Hz, CH),163.4 (C), 163.7 (d, J = 249.7 Hz, C), 169.7 (C). ESI/HRMS (m/z): 232.0768 calcd. for C13H11FNO2+ [M+H]+, found 232.0778.

5-Methoxy-4-(prop-2-yn-1-yl)-3-(thiophen-2-yl)isoxazole (2h). Compound 2h was prepared following the general procedure B from isoxazolone 13h (1.66 g, 8.1 mmol) in 1.04 g (59%) yield as a colorless solid, mp 68-69 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ 2.05 (t, J = 2.6 Hz, 1H), 3.34 (d, J = 2.6 Hz, 2H), 7.15 (dd, J = 5.0, 3.8 Hz, 1H), 7.44 (dd, J = 5.0, 0.7 Hz, 1H), 7.62 (dd, J = 3.8, 0.7 Hz, 1H).

13

C NMR (CDCl3, 100 MHz, 23 °C): δ = 11.5 (CH2), 58.1 (CH3), 69.1

(CH), 80.7 (C), 86.6 (C), 127.5 (CH), 127.6 (CH), 128.2 (CH), 130.3 (C), 158.9 (C), 169.5 (C). ESI/HRMS (m/z): 220.0427 calcd. for C11H10NO2S+ [M+H]+, found 220.0437.

General Procedure C for the Synthesis of 3-Substituted 4-(3-Bromoprop-2-yn-1-yl)-5methoxyisoxazoles 4. AgNO3 was added (0.25-0.3 mmol) to a solution of 5-methoxy-4propargylisoxazole 2 (1 mmol) and NBS (1.2 mmol) in acetone (15 mL), and the mixture was stirred in dark overnight. The precipitate was filtered off, washed with DCM, the solvents were evaporated in vacuo, and the residue was purified by chromatography on silica (light petroleum/ethyl acetate 8:1).19 Spectral data of 3-(4-bromophenyl)-4-(3-bromoprop-2-yn-1-yl)-5-methoxyisoxazole 4c, 4-(3-Bromoprop-2-yl-yl)3-cyclopropyl-5-methoxyisoxazole

4e,

4-(3-bromoprop-2-yn-1-yl)-5-methoxy-3-(4-

methoxyphenyl)isoxazole 4f, 4-(3-bromoprop-2-yn-1-yl)-5-methoxy-3-(4-methylphenyl)isoxazole 4g, 4(3-bromoprop-2-yn-1-yl)-5-methoxy-3-phenylisoxazole

4h,

4-(3-bromoprop-2-yn-1-yl)-3-(4-

chlorophenyl)-5-methoxyisoxazole 4i were in agreement with previously reported values.19

4-(3-Bromoprop-2-yn-yl)-3-(4-(tert-butyl)phenyl)-5-methoxyisoxazole (4a). Compound 4a was prepared following the general procedure C from isoxazole 2c (404 mg, 1.5 mmol), NBS (322 mg, 16 ACS Paragon Plus Environment

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1.8 mmol) and AgNO3 (76 mg, 0.45 mmol) in 434 mg (83%) yield as a light brown solid, mp 100-101 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.36 (s, 9H), 3.27 (s, 2H), 4.16 (s, 3H), 7.49-7.52 (m, 2H), 7.62-7.65 (m, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 31.2 (CH3), 34.7 (C), 52.5 (CH3), 125.2 (CH), 125.6 (C), 125.7 (CH), 128.4 (CH), 135.5 (C), 139.9 (CH), 143.7 (C), 152.5 (C), 159.8 (C), 168.0 (C). ESI/HRMS (m/z): 348.0594 calcd. for C17H19BrNO2+ [M+H]+, found 348.0596.

4-(3-Bromoprop-2-yn-1-yl)-3-(4-fluorophenyl)-5-methoxyisoxazole (4b). Compound 4b was prepared following the general procedure C from isoxazole 2d (961 mg, 4.2 mmol), NBS (888 mg, 5.0 mmol) and AgNO3 (211 mg, 1.25 mmol) in 1098 mg (85%) yield as a yellowish solid, mp 60-61 °C (ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.25 (s, 2H), 4.16 (s, 3H), 7.15-7.20 (m, 2H), 7.67-7.71 (m, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 12.8 (CH2), 39.8 (C), 58.0 (CH3), 86.4 (C), 115.9 (d, J = 21.7, CH), 125.5 (d, J = 3.1 Hz, C), 130.0 (d, J = 8.5 Hz, CH), 163.4 (C), 163.7 (d, J = 250.2 Hz, C), 169.7 (C). ESI/HRMS (m/z): 309.9873 calcd. for C13H10BrFNO2+ [M+H]+, found 309.9888.

4-(3-Bromoprop-2-yn-1-yl)-5-methoxy-3-(thiophen-2-yl)isoxazole (4d). Compound 4d was prepared following the general procedure C from isoxazole 2h (340 mg, 1.6 mmol), NBS (331 mg, 1.9 mmol) and AgNO3 (79 mg, 0.47 mmol) in 329 mg (71%) yield as a light brown solid, mp 79-80 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.35 (s, 2H), 4.15 (s, 3H), 7.17 (dd, J = 5.0, 3.7 Hz, 1H), 7.45 (dd, J = 5.0, 0.9 Hz, 1H), 7.56 (dd, J = 3.7, 0.9 Hz, 1H).

13

C NMR (CDCl3, 100

MHz, 23 °C): δ = 12.8 (CH2), 39.7 (C), 58.1 (CH3), 76.6 (C), 86.2 (C), 127.6 (CH), 127.7 (CH), 128.1 (CH), 130.2 (C), 158.9 (C), 169.6 (C). ESI/HRMS (m/z): 297.9532 calcd. for C11H9BrNO2S+ [M+H]+, found 297.9527.

General Procedure D for the Synthesis of Methyl 2-Substituted 6-Bromonicotinates 5. A solution of 3-substituted 4-(3-bromoprop-2-yn-1-yl)-5-methoxyisoxazoles 4 (1 mmol), Fe(NTf2)2 (0.05 mmol, 5 mol %) and Au(NTf2)PPh3 (0.05 mmol, 5 mol %) was stirred under reflux until completion of the 17 ACS Paragon Plus Environment


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reaction as judged by TLC. The solvent was evaporated and the residue was purified by chromatography on silica (light petroleum/ethyl acetate 10:1 + 1% of Et3N or toluene (for poorly soluble substances) as eluent). The solid obtained after chromatography was washed with pentane and dried on air. Spectral data of methyl 6-bromo-2-(4-bromophenyl)nicotinate 5c, methyl 6-bromo-2-cyclopropylnicotinate 5e, methyl 6-bromo-2-(4-methoxyphenyl)nicotinate 5f, methyl 6-bromo-2-(4-methylphenyl)nicotinate 5g, methyl 6bromo-2-phenylnicotinate 5h, 6-bromo-2-(4-chlorophenyl)nicotinate 5i were in agreement with previously reported values.19

Methyl 6-bromo-2-(4-(tert-butyl)phenyl)nicotinate (5a). Compound 5a was prepared following the general procedure D from isoxazole 4a (400 mg, 1.15 mmol), Fe(NTf2)2 (35.4 mg, 60 µmol), Au(NTf2)PPh3 (42.5 mg, 60 µmol) in 314 mg (79%) yield as a light yellow solid, mp 86-87 °C (toluene). 1

Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.34 (s, 9H), 3.72 (s, 3H), 7.43-7.50 (m, 5H), 7.90 (d, J = 8.2 Hz,

1H).

13

C NMR (CDCl3, 100 MHz, 23 °C): δ = 31.2 (CH3), 34.7 (C), 52.5 (CH3), 125.2 (CH), 125.6 (C),

125.7 (CH), 128.4 (CH), 135.5 (C), 139.9 (CH), 143.7 (C), 152.5 (C), 159.8 (C), 168.0 (C). ESI/HRMS (m/z): 248.0594 calcd for. C17H19BrNO2+ [M+H]+, found 348.0591.

Methyl 6-bromo-2-(4-fluorophenyl)nicotinate (5b). Compound 5b was prepared following the general procedure D from isoxazole 4b (900 mg, 2.90 mmol), Fe(NTf2)2 (92.4 mg, 150 µmol), Au(NTf2)PPh3 (110.9 mg, 150 µmol) in 695 mg (77%) yield as a colorless solid, mp 133-134 °C (toluene). 1

Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.73 (s, 3H), 7.10-7.14 (m, 2H), 7.51-7.54 (m, 3H), 7.94 (d, J =

8.2 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.5 (CH3), 115.3 (d, J = 22.1 Hz, CH), 125.6 (C), 126.2 (CH), 130.7 (d, J = 8.5 Hz, CH), 134.6 (d, J = 3.3 Hz, C), 140.2 (CH), 143.9 (C), 158.8 (C), 163.5 (d, J = 249.6 Hz, C), 167.5 (C). ESI/HRMS (m/z): 309.9873 calcd. for C13H10BrFNO2+ [M+H]+, found 309.9870.


