Copper-Promoted CâSe Cross-Coupling of 2-Selenohydantoins with

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Copper-promoted C-Se Cross-Coupling of 2selenohydantoins with Arylboronic Acids in an Open Flask Oleksandr Vyhivskyi, Egor A. Dlin, Alexander V. Finko, Saiyyna P. Stepanova, Yan A. Ivanenkov, Dmitry Skvortsov, Andrei V. Mironov, Nikolay Vasil'evich Zyk, Alexander G. Majouga, and Elena K. Beloglazkina ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00021 • Publication Date (Web): 22 Apr 2019 Downloaded from http://pubs.acs.org on April 23, 2019

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ACS Combinatorial Science

Copper-Promoted C-Se Cross-Coupling of 2-selenohydantoins with Arylboronic Acids in an Open Flask Oleksandr Vyhivskyi,† Egor A. Dlin,† Alexander V. Finko,*,† Saiyyna P. Stepanova,† Yan A. Ivanenkov,†,‡,§, Dmitry A. Skvortsov,† Andrei V. Mironov,† Nikolay V. Zyk,† Alexander G. Majouga,†,‡,₪, Elena K. Beloglazkina† †Moscow

State University, Chemistry Dept., Leninskie Gory, Building 1/3, GSP-1, Moscow 119991, Russia University of Science and Technology (MISiS), Leninskii pr., 4, Moscow 119049, Russia §Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Institutsky per. 9, Moscow 141701, Russia ₪D. Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, 125047 Moscow, Russia Supporting Information Placeholder ‡National

Supporting Information ABSTRACT: The modification of Chan-Lam-Evans crosscoupling reaction for the selective Se-arylation of 2selenohydantoins under base-free mild conditions via aryl boronic acids is described herein. This approach was used to synthesize novel 5-arylidene-3-substituted-2(arylselanyl)-imidazoline-4-ones with high yields. The anticancer activity of the final compounds was evaluated in vitro against different cancer cells and thus the possibility of 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4ones successful application as cytotoxic agents was demonstrated.

O

B(OH)2

X N

O

Se Y

N H

X = Alk, Ar Y = Ar, HetAr R = EWG, EDG

Se

R CuII rt, open flask 2-6 hours

X N N

Y

R

33 examples, up to 93% yield

Keywords: Se-arylation, Chan-Lam-Evans reaction, cross-coupling, 2-selenohydantoins, boronic acids, selenoureas, cytotoxicity, in vitro, open flask.

ACS Paragon Plus Environment

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INTRODUCTION The synthesis of compounds with various biological activity is one of the key tasks of modern medicinal chemistry. Hydantoin and 2-thiohydantoin derivatives have proved to be very useful in this field. In particular, the hydantoin core with different aryl substituents could provide anticonvulsant activity1. Moreover, some thiohydantoins appear to be antagonists of fibrinogen and serotonin receptors2 and aldose reductase inhibitors3. For the last few years the anticancer potential of some thiohydantoin derivatives has attracted the attention of biochemists. Even preliminary evaluations have shown that these compounds have cytotoxic effect on a large number of cancer cell lines4. However, while 2-thiohydantoin derivatives are well studied, their selenium-containing analogs were mistakenly considered as extremely poisonous substances until recently. One of the last studies of selenohydantoin derivatives that was done by our research group5 revealed the ability of 2-selenohydantoins to show anticancer activity against HepG2, SiHa and MCF-7 cells. Furthermore, some of them were found to be more cytotoxic towards cancer cells than their sulfur-analogs5.

RESULTS AND DISCUSSION The current study is devoted to the synthesis of novel modified 2-selenohydantoins. The last stage of our synthetic approach is the arylation process that requires 3-substituted 5-arylidene-2-selenohydantoins as starting component for the C-Se cross-coupling reaction. The classical method for the synthesis of 3-substituted 5-arylidene-2-selenohydantoins is based on the reaction of selenoureas with aromatic aldehydes6. In this work selenoureas were obtained through the reaction between ethyl acetate-isoselenocyanate and aromatic amines7. Due to the low solubility of the selenourea derivatives diethyl ether is used as a solvent in the present study instead of THF5 or DCM8 as it allows to simplify the process of purification and decrease the amount of impurities. However, in contrast to our previous work5 some specific amines, especially with electron-withdrawing groups, do not react appropriately with ethyl 2-isoselenocyanatoacetate in the absence of a base. This phenomenon can be explained by the fact, that in contrast to aliphatic or activated aromatic amines, which have been used recently5, anilines 2{7}, 2{10}, 2{11}, 2{12}, 2{15} have lower NH2-nucleophilicity and, as a result, are not able to attack the carbon atom of the isoselenocyanate group without an activator. Thus, we suggest a multipurpose method of obtaining ethyl 2-(3-arylselenoureido) acetates which is based on the reaction between ethyl 2-isoselenocyanatoacetate and amines in the presence of catalytic amounts of 4-dimethylaminopyridine (1 mol %) in diethyl ether. This approach leads to selenoureas with high yields even with such electron-deficient amines as 4(trifluoromethyl)aniline, 4-aminobenzonitrile, 4-chloropyridin-2-amine. Next in our investigation, urea 3{1} have been chosen as a model substrate to obtain 3-substituted 5-arylidene-2-selenohydantoins (the choice is based on the commercial availability of the starting amine 2{1}) by condensation with wide range of aldehydes. Other ureas 3{2}-3{15} reacted with 4-ethoxybenzaldehyde. Consequently we have obtained a broad spectrum of 3-substituted 5arylidene-2-selenohydantoins with various substituents in the third and fifth positions.

Table 1. Optimization of Reaction Conditions and Anilines Scopea NH2 O Se

C

N

R1 2

Se

R2

N H

N H

R3

COOEt

3

NH2

NH2

R1

solvent R2 DMAP (1 mol%) or no base

OEt

1 NH2

R3

NH2

NH2

NH2

NH2

NH2

MeO OMe OMe

OMe OMe 2{4}

2{3}

2{2}

2{1} NH2

NH2

2{6} NH2

NH2

NH2

F 2{7}

2{5} NH2

Cl 2{8}

NH2 N

2{13}

Cl Br

F 2{10}

2{9} MeO

Se COOEt MeO

COOEt

3{4}, 98%

F

N H

F

N H

N H

N H

3{13}, 97%

Br

NC

Se N H

c

N H

3{11}, 54%

COOEt

N H

N H

Se

3{14}, 88%


Cl

COOEt

3{9}, 84% Se N H

N H N

COOEt

N H

N H

3{12}, 59%

Se

COOEt

3{6}, 85%

COOEt c

N H

N H

COOEt

3{8}, 69%c

Se N H

c

N H

N H

COOEt

3{10}, 68%

COOEt

Se

F3C

Se

Cl

3{5}, 41%

COOEt

3{7}, 74%c

Se

N H

N H Cl

Se N H

N COOEt N H H OMe 3{3}, 90%c

Se

N H

N H

COOEt

3{2}, 91%

Se

MeO

Se

N H

N H

3{1}, 89%c

MeO

2{15}

Se

N H

N H

Cl 2{14}

CN 2{12}

CF3 2{11}

COOEt c

Se N H

N H

COOEt

3{15}, 42%c

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entry 2, R1, R2, R3 solvent 3, yieldb (%) 1 2{1} THF 3{1}, 81 2 2{1} Et2O 3{1}, 83 3 2{1} Et2O 3{1}, 89c aThe reaction of 1 (1.1 mmol), 2 (1 mmol) carried out in 2 mL of Et O at rt for 1-2 hours. bIsolated yields. cThe reaction is carried 2 out with DMAP (1 mol %) as the catalyst. Treatment of the obtained ureas 3 with various benzaldehydes in the presence of potassium hydroxide leads to 5-substituted 2selenohydantoins (Scheme 1). This method is proven to be among the best ones to obtain 5-substituted thiohydantoins, giving the minimum amount of impurities and, as a result, leading to higher yields9. In this work we have expanded this method and proven its efficiency in the case of selenium derivatives of hydantoin. Considering the low stability of 2-selenohydantoin derivatives in acidic media, the isolation process of desired products is slightly changed. Instead of using hydrochloric acid solution8, a saturated solution of ammonium chloride is used to neutralize the reaction mixture.