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Methyl 6-bromo-2-(thiophen-2-yl)nicotinate (5d). Compound 5d was prepared following the general procedure D from isoxazole 4d (288 mg, 0.97 mmol), Fe(NTf2)2 (29.8 mg, 50 µmol), Au(NTf2)PPh3 (35.7 mg, 50 µmol) in 210 mg (73%) yield as a light brown solid, mp 58-59 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.87 (s, 3H), 7.06-7.09 (m, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.42-7.43 (m, 1H), 7.47-7.49 (m, 1H), 7.75 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.8 (CH3), 124.5 (C), 125.5 (CH), 127.8 (CH), 128.8 (CH), 129.5 (CH), 139.6 (CH), 140.9 (C), 143.0 (C), 151.7 (C), 168.0 (C). ESI/HRMS (m/z): 297.9532 calcd. for C11H9BrNO2S+ [M+H]+, found 297.9529.

General Procedure E for the Synthesis of Symmetrical Binicotinates 1 Using Eglinton Coupling. A mixture of 5-methoxy-4-propargylisoxazole 2 (1 mmol), Cu(OAc)2·H2O (2.1 mmol) and K2CO3 (1.2 mmol) in acetonitrile (20-25 mL) was stirred at rt for 20 min and then was heated at 60 °C for 2 h.24 The precipitate was filtered off, washed with chloroform and the solvents were evaporated. The residue was passed through silica (40 mL) using ethyl acetate as an eluent. After evaporation of the solvent, the residue was dissolved in dichloroethane, Fe(NTf2)2 and Au(NTf2)tBuXPhos (4-5 mol %) was added, and solution was stirred at 60 °C for 6 h. The solvent was evaporated, the residue was dissolved in toluene and passed through silica (15-20 mL) (eluted with toluene + 0.5% Et3N). After evaporation of toluene a colorless solids were washed with pentane and dried.

Dimethyl 6,6’-diphenyl-[2,2’-bipyridine]-5,5’-dicarboxylate (1h). Compound 1h was prepared following the general procedure E from isoxazole 2a (426 mg, 2 mmol), Cu(OAc)2·H2O (840 mg, 4.2 mmol), K2CO3 (332, 2.4 mmol), Fe(NTf2)2 (56.4 mg, 92 µmol) and Au(NTf2)tBuXPhos (85.4 mg, 92 µmol) in 222 mg (52%) yield as a colorless solid, mp 199-200 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.74 (s, 6H), 7.48-7.51 (m, 6H), 7.67-7.69 (m, 4H), 8.22 (d, J = 8.1 Hz, 2H), 8.61 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.4 (CH3), 119.4 (CH), 127.1 (C), 128.1 (CH), 128.74 19 ACS Paragon Plus Environment


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(CH), 128.84 (CH), 139.0 (CH), 140.0 (C), 156.2 (C), 158.2 (C), 168.6 (C). ESI/HRMS (m/z): 447.1315 calcd for C26H20N2NaO4+ [M+Na]+, found 447.1322.

Dimethyl 6,6’-di-p-tolyl-[2,2’-bipyridine]-5,5’-dicarboxylate (1i). Compound 1i was prepared following the general procedure E from isoxazole 2b (227 mg, 1 mmol), Cu(OAc)2·H2O (420 mg, 2.1 mmol), K2CO3 (166, 1.2 mmol), Fe(NTf2)2 (31.2.mg, 50 µmol) and Au(NTf2)tBuXPhos (46.2 mg, 50 µmol) in 134 mg (59%) yield as a colorless solid, mp 183-184 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 2.44 (s, 6H), 3.76 (s, 6H), 7.30 (d, J = 7.9 Hz, 4H), 7.58 (d, J = 7.9 Hz, 4H), 8.19 (d, J = 8.2 Hz, 2H), 8.58 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 21.4 (CH3), 52.4 (CH3), 119.1 (CH), 126.9 (C), 128.7 (CH), 128.9 (CH), 137.2 (C), 138.8 (C), 138.9 (CH), 156.2 (C), 158.1 (C), 168.7 (C). ESI/HRMS (m/z): 475.1628 calcd. for C28H24N2NaO4+ [M+Na]+, found 475.1619.

Dimethyl 6,6’-bis(4-(tert-butyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1j). Compound 1j was prepared following the general procedure E from isoxazole 2c (269 mg, 1 mmol), Cu(OAc)2·H2O (420 mg, 2.1 mmol), K2CO3 (166, 1.2 mmol), Fe(NTf2)2 (31.0.mg, 50 µmol) and Au(NTf2)tBuXPhos (46.7 mg, 50 µmol) in 108 mg (40%) yield as a colorless solid, mp 237-238 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.39 (s, 18H), 3.76 (s, 6H), 7.50-7.52 (m, 4H), 7.62-7.65 (m, 4H), 8.18 (d, J = 8.1 Hz, 2H), 8.58 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 31.3 (CH3), 34.7 (C), 52.4 (CH3), 119.1 (CH), 125.1 (CH), 126.9 (C), 128.5 (CH), 137.0 (C), 138.9 (CH), 152.0 (C), 156.2 (C), 158.0 (C), 168.8 (C). ESI/HRMS (m/z): 537.2748 calcd. for C34H37N2O4+ [M+H]+, found 537.2747.

Dimethyl 6,6’-bis(4-clorophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1l). Compound 1l was prepared following the general procedure E from isoxazole 2e (495 mg, 2 mmol), Cu(OAc)2·H2O (840 mg, 4.2 mmol), K2CO3 (332, 2.4 mmol), Fe(NTf2)2 (52.3 mg, 85 µmol) and Au(NTf2)tBuXPhos (79.4 mg, 85 µmol) in 302 mg (62%) yield as a colorless solid, mp 206-207 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.77 (s, 6H), 7.45-7.48 (m, 4H), 7.59-7.61 (m, 4H), 8.24 (d, J = 8.1 Hz, 2H), 8.58 (d, J = 20 ACS Paragon Plus Environment

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8.1 Hz, 2H).


13

C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.5 (CH3), 119.6 (CH), 127.0 (C), 128.4 (CH),

130.2 (CH), 135.1 (C), 138.5 (C), 139.3 (CH), 156.2 (C), 157.2 (C), 168.1 (C). ESI/HRMS (m/z): 493.0716 calcd. for C26H19Cl2N2O4+ [M+H]+, found 493.0730.

Dimethyl 6,6’-bis(4-bromophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1m). Compound 1m was prepared following the general procedure E from isoxazole 2f (292 mg, 1 mmol), Cu(OAc)2·H2O (420 mg, 2.1 mmol), K2CO3 (166, 1.2 mmol), Fe(NTf2)2 (30.9 mg, 50 µmol) and Au(NTf2)tBuXPhos (46.8 mg, 50 µmol) in 61 mg (21%) yield as a colorless solid, mp 216-217 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.77 (s, 6H), 7.52-7.54 (m, 4H), 7.61-7.63 (m, 4H), 8.24 (d, J = 8.2 Hz, 2H), 8.58 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.5 (CH3), 119.7 (CH), 123.4 (C), 126.9 (C), 130.4 (CH), 131.3 (CH), 138.9 (C), 139.3 (CH), 156.2 (C), 157.3 (C), 168.1 (C). ESI/HRMS (m/z): 580.9706 calcd. for C26H19Br2N2O4+ [M+H]+, found 580.9736.

Dimethyl 6,6’-bis(4-methoxyphenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1n). Compound 1n was prepared following the general procedure E from isoxazole 2g (243 mg, 1 mmol), Cu(OAc)2·H2O (420 mg, 2.1 mmol), K2CO3 (166, 1.2 mmol), Fe(NTf2)2 (30.7 mg, 50 µmol) and Au(NTf2)tBuXPhos (46.7 mg, 50 µmol) in 127 mg (52%) yield as a colorless solid, mp 195-196 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ 3.77 (s, 6H), 3.89 (s, 6H), 7.00-7.04 (m, 4H), 7.64-7.66 (m, 4H), 8.17 (d, J = 8.1 Hz, 2H), 8.55 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.4 (CH3), 55.3 (CH3), 113.6 (CH), 118.8 (CH), 126.6 (C), 130.2 (CH), 132.4 (C), 138.9 (CH), 156.2 (C), 157.6 (C), 160.4 (C), 168.9 (C). ESI/HRMS (m/z): 485.1707 calcd. for C28H25N2O6+ [M+H]+, found 485.1687.

Dimethyl 6,6’-di(thiophen-2-yl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1o). Compound 1o was prepared following the general procedure E from isoxazole 2h (219 mg, 1 mmol), Cu(OAc)2·H2O (420 mg, 2.1 mmol), K2CO3 (166, 1.2 mmol), Fe(NTf2)2 (30.8 mg, 50 µmol) and Au(NTf2)tBuXPhos (46.7 mg, 50 µmol) in 78 mg (36%) yield as a colorless solid, mp 185-186 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 21 ACS Paragon Plus Environment


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23 °C): δ = 3.92 (s, 6H), 7.11-7.13 (m, 2H), 7.46-7.50 (m, 4H), 8.08 (d, J = 8.1 Hz, 2H), 8.48 (d, J = 8.1 Hz, 2H).

13

C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.7 (CH3), 118.9 (CH), 127.81 (CH), 127.83 (CH),

128.7 (CH), 138.7 (CH), 143.0 (C), 150.0 (C), 155.5 (C), 168.7 (C). ESI/HRMS (m/z): 437.0624 calcd. for C22H17N2O4S2+ [M+H]+, found 437.0634.

Dimethyl 6,6’-dicyclopropyl-[2,2’bipyridine]-5,5’-dicarboxylate (1p). Compound 1p was prepared following the general procedure E from isoxazole 2i (177 mg, 1 mmol), Cu(OAc)2·H2O (420 mg, 2.1 mmol), K2CO3 (166, 1.2 mmol), Fe(NTf)2 (30.8 mg, 50 µmol) and Au(NTf2)tBuXPhos (46.7 mg, 50 µmol) in 20 mg (14%) yield as a colorless solid, mp 177-178 °C (toluene). 1Н NMR (CDCl3, 400 MHz): δ 1.05-1.09 (m, 4H), 1.27-1.30 (m, 4H), 3.10-3.16 (m, 2H), 3.96 (s, 3H), 8.15 (d, J = 8.2 Hz, 2H), 8.21 (d, J = 8.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 11.3 (CH2), 14.2 (CH), 52.3 (CH3), 117.1 (CH), 125.1 (C), 139.0 (CH), 156.8 (C), 163.0 (C), 167.5 (C). ESI/HRMS (m/z): 353.1496 calcd. for C20H21N2O4+ [M+H]+, found 353.1498.

General Procedure F for the Synthesis of Symmetrical Binicotinates 1 Using Stille Coupling. Compounds 1 were prepared following the modified procedure.22 Sn2Bu6 (0.5 mmol), Pd(PPh3)4 (0.08 mmol, 7-10 mol %) and CuI (0.15 mmol, 15 mol %) was added under Ar atmosphere to the degassed solution of appropriate 6-bromonicotinate 5 (1 mmol) in m-/p-xylene (5-8 mL). The solution was stirred at 120 °C for 3 h. The solvents were evaporated, the residue was dissolved in toluene and passed through silica (15-20 mL) (eluted with toluene + 0.5% Et3N). After evaporation of toluene a colorless solids were washed with pentane and dried.

Dimethyl 6,6’-bis(4-(tert-butyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1j). Compound 1j was prepared following the general procedure F from methyl 6-bromo-2-(4-(tert-butyl)phenyl)nicotinate 5a (174 mg, 0.50 mmol), Sn2Bu6 (145 mg, 0.25 mmol), Pd(PPh3)4 (40.5 mg, 35 µmol), CuI (14.3 mg, 75 µmol) in 109 mg (81%) yield as colorless solid. 22 ACS Paragon Plus Environment

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Dimethyl 6,6’-bis(4-fluorophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1k). Compound 1k was prepared following the general procedure F from methyl 6-bromo-2-(4-flurophenyl)nicotinate 5b (155 mg, 0.50 mmol), Sn2Bu6 (145 mg, 0.25 mmol), Pd(PPh3)4 (40.5 mg, 35 µmol), CuI (14.3 mg, 75 µmol) in 106 mg (92%) yield as a colorless solid , mp 230-231 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.76 (s, 6H), 7.16-7.20 (m, 4H), 7.64-7.67 (m, 4H), 8.23 (d, J = 8.1 Hz, 2H), 8.57 (d, J = 8.1 Hz, 2H).

13

C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.5 (CH3), 115.2 (d, J = 21.7 Hz, CH), 119.4 (CH),

127.0 (C), 130.7 (d, J = 8.2 Hz, CH), 136.1 (d, J = 3.3 Hz, C), 139.2 (CH), 156.2, 157.3 (C), 163.3 (d, J = 248.3 Hz, C), 168.3 (C). ESI/HRMS (m/z): 461.1307 calcd. for C26H19F2N2O4+ [M+H]+, found 461.1323.

Dimethyl 6,6’-bis(4-bromophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1m). Compound 1m was prepared following the general procedure F from methyl 6-bromo-2-(4-bromophenyl)nicotinate 5c (98 mg, 0.26 mmol), Sn2Bu6 (78.2mg, 0.13 mmol), Pd(PPh3)4 (31.9 mg, 27 µmol), CuI (9.6 mg, 50 µmol) in 49 mg (62%) yield as a colorless solid.

Dimethyl 6,6’-di(thiophen-2-yl)-[2,2’-bipyridine]-5,5’-dicarboxylate (1o). Compound 1o was prepared following the general procedure F from methyl 6-bromo-2-(thiophen-2-yl)nicotinate 5d (175 mg, 0.59 mmol), Sn2Bu6 (170.3 mg, 0.29 mmol), Pd(PPh3)4 (48.3 mg, 42 µmol), CuI (15.7 mg, 82 µmol) in 119 mg (93%) yield as a colorless solid.

Dimethyl 6,6’-dicyclopropyl-[2,2’bipyridine]-5,5’-dicarboxylate (1p). Compound 1p was prepared following the general procedure F from methyl 6-bromo-2-cyclopropylnicotinate 5e (205 mg, 0.80 mmol), Sn2Bu6 (232 mg, 0.40 mmol), Pd(PPh3)4 (75.0 mg, 64 µmol), CuI (23.0 mg, 120 µmol) in 121 mg (86%) yield as a colorless solid.

General Procedure G for Sonogashira Coupling of 6-Bromonicotinates and 4Propargylisoxasoles. Diisopropilamine (2-3 mmol) and Pd(PPh3)4 (0.08 mmol, 8 mol %) was added to degassed solution on 4-propargylisoxazole 2 (1.00 mmol) and 6-bromonicotinate 5 (1.00-1.05) in 23 ACS Paragon Plus Environment


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benzene (10-15 mL). Reaction mixture was stirred under reflux overnight.25 The solvent was evaporated, the residue was purified by column chromatography (light petroleum/ethyl acetate: 20:1+1% Et3N; 10:1+1% Et3N; 4:1+1% Et3N). After evaporation of the solvents the product 6 was washed with cold methanol and dried on air.

Methyl

2-(4-(tert-butyl)phenyl)-6-(3-(3-(4-chlorophenyl)-5-methoxyisoxazol-4-yl)prop-1-

yn-1-yl)nicotinate (6a). Compound 6a was prepared following the general procedure G from methyl 6bromo-2-(4-(tert-butyl)phenyl)nicotinate 5a (258 mg, 0.74 mmol), 3-(4-chlorophenyl)-5-methoxy-4(prop-2-yn-1-yl)isoxazole 2e (173 mg, 0.70 mmol), Pd(PPh3)4 (65.1 mg, 56 µmol), HN(i-Pr)2 (0.35 mL, 2.5 mmol) in 301 mg (84%) yield as a yellowish solid, mp 105-106 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.34 (s, 3H), 3.52 (s, 2H), 3.70 (s, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.44-7.47 (m, 6H), 7.70-7.73 (m, 2H), 8.00 (d, J = 8.0Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 12.6 (CH2), 31.2 (CH3), 34.7 (C), 52.3 (CH3), 58.1 (CH3), 80.7 (C), 86.3 (C), 88.8 (C), 124.3 (CH), 125.1 (CH), 125.4 (C), 128.0 (C), 128.3 (CH), 129.1 (CH), 129.4 (CH), 136.0 (C), 136.6 (C), 138.0 (CH), 144.7 (C), 151.9 (C), 159.2 (C), 163.4 (C), 168.1 (C), 169.8 (C). ESI/HRMS (m/z): 515.1732 calcd. for C30H28ClN2O4+ [M+H]+, found 515.1749.

Methyl

6-(3-(3-(4-chlorophenyl)-5-methoxyisoxazol-4-yl)prop-1-yn-1-yl)-2-(4-

fluorophenyl)nicotinate (6b). Compound 6b was prepared following the general procedure G from methyl 6-bromo-2-(4-fluorophenyl)nicotinate 5b (156 mg, 0.50 mmol), 3-(4-chlorophenyl)-5-methoxy-4(prop-2-yn-1-yl)isoxazole 2e (124 mg, 0.50 mmol), Pd(PPh3)4 (35.3 mg, 46 µmol), HN(i-Pr)2 (0.21 mL, 1.50 mmol) in 174 mg (73%) yield as a yellowish solid, mp 113-114 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.53 (s, 2H), 3.70 (s, 3H), 4.17 (s, 3H), 7.08-7.12 (m, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.48-7.50 (m, 2H), 7.71 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 12.6 (CH2), 52.4 (CH3), 58.1 (CH3), 80.5 (C), 86.2 (C), 89.3 24 ACS Paragon Plus Environment

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(C), 115.1 (d, J = 21.7 Hz, CH), 124.8 (CH), 125.4 (C), 129.1 (CH), 129.4 (CH), 130.5 (d, J = 8.4 Hz, CH), 135.6 (d, J = 3.1 Hz, C), 135.6 (C), 136.0 (C), 138.3 (CH), 144.8 (C), 158.3 (C), 163.2 (d, J = 248.4 Hz, C), 163.3 (C), 167.7 (C), 169.8 (C). ESI/HRMS (m/z): 477.1012 calcd. for C26H19ClFN2O4+ [M+H]+, found 477.1037.