Scheme 1. Scope of Aldehydesa R1

R6

R1

Se

R2 R3

R

O1. KOH 2%, EtOH R6 2. NH4Cl/H2O R5

OEt

N H

N H

R4

O

4

3 CHO

O

5

CHO

CHO

CHO

CHO

Se

CHO

CHO

Cl

OEt

4{2}

OMe

O

N

OMe

N

Se O

NH

Cl

F 4{4}

4{3}

Se O

N

CF3 4{8}

4{7}

4{5}

OMe

NH

4{6}

Se O

N

NH

Se O

N

CN 4{9} OMe

OMe

OMe

CHO

N

S

4{10}

4{11}

N

Cl 4{1}

R3

5

R4

CHO

CHO

CHO

R2

N N H

Se O

N

NH

Se O

NH

NH

OMe

OMe

N

N

Se O

Se

NH

NH Cl

Cl OEt 5{1,1}, 75%

5{1,2}, 80%

OMe

5{1,3}, 66%

OMe

Cl 5{1,5}, 74%

F 5{1,4}, 97%

5{1,6}, 79%

CF3 5{1,8}, 89%

5{1,7}, 90%

F

OMe OMe OMe

O

N

N

Se O

Se O NH

NH

N

Se O NH

N

N

Se O

N

Se O

NH

NH

N

Se

O

N

NH

NH

OEt

OEt

N

Se O

Se

NH

S

N CN 5{1,9}, 98% Cl

5{1,10}, 84%

5{1,11}, 82%

Br

F

OEt

OEt 5{2,1}, 69% CF3

5{3,1}, 72% CN

N

Se O

OEt

5{5,1}, 70% 5{6,1}, 74%

5{7,1}, 82%

Cl

O

N

Se O

NH

OEt 5{8,1}, 77%

N

Se O

NH

OEt 5{9,1}, 89%

N

Se O

NH

OEt 5{10,1}, 76%

NH

OEt 5{11,1}, 43%

N

Se O

NH

OEt 5{12,1}, 39%

aIsolated

N

Se

NH

OEt 5{13,1}, 87%

O

N

Se

NH

OEt 5{14,1}, 84%

yields. Reaction of 3 (1 mmol), 4 (1.2 mmol) carried out in 5 mL of EtOH at rt for 2 hours. Resulted yields show that this reaction is more preferable for aldehydes containing acceptor substituents. This effect is due to the fact that during the first stage of condensation selenoureas are converted to the corresponding 3-substituted 2-selenohydantoins (according to the intramolecular cyclization which were suggested for ureas, their sulfur and seleno analogues9,10), which then undergo the Knoevenagel reaction with the aldehyde present in the reaction mixture. In this case, the presence of acceptors in the aromatic core of substrates 4 leads to a more complete course of condensation. After column chromatography, 3-substituted 5-arylidene-2-selenohydantoins have been obtained as a mixture of Z- and Eisomers. Further recrystallisation from glacial acetic acid provides pure Z-isomers of the desired compounds 5 (according to NMR 1H and single-crystal X-Ray diffraction (Figure 1)). While recording NMR spectra of isolated Z-isomers of products 5, they isomerize back into a mixture of Z- and E-isomers with a different ratio in the solution of DMSO-d6 (according to NMR 1H).