Methyl 2-(4-(bromophenyl)-6-(3-(3-(4-chlorophenyl)-5-methoxyisoxazol-4-yl)prop-1-yn-1yl)nicotinate (6c). Compound 6c was prepared following the general procedure G from methyl 6bromo-2-(4-bromophenyl)nicotinate 5c (275 mg, 0.74 mmol), 3-(4-chlorophenyl)-5-methoxy-4-(prop-2yn-1-yl)isoxazole 2e (173 mg, 0.70 mmol), Pd(PPh3)4 (65.4 mg, 56 µmol), HN(i-Pr)2 (0.35 mL, 2.5 mmol) in 347 mg (93%) yield as a yellowish solid, mp 143-144 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.52 (s, 2H), 3.71 (s, 3H), 4.18 (s, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 12.7 (CH2), 52.5 (CH3), 58.1 (CH3), 80.5 (C), 86.2 (C), 89.4 (C), 123.4 (C), 125.0 (CH), 125.3 (C), 127.9 (C), 129.1 (CH), 129.4 (CH), 130.2 (CH), 131.3 (CH), 136.0 (C), 138.4 (CH), 138.5 (C), 144.9 (C), 158.3 (C), 163.4 (C), 167.5 (C), 169.8 (C). ESI/HRMS (m/z): 559.0031 calcd. for C26H18BrClN2NaO4+ [M+Na]+, found 559.0021.

Methyl

6-(3-(3-(4-chlorophenyl)-5-methoxyisoxazol-4-yl)prop-1-yn-1-yl)-2-(4-

methoxyphenyl)nicotinate (6d). Compound 6d was prepared following the general procedure G from methyl 6-bromo-2-(4-methoxyphenyl)nicotinate 5f (172 mg, 0.53 mmol), 3-(4-chlorophenyl)-5-methoxy4-(prop-2-yn-1-yl)isoxazole 2e (124 mg, 0.50 mmol), Pd(PPh3)4 (47.9 mg, 42 µmol), HN(i-Pr)2 (0.3 mL, 2.0 mmol) in 160 mg (65%) yield as a yellowish solid solid, mp 116-117 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.52 (s, 2H), 3.71 (s, 3H), 3.84 (s, 3H), 4.17 (s, 3H), 6.94 (d, J = 8.5 Hz, 2H), 7.19 (d, J =8.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 12.7 (CH2), 52.4 25 ACS Paragon Plus Environment


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(CH3), 55.3 (CH3), 58.1 (CH3), 80.8 (C), 86.3 (C), 88.8 (C), 113.6 (CH), 124.2 (CH), 125.3 (C), 128.0 (C), 129.1 (CH), 129.4 (CH), 130.1 (CH), 131.9 (C), 136.0 (C), 138.1 (CH), 144.6 (C), 158.7 (C), 160.3 (C), 163.4 (C), 168.4 (C), 169.8 (C). ESI/HRMS (m/z): 489.1212 calcd. for C27H22ClN2O5+ [M+H]+, found 489.1221.

Methyl

6-(3-(3-(4-bromophenyl)-5-methoxyisoxazol-4-yl)prop-1-yn-1-yl)-2-(thiophen-2-

yl)nicotinate (6e). Compound 6e was prepared following the general procedure G from methyl 6bromo-2-(thiophen-2-yl)nicotinate 5d (161 mg, 0.54 mmol), 3-(4-bromophenyl)-5-methoxy-4-(prop-2-yn1-yl)isoxazole 2f (146 mg, 1.50 mmol), Pd(PPh3)4 (46.2 mg, 40 µmol), HN(i-Pr)2 (0.3 mL, 2.0 mmol) in 207 mg (81%) yield as a colorless solid, mp 117-118 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.53 (s, 2H), 3.85 (s, 3H), 4.19 (s, 3H), 7.05-7.08 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.33-7.34 (m, 1H), 7.44-7.46 (m, 1H), 7.62-7.68 (m, 4H), 7.84 (d, J = 8.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 12.6 (CH2), 52.7 (CH3), 58.1 (CH3), 80.5 (C), 86.3 (C), 88.9 (C), 124.26 (CH), 124.32 (C), 124.7 (C), 127.6 (CH), 128.0 (CH), 128.4 (C), 128.8 (CH), 129.7 (CH), 132.1 (CH), 137.6 (CH), 141.9 (C), 144.4 (C), 151.1 (C), 163.5 (C), 168.3 (C), 169.8 (C). ESI/HRMS (m/z): 530.9985 calcd. for C24H17BrN2NaO4S+ [M+Na]+, found 530.9985.

Methyl

6-(3-(3-cyclopropyl-5-methoxyisoxazol-4-yl)prop-1-yn-1-yl)-2-(p-tolyl)nicotinate

(6f). Compound 6f was prepared following the general procedure G from methyl 6-bromo-2-(4methylphenyl)nicotinate 5g (304 mg, 0.99 mmol), 3-cyclopropyl-5-methoxy-4-(prop-2-yn-1-yl)isoxazole 2i (195 mg, 1.10 mmol), Pd(PPh3)4 (96.7 mg, 81 µmol), HN(i-Pr)2 (0.45 mL, 3.0 mmol) in 329 mg (82%) yield as a light brown oil. 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 0.94-1.01 (m, 4H), 1.84-1.91 (m, 1H), 2.39 (s, 3H), 3.48 (s, 2H), 3.70 (s, 3H), 4.07 (s, 3H), 7.21 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 6.6 (CH2), 6.7 (CH3), 11.9 (CH2), 21.3 (CH), 52.3 (CH3), 57.8 (CH3), 80.1 (C), 87.0 (C), 89.1 (C), 124.4 (CH), 125.4 (C), 26 ACS Paragon Plus Environment

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128.5 (CH), 128.8 (CH), 136.6 (C), 138.0 (CH), 138.7 (C), 144.9 (C), 159.2 (C), 167.0 (C), 168.2 (C), 168.6 (C). ESI/HRMS (m/z): 403.1652 calcd. for C24H23N2O4+ [M+H]+, found 403.1640.

General Procedure H for the Synthesis of Unsymmetrical Binicotinates 7. Fe(NTf2)2 (5 µmol, 5 mol %) and Au(NTf2)tBuXPhos (5 µmol, 5 mol %) was added to a solution of compound 6 (0.1 mmol) in DCE (5-10 mL) and the mixture was stirred under reflux overnight. The solvent was evaporated, the residue was dissolved in toluene and passed through silica (15-20 mL) (eluted with toluene). After evaporation of toluene a colorless solids were washed with pentane and dried.

Dimethyl 6-(4-(tert-butyl)phenyl)-6’-(4-chlorphenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (7a). Compound 7a was prepared following the general procedure H from nicotinate 6a (139 mg, 0.27 mmol), Fe(NTf2)2 (8.3 mg, 13.5 µmol), Au(NTf2)tBuXPhos (12.6 mg, 13.5 µmol) in 106 mg (76%) yield as a colorless solid, mp 228-229 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.39 (s, 9H), 3.76 (s, 3H), 3.77 (s, 3H), 7.45-7.47 (m, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.60-7.62 (m, 2H), 7.63 (d, J = 8.3 Hz, 2H), 8.19 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 8.2 Hz), 8.53 (d, J = 8.1 Hz, 1H), 8.62 (d, J = 8.2 Hz, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 31.3 (CH3), 34.7 (C), 52.4 (CH3), 52.5 (CH3), 119.0 (CH), 119.7 (CH), 125.2 (CH), 126.8 (C), 127.1 (C), 128.4 (CH), 128.5 (CH), 130.2 (CH), 135.0 (C), 136.9 (C), 138.6 (C), 138.9 (CH), 139.2 (CH), 152.1 (C), 155.9 (C), 156.5 (C), 157.1 (C), 158.0 (C), 168.2 (C), 168.7 (C). ESI/HRMS (m/z): 515.1732 calcd. for C30H28ClN2O4+ [M+H]+, found 515.1753.