Table 2. Screening of the C-Se Cross-Coupling Reaction Conditionsb



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OMe

OMe

O

O N

N H

Se

PhB(OH)2

solvent, rt or MW

6{1}

5{1,1}

EtO

N

cat, ligand

EtO

N

Se Ph

7{1,1,1} OH

ligands:

N

N

N

NH HN N

L1

L2

N H

O L4

L3

yieldg (%) 1 none none DCE nr 2 Cu(OAc)2•H2O (0.1 equiv) L1 DCE tracea,b 3 Cu(OAc)2•H2O (1.0 equiv) L1 DCE tracea,b 4 Cu(OAc)2•H2O (1.1 equiv) L1 DCE 83 %b 5 Cu(OAc)2•H2O (1.1 equiv) L1 DCE 79 %c 6 Cu(OAc)2•H2O (1.1 equiv) L1 DCE 51 %d 7 Cu(OAc)2•H2O (1.1 equiv) L1 DCE 11 %e 8 Cu(OAc)2•H2O (1.1 equiv) L1 DCE 73 %b,f 9 Cu(OAc)2•H2O (1.1 equiv) L1 MeOH tracea,b 10 Cu(OAc)2•H2O (1.1 equiv) L1 dioxane 64 %b 11 Cu(OAc)2•H2O (1.1 equiv) L2 DCE 56 %b 12 Cu(OAc)2•H2O (1.1 equiv) L3 DCE tracea,b 13 Cu(OAc)2•H2O (1.1 equiv) L4 DCE 47%b 14 CuI (1.1 equiv) L1 DCE 73%b aAccording to TLC. bReaction of 5{1,1} (0.25 mmol), 6{1} (1 mmol) carried out in 1 mL of solvent with stated amount of catalyst and ligand (2 equiv according to the amount of catalyst) at rt in an open flask for 2 hours. c3 equiv (0.75 mmol) of 6{1} are used d2 equiv (0.5 mmol) of 6{1} are used. e1 equiv (0.25 mmol) of 6{1} is used. fThe reaction was carried out under MW irradiation – 800C. gIsolated yields. In our earlier work11, we conducted arylation of 5-arylidene-2-thiohydantoins under MW-irradiation and mild conditions for some specific substrates (12h, rt, 2 × dilution, 12 h, air conditions). The resulting compounds showed high cytotoxicity (IC50 < 50 μM) towards different cancer cell lines. In this connection, the next stage of the current work is devoted to cross-coupling reaction between arylboronic acids and compounds synthesized during the previous stage 5. We decided to repeat the reaction set forth in our earlier investigation11 and conducted by Carreaux and co-workers12. entry

5{13,1}

catalyst

L

solvent

7{3,1,5}

Figure 1. Crystal structure of selenohydantoin 5{13,1} (CCDC 1874217) and arylated product 7{3,1,5} (CCDC 1874216). We have used 2-selenohydantoin 5{1,1} and phenylboronic acid 6{1} as starting compounds for the model reaction to optimize the conditions. In the study, done by Rao and colleagues13 selenourea was used just as a source of selenium with the production of biaryl selenides, while in the current investigation we observe a selective arylation process without decomposition of the urea fragment in the hydantoin core. When less than 1 equiv of copper acetic monohydrate is used during the arylation process only trace of the desired product 7{1,1,1} is obtained. Increasing the amount of catalyst up to 1.1 equiv provides compound 7{1,1,1} with 83 % yield, which is probably explained by the coordination of copper (1 equiv) with the selenohydantoin (1 equiv) in DCE solution, while the rest of Cu(OAc)2 ensures catalytic activity. The study also showed that the use of other nitrogen-containing ligands (bpy, dmeda, proline) instead of 1,10-phenanthroline and the reduction of the amount of arylboronic acid (less than 4 equiv), as in the case of sulfur-containing analogues11, results in a larger amount of impurities (according to LCMS) and lower yields. MW-irradiation also is not important in obtaining compound 7{1,1,1}. Moreover, under MW-conditions the yield of the final product (Table 2, entry 8) is lower probably due to the instability of selenium-containing hydantoins under high temperatures. Benzene and biphenyl are detected in the model reaction as main by-products, according to deborylation and dimerization processes. Protodeboronation can be explained by the presence of water, as we use copper acetate (II) monohydrate as the catalyst14.