Dimethyl 6-(4-chlorophenyl)-6’-(4-fluorophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate (7b). Compound 7b was prepared following the general procedure H from nicotinate 6b (143 mg, 0.30 mmol), Fe(NTf2)2 (9.2 mg, 15 µmol), Au(NTf2)tBuXPhos (14.0 mg, 15 µmol) in 136 mg (95%) yield as a colorless solid, mp 200-201 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.77 (s, 3H), 3.77 (s, 3H), 7.16-7.20 (m, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.63-7.67 (m, 2H), 8.22 (m, 2H), 8.55-8.59 (m, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.45 (CH3), 52.49 (CH3), 115.2 (d, J = 27 ACS Paragon Plus Environment


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21.9 Hz, CH), 119.4 (CH), 119.6 (CH), 126.9 (C), 127.0 (C), 128.4 (CH), 130.2 (CH), 130.7 (d, J = 8.3 Hz, CH), 135.1 (C), 136.1 (d, J = 3.2 Hz, C), 138.5 (C), 139.2 (CH), 139.3 (CH), 156.1 (C), 156.2 (C), 157.2 (C), 157.3 (C), 163.3 (d, J = 248.4 Hz, C), 168.1 (C), 168.3 (C). ESI/HRMS (m/z): 477.1012 calcd. for C26H19ClFN2O4+ [M+H]+, found 477.0995.

Dimethyl

6-(4-bromophenyl)-6’-(4-chlorophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate

(7c). Compound 7c was prepared following the general procedure H from nicotinate 6c (140 mg, 0.26 mmol), Fe(NTf2)2 (8.0 mg, 13 µmol), Au(NTf2)tBuXPhos (12.1 mg, 13 µmol) in 111 mg (79%) yield as a colorless solid, mp 203-204 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.77 (pseudo-s, 6H), 7.45-7.47 (m, 2H), 7.52-7.54 (m, 2H), 7.59-7.63 (m, 2H), 8.23-8.25 (m, 2H), 8.56-8.59 (m, 2H). 13C NMR (CDCl3, 100 MHzб 23 °C): δ = 52.5 (CH3), 52.5 (CH3), 119.6 (CH), 119.7 (CH), 123.4 (C), 126.9 (C), 127.0 (C), 128.4 (CH), 130.2 (CH), 130.4 (CH), 131.3 (CH), 135.1 (C), 138.5 (C), 138.9 (C), 139.28 (CH), 139.29 (CH), 156.15 (C), 156.20 (C), 157.2 (C), 157.3 (C), 168.06 (C), 168.09 (C). ESI/HRMS (m/z): 559.0031 calcd. for C26H18BrClN2NaO4+ [M+Na]+, found 559.0055.

Dimethyl

6-(4-chlorophenyl)-6’-(4-methoxyphenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate

(7d). Compound 7d was prepared following the general procedure H from nicotinate 6d (147 mg, 0.30 mmol), Fe(NTf2)2 (9.3 mg, 15 µmol), Au(NTf2)tBuXPhos (11.9 mg, 15 µmol) in 140 mg (95%) yield as a colorless solid, mp 166-167 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.77 (s, 3H), 3.78 (s, 3H), 3.89 (s, 3H), 7.02 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 8.17 (d, J = 8.1 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.51 (d, J = 8.1 Hz, 1H), 8.61 (d, J = 8.2 Hz, 1H).

13

C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.40 (CH3), 52.44 (CH3), 55.33 (CH3), 113.7 (CH),

118.8 (CH), 119.6 (CH), 126.8 (C), 126.8 (C), 128.3 (CH), 130.17 (CH), 130.20 (CH), 132.3 (C), 135.0 (C), 138.5 (C), 139.0 (CH), 139.2 (CH), 155.8 (C), 156.5 (C), 157.1 (C), 157.6 (C), 160.4 (C), 168.2 (C), 168.8 (C). ESI/HRMS (m/z): 489.1212 calcd. for C27H22ClN2O5+ [M+H]+, found 489.1232. 28 ACS Paragon Plus Environment

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Dimethyl 6-(4-bromophenyl)-6’-(thiophen-2-yl)-[2,2’-bipyridine]-5,5’-dicarboxylate (7e). Compound 7e was prepared following the general procedure H from nicotinate 6e (78 mg, 0.15 mmol), Fe(NTf2)2 (4.7 mg, 7.7 µmol), Au(NTf2)tBuXPhos (7.2 mg, 7.7 µmol) in 68 mg (87%) yield as a colorless solid, mp 195-196 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ 3.77 (s, 3H), 3.92 (s, 3H), 7.117.13 (m, 1H), 7.46-7.48 (m, 1H), 7.49-7.51 (m, 1H), 7.52-7.54 (m, 2H), 7.60-7.63 (m, 2H), 8.05 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.60 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ = 52.5 (CH3), 52.7 (CH3), 118.9 (CH), 119.6 (CH), 123.4 (C), 125.8 (C), 126.8 (C), 127.8 (CH), 127.9 (CH), 128.8 (CH), 130.4 (CH), 131.3 (CH), 138.7 (CH), 139.0 (C), 139.3 (CH), 143.0 (C), 150.0 (C), 155.6 (C), 156.1 (C), 157.2 (C), 168.1 (C), 168.7 (C).ESI/HRMS (m/z): 530.9985 calcd. for C24H17BrN2NaO4S+ [M+Na]+, found 530.9992.

Dimethyl

6-cyclopropyl-6’-(4-methylphenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate

(7f).

Compound 7f was prepared following the general procedure H from nicotinate 6f (250 mg, 0.62 mmol), Fe(NTf2)2 (19.1 mg, 31 µmol), Au(NTf2)tBuXPhos (29.0 mg, 31 µmol) in 176 mg (70%) yield as a colorless solid, mp 118-119 °C (toluene). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.07-1.12 (m, 2H), 1.31-1.34 (m, 2H), 2.43 (s, 3H), 3.12-3.19 (m, 1H), 3.75 (s, 3H), 3.96 (s, 3H), 7.26-7.29 (m, 2H), 7.547.56 (m, 2H), 8.17 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.38 (d, J = 8.1 Hz, 1H).

C NMR (CDCl3, 100 MHz, 23 °C): δ = 11.4 (CH2), 14.3 (CH), 21.4 (CH3), 52.3 (CH3), 52.4

13

(CH3), 117.4 (CH), 118.8 (CH), 125.3 (C), 126.8 (C), 128.7 (CH), 128.9 (CH), 137.2 (C), 138.8 (CH), 139.1 (CH), 156.47 (C), 156.51 (C), 158.1 (C), 163.1 (C), 167.5 (C), 168.8 (C). ESI/HRMS (m/z):403.1652 calcd. for C24H23N2O4+ [M+H]+, found 403.1670.

General Procedure I for the Synthesis of Unsymmetrical Binicotinates 8 via Stille Coupling. Compounds 8 were prepared according to the modified procedure.26 Pd(PPh3)4 (0.08 mmol, 8 mol %) and CuI (0.15 mmol, 15 mol %) were added to degassed solution of 6-bromonicotinate 5 (1 mmol) 29 ACS Paragon Plus Environment


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and 2-(tributylstannyl)pyridine 9 (1.4-1.8 mmol)) in m-/p-xylene (10-15 mL). The reaction mixture was stirred at 120 °C overnight. The solvent was evaporated and the residue was purified by column chromatography (light petroleum/ethyl acetate: 20:1+1% Et3N, 10:1+1% Et3N). After evaporation of the solvents a solid was washed with pentane and dried on air.

Methyl 6-phenyl-[2,2’-bipyridine]-5-carboxylate (8a). Compound 8a was prepared following the general procedure I from nicotinate 5h (204 mg, 0.7 mmol), 2-(tributylstannyl)pyridine 9 (451 mg, 1.23 mmol), Pd (PPh3)4 (65.0 mg, 56 µmol), CuI (20.0 mg, 105 µmol) in 178 mg (88%) yield as a yellowish solid, mp 109-110 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.73 (s, 3H), 7.32 -7.36 m( 1H), 7.45-7.50 (m, 3H), 7.65-7.67 (m, 2H), 7.79-7.84 (m, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.70-8.71 (m, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.3 (CH3), 118.5 (CH), 121.9 (CH), 124.3 (CH), 126.5 (C), 128.1 (CH), 128.7 (CH), 128.8 (CH), 136.9 (CH), 139.0 (CH), 140.2 (C), 149.2 (CH), 155.1 (C), 157.3 (C), 158.2 (C), 168.6 (C). ESI/HRMS (m/z): 313.0947 calcd. for C18H14N2NaO2+ [M+Na]+, found 313.0943.