Scheme 2. Alkylation process of starting material 5{1,1}


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B(OH)2

N

OMe

OMe

Cu(OAc)2  H2O PhB(OH)2 O

N

O

cat Se solvent = DCE

N H

L = 1,10-phen

Se N

PhB(OH)2 Base Cu(OAc)2  H2O

5{1,1}

Cu(OAc)2  H2O

OEt

(HO)2B

cat Fe(acac)2 Ni(OAc)2  4H2O Co(OAc)2  5H2O

N

8

Cl

OEt

Fe

yield (8), % 69d 172 8d

base NEt3 (1 eq) nBu4NOH

843 794

Recent investigations15, 16 showed the possibility of conducting the Chan-Lam-Evans arylation in the presence of nickel salts. In this work we tried to provide formation of the final compound 7{1,1,1} using different transition metals, such as iron, nickel and cobalt. Unexpectedly, under applied conditions (Scheme 2) the formation of alkylated product 8 has been observed. Replacement of the solvent by dioxane or methanol does not lead to any desired products. In the next stage of the present investigation, we used conditions described in Table 2 (entry 4) for the arylation of obtained compounds 5 using a wide range of aryl boronic acids. It is important to note the extremely high regioselectivity of the arylation. Compounds 7 have two reaction centres potentially capable of the Chan-Lam-Evans coupling with arylboronic acids. Hugel et. all work17 describes selective arylation of 5-dimethyl hydantoin via the nitrogen atom. The selectivity of Se-arylation was confirmed by single-crystal X-Ray diffraction (Figure 1.) and 77Se NMR spectrum (shift into low field was observed for 7{1,1,2}, compared with unarylated starting material 5{1,1}. Moreover, an isomeric product affecting the NH group in the reaction mixture was not observed (according to LCMS) under the chosen conditions.

Table 3. Scope of the arylated C-Se productsa,b



Page 6 of 11

R

R B(OH)2

O

N

O

cat, 1,10-phen

Se N H

N Se

DCE, rt

R''

N

6

B(OH)2

B(OH)2 Me

B(OH)2

B(OH)2

6{2}

OMe

O

6{3}

Me 6{5}

6{4}

OMe

O

N

O Se

B(OH)2

B(OH)2

B(OH)2

OMe

O

N

OMe

O

N

Se

Me

N

NO2 6{8}

CN 6{7}

Cl 6{6}

OMe

N

Se N

B(OH)2

7

OMe

F 6{1}

R'' R'

5

R'

N

Se

N

Se

N

N

F

OMe Me

OEt 7{1,1,1}, 83%

OEt 7{1,1,2}, 70% OMe

OMe

O

OEt 7{1,1,3}, 58%

O

N

OMe

O

N

O

CN OEt 7{1,1,8}, 74% OMe

O

O

O

N

Se

O

O

O

N

Cl

Cl

O

7{1,6,5}, 70% OMe

O

N

Se

Se

N

N Se

N

N

OMe

Me

Me

Cl CF3 7{1,7,6}, 81%

7{1,7,5}, 83% OMe

7{1,5,6}, 69% OMe

N

Se

N

Me

Cl

OMe

N

Se

Se

Cl Cl

7{1,5,5}, 77%

7{1,4,6}, 75%

N N

Me

OMe

N

O

N Se

Cl

OMe

Me Me 7{1,3,5}, 66% OMe

N

Cl F

7{1,4,5}, 95%

O Se

N

N

Me F

Me

7{1,2,5}, 69% OMe

N

Se

N

N

NO2

OEt 7{1,1,7}, 82% OMe

N Se

N

OEt 7{1,1,6}, 87% OMe

N

O Se

N

Cl

OMe

N

Se

N

OEt 7{1,1,5}, 93%

OMe

N

Se

Se N

OEt 7{1,1,4}, 66%

Me CN 7{1,9,4}, 47%

7{1,8,5}, 64%

CN 7{1,9,5}, 65% Me

OMe O

O

N

O

N

Se

N

N

OMe

7{1,11,5}, 66%

OEt 7{3,1,5}, 70% Br

Cl

N Se N

Me

Me

F

Se N

S OEt 7{2,1,5}, 87%

O

N

N

N

Me

O

Se

Se

Me OEt 7{5,1,5}, 79%

Me OEt 7{6,1,5}, 93%

F

CF3 Cl

O

O

N

O

N

Se N

Se

Me OEt

7{9,1,5}, 84%

7{10,1,5}, 66%

CN

O

O

N Se

O

N

N

N

Me OEt 7{12,1,5}, 56%

N Se

Se

N

Me

Me OEt 7{13,1,5}, 68%

N N

Me OEt

7{8,1,5}, 89%

7{7,1,5}, 96%

Se N

Me OEt

O

N

Se N

N

Me OEt

O

N

Se

OEt 7{14,1,5}, 64%


Me OEt 7{11,1,5}, 72%

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aReaction

of 5 (0.25 mmol), 6 (1 mmol) carried out in 1 mL of DCE with Cu(OAc)2•H2O (1.1 mmol) as catalyst, 1,10phenanthroline (2.2 mmol) as ligand at rt in an open flask for 2-6 hours. bIsolated yields. The presence of electron-withdrawing groups in tested boronic acids such as cyano or nitro leads to lower yields and reaction rates in contrast to 4-methyl or 4-chlorophenylboronic acid. The reaction with 2-methylphenylboronic acid produced compound 7{1,1,2} with the lowest yield (70%) among the scope of starting material 5{1,1} and boronic acids with electron-donating groups, which might be explained by steric hindrances during the transmetallation and reductive elimination steps (Scheme 3). Compound 5{1,11}, which contains the thiophene core, does not react with p-tolylboronic acid in the presence of 1.1 equiv of copper acetate due to coordination of the catalyst to thiophenic sulfur. Increasing the amount of Cu(OAc)2 to 2.1 equiv allows to obtain compound 7{1,11,5} with 66% yield. In addition, attempts to synthesize the desired compound with such difficult to react boronic acids as 4pyridinyl and ferrocenyl lead to the previously discovered compound 8.

Scheme 3. Proposed mechanism CuII(OAc)2 phen Ar2B(OH)2

1/2H2O

(phen)CuII(OAc)2

(A)

B(OH)2OAc

1/4O2 + AcOH

Ar2

(phen)CuIOAc

O

OAc CuII(phen) Ar2

(B)

Se

R N

AcOH +

(D)

(phen)CuII(OAc)2

(C)

N Ar1

7

O

Ar1

R N N H

Ar2

OAc CuIII(phen) OAc

(phen)CuIOAc

Se

R N

O

5

N Ar

X

1

9 R N

O

SeAr2 + (phen)CuIOAc + AcOH (D)

N Ar

1

2

7

Proposed resting state (Stage C-D) O

R N

Se

N Ar1 5

H O

O Ar2 III

O Cu (phen) OAc (C)

R N

SeAr2 + AcOH + (phen)CuIOAc (D)