Methyl 6-(4-methylphenyl)-[2,2’-bipyridine]-5-carboxylate (8b). Compound 8b was prepared following the general procedure I from nicotinate 5g (306 mg, 1.0 mmol), 2-(tributylstannyl)pyridine 9 (644 mg, 1.75 mmol), Pd (PPh3)4 (95.0 mg, 82 µmol), CuI (28.6 mg, 150 µmol) in 247 mg (81%) yield as a yellowish solid, mp 108-109 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 2.43 (s, 3H), 3.76 (s, 3H), 7.28 (d, J = 8.0 Hz, 2H), 7.32-7.35 (m, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.79-7.83 (m, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.69-8.71 (m, 1H).13C NMR (CDCl3, 100 MHz, 23 °C): δ = 21.3 (CH3), 52.3 (CH3), 118.3 (CH), 121.9 (CH), 124.3 (CH), 126.3 (C), 128.7 (CH), 128.8 (CH), 136.9 (CH), 137.3 (C), 138.7 (C), 138.9 (CH), 149.2 (CH), 155.2 (C), 157.2 (C), 158.1 (C), 168.8 (C). ESI/HRMS (m/z): 305.1285 calcd. for C19H17N2O2+ [M+H]+, found 305.1260


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Methyl 6-(4-tert-butyl)phenyl)-[2,2’-bipyridine]-5-carboxylate (8c). Compound 8c was prepared following the general procedure I from nicotinate 5a (195 mg, 0.56 mmol), 2(tributylstannyl)pyridine 9 (368 mg, 1.00 mmol), Pd (PPh3)4 (52.0 mg, 45 µmol), CuI (16.0 mg, 84 µmol) in 176 mg (91%) yield as a yellowish solid, mp 103-104 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.38 (s, 9H), 3.76 (s, 3H), 7.32-7.35 (m, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.79-7.83 (m 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H0, 8.70-8.71 (m, 1H).

13

C NMR (CDCl3, 100 MHz): δ 31.3 (CH3), 34.7 (C), 52.3 (CH3), 118.2

(CH), 121.9 (CH), 124.3 (CH), 125.1 (CH), 126.3 (C), 128.5 (CH), 136.9 (CH), 137.2 (C), 138.9 (CH), 149.2 (CH), 151.8 (C), 155.2 (C), 157.2 (C), 158.0 (C), 168.8 (C). ESI/HRMS (m/z): 347.1754 calcd. for C22H23N2O2+ [M+H]+, found 347.1748.

Methyl 6-(4-fluorophenyl)-[2,2’-bipyridine]-5-carboxylate (8d). Compound 8d was prepared following the general procedure I from methyl nicotinate 5b (176 mg, 0.57 mmol), 2(tributylstannyl)pyridine 9 (418 mg, 1.14 mmol), Pd (PPh3)4 (53.5 mg, 46 µmol), CuI (16.2 mg, 85 µmol) in 157 mg (90%) yield as a yellowish solid, mp 127-128°C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ 3.76 (s, 3H), 7.14 (m, 2H), 7.33-7.36 (m, 1H), 7.62-7.66 (m, 2H), 7.80-7.84 (m, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.54 (d, J = 7.9 Hz, 1H), 8.70-8.71 (m, 1H).13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.3 (CH3), 115.1 (d, J = 21.6 Hz, CH), 118.7 (CH), 121.8 (CH), 124.4 (CH), 126.2 (C), 130.7 (d, J = 8.1 Hz, CH) 136.3 (d, J = 3.1 Hz, C), 136.9 (CH), 139.2 (CH), 149.3 (CH), 155.0 (C), 157.2 (C), 157.4 (C), 163.2 (d, J = 247.8 Hz, C), 168.4 (C). ESI/HRMS (m/z): 331.0853 calcd. for C18H13FN2NaO2+ [M+Na]+, found 331.0853.

Methyl 6-(4-chlorophenyl)-[2,2’-bipyridine]-5-carboxylate (8e). Compound 8e was prepared following the general procedure I from methyl nicotinate 5i (229 mg, 0.7 mmol), 2(tributylstannyl)pyridine 9 (460 mg, 1.25 mmol), Pd (PPh3)4 (65.5 mg, 56 µmol), CuI (20.1 mg, 105 µmol) 31 ACS Paragon Plus Environment


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in 190 mg (84%) yield as a yellowish solid, mp 152-153 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.76 (s, 3H), 7.34-7.37 (m, 1H), 7.44-7.46 (m, 2H), 7.58-7.61 (m, 2H),8.26 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.52-8.55 (m, 1H), 8.70-8.72 (m, 1H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.4 (CH3), 118.9 (CH), 121.9 (CH), 124.5 (CH), 126.2 (C), 128.3 (CH), 130.2 (CH), 134.9 (C), 137.0 (CH), 138.7 (C), 139.3 (CH), 149.3 (CH), 154.9 (C), 157.1 (C), 157.5 (C), 168.2 (C). ESI/HRMS (m/z): 347.0558 calcd. for C18H13ClN2NaO2+ [M+Na]+, found 347.0544.

Methyl 6-(4-bromophenyl)-[2,2’-bipyridine]-5-carboxylate (8f). Compound 8f was prepared following the general procedure I from methyl nicotinate 5c (206 mg, 0.56 mmol), 2(tributylstannyl)pyridine 9 (368 mg, 1.00 mmol), Pd (PPh3)4 (52.2 mg, 45 µmol), CuI (16.3 mg, 84 µmol) in 102 mg (50%) yield as a yellowish solid, mp 162-163 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.76 (s, 3H), 7.33-7.37 (m, 1H), 7.51-7.54 (m, 2H), 7.59-7.62 (m, 2H), 7.80-7.85 (m, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.52-8.54 (m, 1H), 8.70-8.72 (m, 1H).13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.4 (CH3), 118.9 (CH), 121.9 (CH), 123.2 (C), 124.5 (CH), 126.1 (C), 130.5 (CH), 131.2 (CH), 137.0 (CH), 139.2 (C), 139.3 (CH), 149.3 (CH), 154.9 (C), 157.2 (C), 157.5 (C), 168.2 (C). ESI/HRMS (m/z): 369.0233 calcd. for C18H14BrN2O2+ [M+H]+, found 369.0226.

Methyl 6-(4-methoxyphenyl)-[2,2’-bipyridine]-5-carboxylate (8g). Compound 8g was prepared following the general procedure I from nicotinate 5f (258 mg, 0.80 mmol), 2-(tributylstannyl)pyridine 9 (515 mg, 1.40 mmol), Pd(PPh3)4 (76.0 mg, 66 µmol), CuI (22.9 mg, 120 µmol) in 198 mg (77%) yield as a yellowish solid, mp 115-116 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.77 (s, 3H), 3.88 (s, 3H), 6.98-7.02 (m, 2H), 7.32-7.35 (m, 1H), 7.62-7.65 (m, 1H), 7.79-7.84 (m, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.56-8.58 (m, 1H), 8.69-8.71 (m, 1H).13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.3 (CH3), 55.3 (CH3), 113.6 (CH), 118.0 (CH), 121.8 (CH), 124.3 (CH), 126.1


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(C), 130.2 (CH), 132.6 (C), 136.9 (CH), 139.0 (CH), 149.2 (CH), 155.2 (C), 157.1 (C), 157.5 (C), 160.3 (C), 168.9 (C). ESI/HRMS (m/z): 321.1234 calcd. for C19H17N2O3+ [M+H]+, found 321.1239.

Methyl 6-(thiophen-2-yl)-[2,2’-bipyridine]-5-carboxylate (8h). Compound 8h was prepared following the general procedure I from nicotinate 5d (209 mg, 0.70 mmol), 2-(tributylstannyl)pyridine 9 (442 mg, 1.20 mmol), Pd (PPh3)4 (65.0 mg, 56 µmol), CuI (20.0 mg, 105 µmol) in 166 mg (80%) yield as a yellowish solid, mp 97-98 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.91 (s, 3H), 7.10-7.12 (m, 1H), 7.33-7.36 (m, 1H), 7.46-7.48 (m, 2H), 7.83-7.87 (m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.55-8.58 (m, 1H), 8.68-8.70 (m, 1H).13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.6 (CH3), 118.1 (CH), 121.8 (CH), 124.4 (CH), 125.0 (C), 127.7 (CH), 127.8 (CH), 128.6 (C), 137.0 (CH), 138.7 (CH), 143.3 (C), 149.2 (CH), 149.9 (C), 154.8 (C), 156.9 (C), 168.8 (C). ESI/HRMS (m/z): 297.0692 calcd. for C16H13N2O2S+ [M+H]+, found 297.0681.

Methyl 6-(4-pyridin-2-yl)phenyl)-[2,2’-bipyridine]-5-carboxylate (8i). Compound 8i was prepared following the general procedure I from nicotinate 5c (223 mg, 0.60 mmol), 2(tributylstannyl)pyridine 9 (795mg, 2.16 mmol), Pd (PPh3)4 (112.0 mg, 96 µmol), CuI (34.5 mg, 180 µmol) in 82 mg (37%) yield as a yellowish solid, mp 159-160 °C (light petroleum/ethyl acetate). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.75 (s, 3H), 7.25-7.28 (m, 1H), 7.34-7.37 (m, 1H), 7.76-7.86 (m, 5H), 8.11-8.14 (m, 2H), 8.25 (d, J = 8.2 Hz, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.58-8.60 (m, 1H), 8.71-8.75 (m, 2H).13C NMR (CDCl3, 100 MHz, 23 °C): δ = 52.4 (CH3), 118.7 (CH), 120.7 (CH), 121.9 (CH), 122.3 (CH), 124.4 (CH), 126.5 (C), 126.6 (CH), 129.3 (CH), 136.8 (CH), 137.0 (CH), 139.1 (CH), 139.6 (C), 140.8 (C), 149.3 (CH), 149.8 (CH), 155.1 (C), 156.9 (C), 157.4 (C), 157.6 (C), 168.7 (C). ESI/HRMS (m/z): 368.1394 calcd. for C23H18N3O2+ [M+H]+, found 368.1379.