N Ar1

7

Based on previous theoretical observations of the Chan-Lam-Evans18 reaction type we propose the mechanism as follows (Scheme 3).Initially copper acetate coordinates to 1,10-phenantroline to form DCE soluble intermediate A that reacts with an aryl boronic acid. This transmetallation process leads to intermediate B. In the next stage, we suggest the oxidation process of Cu(III) – Cu(II) according to the classical Stahl’s etherification mechanism19. Then, there are two possible ways to form the final compound 7. The first one implies the reaction between intermediate C and selenohydantoin 5. In this part of the catalytic cycle, we suggest a synchronical procces for formation of arylated product 7, in contrast to Watson’s20 and Feng’s21 investigations, where the final product was formed after the coordination of nitrogen and sulfur atoms to copper22. In the current work, we explore a base free process. This is why the starting material 5 reacts in native non-deprotonated form and there is no propulsive force for the Cu-Se bond formation. The second way is depicted at the bottom of Scheme 2, where intermediate C reacts with diselenide 9. There is some research dedicated to cross-coupling reactions between arylboronic acids and disulfides23-25 or diselenides and Se(0) 22, 24, 25-29 in the presence of copper (I) and copper (II) salts. Different investigations show the possibility of diselenides formation from corresponding selenols under air conditions or in the presence of copper salts30-32. However, in the present work, in comparison to our earlier study which is devoted to cross-coupling reaction of sulfur-containing analogues11, the diselenide 9 is not detected in the model arylation reaction according to LCMS investigation and in the blank experiment (selenohydantoin 5{1,1} (1 equiv), copper acetate (II) monohydrate (1.1 equiv), 1,10-phenantroline (2.2 equiv) in dichloroethane). Moreover we have obtained 9 by specific oxidation of 5{1,1} via sulfuryl chloride33, but the reaction between diselenide 9 and phenylboronic acid under standard conditions does not lead to the desired product 7{1,1,1}. Subsequently, we suggested that the investigated arylation process involves only compounds 5 as entry material for the proposed catalytic cycle. The reaction with copper iodide as catalyst (Table 2, entry 14) means that CuI is oxidized by air to form the starting compound A – CuII intermediate. The simplest cytotoxicity based model was used to evaluate the toxicity and anticancer activity of the resulted compounds (Table 4). Our model was based on 72h incubation of four cell lines in presence of tested compounds: A549 – lung adenocarcinoma cell line, MCF7 – breast cancer cell line, HEK293T – human embryonic kidney cell line that has noncancerous origin /etiology/, but has fast growth rate and tumorogenic potential; and VA13 that origins from normal lung fibroblasts and has slow growth rate. Enzalutamide and doxorubicin are used as the control compounds.



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Table 4. Results of the MTS and MTT-test. CC50(µM) Hek293 VA13 MCF-7 A549 7{1,1,1} 2.5±0.3 9±2 19±6 6±1 7{1,1,3} 2.5±0.3 1.8±0.2 1.8±0.4 0.9±0.1 7{1,1,4} 1.8±0.2 13±3 12±3 4.1±0.5 7{1,1,5} 10±4 3.6±0.8 7±3 1.7±0.2 7{1,4,5} 1.6±0.1 0.8±0.1 2±0.3 0.8±0.1 7{1,4,6} 12±5 90±60 24±12 7{1,5,6} 20±10 40±20 50±30 7{1,7,5} 3.8±0.9 1.0±0.1 7.45±1.5 1.37±0.1 7{1,7,6} 20±7 35±10 32±8 29±8 7{6,1,5} 4.4±0.8 3.1±0.4 4.2±0.5 2.5±0.1 Nutlin-3a 8.27 15.12 Enzalutamide 30.9 63.4 21.2 * - do not reach CC50 up to 100 µM The cytotoxicity of tested substances was tested using the MTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide) assay with some modifications.35 2500 cells per well for MCF7, HEK293T and A549 cell lines, or 4000 cells per well for VA-13 cell line were plated out in 135 mcl of DMEM-F12 media (Gibco, USA) in 96-well plate and incubated in the 5% CO2 incubator for first 16 h without treating. Then 15 mcl of media-DMSO solutions of tested substances to the cells (final DMSO concentrations in the media were 1% or less) and treated cells 72 h with 50 nM -100 mcM (eight dilutions) of our substances (triplicate each) and doxorubicin like control substance. The MTT reagent (Paneco LLC, Russia) is then added to the cells up to final concentration of 0.5 g/l (10X stock solution in PBS was used) and incubated for 2 h at 37ºC in the incubator, under the atmosphere of 5% CO2. The MTT solution was then discarded and 140 µl of DMSO (PharmaMed LLC, Russia) was added. The plates were swayed on a shaker (60 rpm) to solubilize the formazan. The absorbance was measured using a microplate reader (VICTOR X5 Light Plate Reader, PerkinElmer, USA) at a wavelength of 565 nm (in order to measure formazan concentration). The results were used to construct a dose-response graph and to estimate CC50 value (GraphPad Software, Inc., San Diego, CA). Cmpd.