General procedure J for the Hydrolysis of Esters of Bipyridinecarboxylic Acids. Bipyridine 1, 7 or 8 (1 mmol) was refluxed in a mixture of methanol/15% aq KOH until completion of the 33 ACS Paragon Plus Environment


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reaction (TLC monitoring). The reaction mixture was cooled, acidified to form the maximum amount of precipitate and the mother liquor became colorless, the precipitate was collected by filtration, washed with cold water and dried.

6,6’-Bis(4-chlorophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylic acid (10a). Compound 10a was prepared following the general procedure J from ester 1l (65 mg, 0.132 mmol) in mixture MeOH/15% aq KOH (6 mL/3 mL) for 12 h in 53 mg (87%) yield as a colorless solid, mp 324-325 °C (dec., water, pH 2).1Н NMR (DMSO-d6, 400 MHz, 23 °C): δ = 7.56 (d, J = 8.3 Hz, 4H), 7.71 (d, J = 8.3 Hz, 4H), 8.32 (d, J = 8.1 Hz, 2H), 8.49 (d, J = 8.1 Hz, 2H), 13.50 (br. s,, 2H).

13

C NMR (DMSO-d6, 100 MHz, 23 °C): δ

119.4 (CH), 128.1 (CH), 128.6 (br. s., C), 130.1 (CH), 133.7 (C), 138.5 (C), 139.2 (CH), 155.0 (C), 155.8 (C), 168.6 (br. s., C). ESI/HRMS (m/z): 465.0403 calcd. for C24H15Cl2N2O4+ [M+H]+, found 465.0409.

6,6’-Dicyclopropyl-[2,2’-bipyridine]-5,5’-dicarboxylic acid (10b). Compound 10b was prepared following the general procedure J from ester 1p (31 mg, 0.088 mmol) in mixture MeOH/15% aq KOH (1 mL/1 mL) for 1 h in 26 mg (91%) yield as a colorless solid, mp 350-351 °C (dec., water, pH 3). 1

Н NMR (DMSO-d6, 400 MHz, 23 °C): δ = 1.03 (m, 4H), 1.15-1.17 (m, 4H), 3.10-3.16 (m, 2H), 8.10 (d, J

= 8.1 Hz, 2H), 8.25 (d, J = 8.1 Hz, 2H), 13.37 (s, 2H). 13C NMR (DMSO-d6, 100 MHz, 23 °C): δ = 11.1 (CH2), 13.8 (CH), 117.0 (CH), 126.3 (C), 139.2 (CH), 155.7 (C), 161.9 (C), 168.0 (C). ESI/HRMS (m/z): 325.1183 calcd. for C18H17N2O4+ [M+H]+, found 325.1172.

6-(4-Bromophenyl)-6’-(thiophen-2-yl)-[2,2’-bipyridine]-5,5’-dicarboxylic

acid

(10c).

Compound 10c was prepared following the general procedure J from ester 7e (45 mg, 0.088 mmol) in mixture MeOH/15% aq KOH (6 mL/3 mL) for 12 h in 41 mg (96%) yield as a colorless solid, mp 305-306 °C (dec., water, pH 3). 1Н NMR (DMSO-d6, 400 MHz, 23 °C): δ = 7.19-7.21 (m, 1H), 7.60-7.61 (m, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.76-7.78 (m, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 8.1 Hz, 2H), 8.48 (d, J = 8.1 Hz, 1H), 13.61 (br. s., 2H).

13

C NMR (DMSO-d6, 100 MHz, 23 °C): δ = 34

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118.9 (CH), 119.2 (CH), 122.4 (C), 127.5 (C), 127.7 (CH), 128.3 (CH), 128.4 (C), 129.6 (CH), 130.9 (CH), 131.0 (CH), 138.3 (CH), 138.9 (C), 139.4 (CH), 142.4 (C), 148.1 (C), 154.3 (C), 154.8 (C), 155.9 (C), 168.5 (C), 169.3 (C). ESI/HRMS (m/z): 480.9852 calcd. for C22H14BrN2O4S+ [M+H]+, found 480.9849.

6-(4-Methoxyphenyl)-[2,2’-bipyridine]-5-carboxylic acid (10d). Compound 10c was prepared following the general procedure J from ester 8g (65 mg, 0.203 mmol) in mixture MeOH/15% aq KOH (1 mL/1 mL) for 1 h in 54 mg (87%) yield as a colorless solid, mp 227-228 °C (dec., water, pH 3). 1Н NMR (DMSO-d6, 400 MHz, 23 °C): δ = 3.83 (s, 3H), 7.05 (d, J = 8.6 Hz, 2H), 7.48-7.51 (m, 1H), 7.66 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 8.1 Hz, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.72-8.73 (m, 1H), 13.25 (br. s., 1H). 13C NMR (DMSO-d6, 100 MHz, 23 °C): δ = 55.2 (CH3), 113.5 (CH), 117.8 (CH), 121.1 (CH), 124.7 (CH), 127.7 (C), 130.1 (CH), 132.0 (C), 137.4 (CH), 138.7 (CH), 149.4 (CH), 154.4 (C), 155.8 (C), 156.0 (C), 159.9 (C), 169.3 (C). ESI/HRMS (m/z): 305.1285 calcd. for C19H17N2O2+ [M+H]+, found 305.1277.

General Procedure K for the Synthesis of NNC-Pd Complexes. Mixture of binicotinate (0.1 mmol) and Pd(MeCN)2Cl2 (0.1 mmol) in MeOH was stirred at 65 °C for 6 h.27 The precipitate was filtered off, washed with benzene, MeOH/ether 1:3, ether and dried on air to give pure product.

(2-(5,5’-Bis(methoxycarbonyl)-6’-phenyl-[2,2’-pyridin]-6-yl)phenyl)palladium(II) chloride (11a). Complex 11a was prepared following the general procedure K from dimethyl 6,6’-diphenyl-[2,2’bipyridine]-5,5’-dicarboxylate 1h (31.0 mg, 73 µmol) and Pd(MeCN)2Cl2 (18.9 mg, 73 µmol) in 34.1 mg (83%) yield as a yellow solid, mp 247-248 °C (dec., methanol). 1Н NMR (DMSO-d6, 400 MHz, 80 °C): δ = 3.59 (s, 3H), 4.02 (s, 3H), 7.00-7.08 (m, 2H), 7.17 (m, 1H), 7.39-7.44 (m, 5H), 7.67-7.69 (m, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.65 (d, J = 8.3 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz, 80 °C): δ = 52.1, 52.9, 120.4, 122.0, 124.3, 125.3, 126.5, 127.1, 128.7, 129.0, 35 ACS Paragon Plus Environment


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129.2, 132.2, 136.2, 136.8, 139.1, 139.6, 144.9, 151.0, 154.3, 155.3, 158.8, 159.8, 165.8, 166.1. ESI/HRMS (m/z): 529.0381 calcd. for C26H19N2O4Pd+ [M-Cl]+, found 529.0372; 570.0647 calcd. for C28H22N3O4Pd+ [M-Cl+MeCN]+, found 570.0637.

(5-(tert-Butyl)-2-(6’-(4-(tert-butyl)phenyl)-5,5’-bis(methoxycarbonyl)-[2,2’-bipyridin]-6yl)phenyl)palladium(II) chloride (11b). Complex 11b was prepared following the general procedure K from dimethyl 6,6’-bis(4-(tert-butyl)phenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate 1j (34.9 mg, 65 µmol) and Pd(MeCN)2Cl2 (16.9 mg, 65 µmol) in 33.3 mg (76%) yield as a yellow solid, mp 215-216 °C (dec., methanol/ether). The product was isolated by evaporation of methanol to 1 mL volume and treatment with ether. After cooling, precipitate was collected on filter, washed with cold ether and dried. 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 1.28 (s, 9H), 1.40 (s, 9H), 3.58 (s, 3H), 3.99 (s, 3H), 7.03 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.99-8.00 (m, 1H), 8.09-8.14 (m, 2H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 31.1, 31.3, 34.8, 35.5, 52.6, 53.1, 118.5, 121.0, 121.9, 124.9, 126.2, 126.3, 129.2, 132.4, 134.2, 134.6, 138.7, 139.5, 142.3, 151.9, 152.8, 154.2, 154.3, 155.4, 161.2, 162.1, 166.80, 166.84. ESI/HRMS (m/z): 641.1636 calcd. for C34H35N2O4Pd [M-Cl]+, found 641.1611; 682.1902 calcd. for C36H38N3O4Pd+ [MCl+MeCN]+, found 682.1885.

(5-Chloro-2-(6’-(4-chlorophenyl)-5,5’-bis(methoxycarbonyl)-[2,2’-bipyridine]-6yl)phenyl)palladium(II) chloride (11c). Complex 11c was prepared following the general procedure K from dimethyl 6,6’-bis(4-clorophenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate 1l (32.1 mg, 65 µmol) and Pd(MeCN)2Cl2 (16.9 mg, 65 µmol) in 34.9 mg (85%) yield as a bright yellow solid, dec > 298 °C without melt (methanol). 1Н NMR (DMSO-d6, 400 MHz, 80 °C): δ = 3.64 (s, 3H), 4.02 (s, 3H), 7.14 (dd, J = 8.5, 2.1 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.67 (d, J = 8.3 Hz, 36 ACS Paragon Plus Environment

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1H). 13C NMR (DMSO-d6, 100 MHz, 80 °C): δ = 52.3, 53.1, 120.9, 122.5, 124.4, 126.69, 126.73, 127.2, 130.9, 131.8, 133.5, 133.9, 135.0, 135.8, 139.5, 140.2, 143.8, 152.0, 154.5, 155.6, 158.0, 159.1, 165.3, 165.7. ESI/HRMS (m/z): 598.9591 calcd. for C26H17Cl2N2O4Pd [M-Cl]+, found 598.9584; 616.9697 calcd. for C26H19Cl2N2O5Pd+ [M-Cl+H2O]+, found 616.9675; 639.9857 calcd. for C28H20Cl2N3O4Pd+ [MCl+MeCN]+, found 639.9849.

(2-(5,5’-Bis(methoxycarbonyl)-6’-(4-methoxyphenyl)-[2,2’-pyridin]-6-yl)-5methoxyphenyl)palladium(II) chloride (11d). Complex 11d was prepared following the general procedure K from dimethyl 6,6’-bis(4-methoxyphenyl)-[2,2’-bipyridine]-5,5’-dicarboxylate 1n (31.5 mg, 65 µmol) and Pd(MeCN)2Cl2 (16.9 mg, 65 µmol) in 35.2 mg (86%) yield as a dark orange solid, mp 228229 °C (dec., methanol). 1Н NMR (DMSO-d6, 400 MHz, 80 °C): δ = 3.62 (s, 3H), 3.70 (s, 3H), 3.82 (s, 3H), 3.98 (s, 3H), 6.63-6.65 (m, 1H), 6.94-6.96 (m, 2H), 7.09-7.11 (m, 1H), 7.21-7.22 (m, 1H), 7.32-7.34 (m, 2H), 8.24-8.32 (m, 2H), 8.42-8.46 (m, 1H), 8.59-8.61 (m, 1H).

13

C NMR (DMSO-d6, 100 MHz, 80

°C): δ = 52.7, 53.4, 55.0, 55.1, 110.9, 113.1, 119.5, 121.1, 122.0, 125.7, 127.1, 130.1, 130.9, 132.3, 137.5, 139.4, 139.9, 153.7, 154.7, 155.7, 158.8, 159.0, 159.6, 160.2, 166.5, 166.6. ESI/HRMS (m/z): 589.0593 calcd. for C28H23N2O6Pd+ [M-Cl]+, found 589.0569; 630.0859 calcd. for C30H26N3O6Pd+ [M-Cl+MeCN]+, found 630.0832.

(2-(5,5’-Bis(methoxycarbonyl)-6’-(thiophen-2-yl)-[2,2’-bipyridin]-6-yl)thiophen-3yl)palladium(II) chloride (11e). Complex 11e was prepared following the general procedure K from dimethyl 6,6’-di(thiophen-2-yl)-[2,2’-bipyridine]-5,5’-dicarboxylate 1o (31.4 mg, 71.8 µmol) and Pd(MeCN)2Cl2 (25.1 mg, 71.8 µmol) in 46.4 mg (97%) yield as a dark orange solid, mp 257-258 °C (dec., methanol). 1Н NMR (DMSO-d6, 400 MHz, 80 °C): δ = 3.72 (s, 3H), 4.00 (s, 3H), 7.08-7.40 (m, 1H), 7.297.30 (m, 1H), 7.65-7.72 (m, 3H), 8.44 (d, J = 8.5 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.62 (d, J = 8.3 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz, 80 °C): δ = 52.36, 52.42, 117.9, 121.0, 122.7, 126.5, 127.6, 127.7, 37 ACS Paragon Plus Environment


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129.1, 129.8, 130.4, 130.7, 133.9, 134.0, 139.6, 141.2, 152.7, 155.2, 156.0, 156.7, 164.3, 165.5. ESI/HRMS (m/z): 540.9508 calcd. for C22H19N2O4PdS2+ [M-Cl]+, found 540.9510.

(2-(5-(Methoxycarbonyl)-[2,2’-bipyridin]-6-yl)-5-methylphenyl)palladium(II)

chloride

(11f). Complex 11f was prepared following the general procedure K from methyl 6-(4-methylphenyl)[2,2’-bipyridine]-5-carboxylate 8b (30.4 mg, 100 µmol) and Pd(MeCN)2Cl2 (25.9 mg, 100 µmol) in 41.7 mg (94%) yield as a light yellow solid, mp 220-225 °C (dec., methanol). 1Н NMR (DMSO-d6, 400 MHz, 80 °C): δ = 2.28 (s, 3H), 4.00 (s, 3H), 6.89-6.91 (m, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 7.80-7.83 (m, 1H), 8.24-8.28 (m, 3H), 8.49 (d, J = 8.1 Hz, 1H), 8.72-8.73 (m, 1H). 13C NMR (DMSO-d6, 100 MHz, 80 °C): δ = 20.9, 52.7, 118.5, 123.4, 125.0, 125.5, 125.8, 127.4, 136.6, 139.2, 139.7, 140.0, 143.1, 148.6, 154.3, 154.6, 154.8, 159.7, 166.0. ESI/HRMS (m/z): 444.9932 calcd. for C19H16ClN2O2Pd+ [M+H]+, found 444.9926; 749.1149 calcd. for C38H32ClN4O4Pd+ [M+8b+H]+, found 749.1152.

Copper(I)

bis[dimethyl

6-(4-chlorophenyl)-6’-(4-fluorophenyl)-[2,2’-bipyridine]-5,5’-

dicarboxylate] tetrafluoroborate (12). To the degassed solution of Сu[MeCN]4BF4 (15.7 mg, 50 µmol) in acetonitrile (5 mL) the degassed solution of dimethyl 6-(4-chlorophenyl)-6’-(4-fluorophenyl)[2,2’-bipyridine]-5,5’-dicarboxylate 7b (47.7 mg, 100 µmol) in DCM was added under Ar atmosphere. The solution was stirred overnight, the solvents were evaporated, the residue was treated with benzene by decantation and crystallized from ether.28 The precipitate was filtered off and dried in vacuo to give a dark violet solid in 49.7 mg (90%) yield, mp 125-126 (dec., ether). 1Н NMR (CDCl3, 400 MHz, 23 °C): δ = 3.69 (s, 12H), 6.49-6.53 (m, 4H), 6.70-6.87 (m, 12H), 8.48-8.65 (m, 8H). 13C NMR (CDCl3, 100 MHz, 23 °C): δ = 53.00, 53.02, 114.6 (d, J = 21.7 Hz), 122.3, 122.7, 127.6, 128.7, 129.6 (d, J = 8.3 Hz), 129.7, 130.2, 134.4 (d, J = 3.3 Hz), 135.2, 136.9, 140.3, 140.7, 151.8, 152.2, 156.4, 156.6, 162.7 (d, J = 252.1 Hz), 165.3, 165.7. 19F NMR (CDCl3, 376 MHz, 23 °C): δ = -153.0 (BF4), -109.8 (ArF). ESI/HRMS (m/z): 1017.1157 calcl. for C52H36Cl2CuF2N4O8+ [M-BF4]+, found 1017.1138. 38 ACS Paragon Plus Environment

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Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.0000000. X-ray diffraction experiments, NMR spectra for all new compounds. Crystallographic data for 1o, 11b, c (CIF). AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. (A. F. Khlebnikov) ORCID Ekaterina E. Galenko: 0000-0001-5021-7142 Mikhail S. Novikov: 0000-0001-5106-4723 Firuza M. Shakirova: 0000-0003-1018-9479 Julia R. Shakirova: 0000-0001-8342-4893 Ilya V. Kornyakov: 0000-0002-8904-6149 Alexander F. Khlebnikov: 0000-0002-6100-0309 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This paper is dedicated to Professor Armin de Meijere on the occasion of his 80th birthday. We gratefully acknowledge the financial support of the Russian Foundation for Basic Research (Grant No. 18-3300182). This research was carried out using resources of the Centre for Magnetic Resonance, the Research Centre for X-ray Diffraction Studies, and the Centre for Chemical Analysis and Materials of St. Petersburg State University.



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An Isoxazole Strategy for the Synthesis of 2,2'-Bipyridine Ligands

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