CONCLUSIONS In summary, we developed a novel and efficient method of synthesis of 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4ones via C-Se cross-coupling reaction under base-free mild conditions. The current reaction proceeded well with a wide range of starting 3,5-disubstituted-2-selenohydantoins and boronic acids as coupling partners in the presence of copper acetate monohydrate and 1,10-phenantroline. The biological activity of target products was evaluated in vitro Table 4. It was noticed that cytotoxicity of 7{1,4,6}, 7{1,5,6}, 7{1,7,6} compounds was close to the nonspecific adverse cytotoxicity of Enzalutamide. Other compounds had stronger cytotoxicity effects in low micromolar concentrations. There was no prominent selectivity of the cytotoxicity after treatment of cell lines of cancerous etiology (MCF7, A549) and noncancerous etiology (HEK293T, VA13) according to the MTT/MTS tested. This absence of selectivity is similar to the commonly used chemotherapy agents such as Doxorubicin and Cisplatin. Only minor selectivity against lung adenocarcinoma A549 cell line was found after treatment with 7{1,1,3}, 7{1,1,5} compounds. Thus, advancement of new synthetic approaches of obtaining 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline4-ones as novel cytotoxic agents is an important task for modern medicinal and organic chemistry.

EXPERIMENTAL SECTION General information: Except where stated, all reagents were purchased from commercial sources and used without further purification. All the solvents were prepared according to standard techniques. NMR spectra were acquired on Bruker Avance 600 and Bruker Avance 400, Agilent 400-MR, Bruker Fourier 300 spectrometer at room temperature; the chemical shifts δ were measured in ppm with respect to solvents (CDCl3: δH = 7.26, δC = 77.0; DMSO-d6: δH = 2.50, δC = 39.5). Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet. Infrared spectra were recorded on Thermo Nicolet iS5 FT-IR, number of scans 32, resolution 4 cm-1, sampling ATR. MALDI-TOF (Matrix Assisted Laser Desorption Ionization / Time of Flight) mass spectra were recorded on Bruker Daltonics Ultraflex II spectrometer in positive mode; anthracene or 1,8,9-trihydroxyanthracene were used as a matrix. Reactions were monitored by LCMS using Thermo Dionex Ultimate 3000 + ABSciex 3200 Qtrap with the colomn Thermo Acclaim RSLC 120 C18 3 µm (150×4.6 mm). Electrospray ionization (ESI) high resolution mass spectra were recorded on a Bruker microTOF II instrument. Direct input. Microwave reactions were performed in a Monowave 300 – Anton Paar microwave reactor in sealed reaction vessels. Mass spectra were measured on high-resolution timeof-flight Bruker maXis instrument using electrospray ionization (ESI-MS) 34. Measurements were performed in positive ion mode, interface capillary voltage at 4.5 kV, effective scan range at m/z 100 – 1600, external calibration (ESI-L Low Concentration Tuning Mix, Agilent Technologies), direct syringe injection at flow rate of 3 μL/min, nitrogen as dry gas at 4 L/min, interface temperature at 180°C. The spectra were processed using Bruker Data Analysis 4.0 software package. X-ray diffraction study has been performed on the Bruker SMART APEX-II CCD (MoKa-radiation, graphite monochromator, w-scan). Column chromatography was performed on silica gel 60 Å, (230 – 400 mesh, Merck). Thin layer chromatography (TLC) was carried out on Merck silica gel 60F254 precoated aluminium foil sheets and were visualised using UV light (254 nm) and stained in iodine camera. The melting point was determined using an OptiMelt MPA100 - Automated melting point system. Programmable ramp rates from 0.1 ºC/min to 20 ºC/min, in 0.1 ºC/min increments and makes temperature measurements to 400 °C with 0.1 °C resolution. Representative procedures for the synthesis of ethyl 2-(3-(4-methoxyphenyl)selenoureido)acetate 3{1}. An oven-dried round bottom flask was charged with corresponding amine (2{1}, 1 mmol) and anhydrous diethyl ether (5 ml). Ethyl 2isoselenocyanatoacetate (1, 1,1 mmol) was added dropwise. Then the reaction was stirred at least for another hour at room temperature. After completion of the reaction according to TLC, the resulted precipitate was filtered and washed with 20 ml of


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diethyl ether to obtain pure product 3{1}. Brown solid. Yield: 274 mg, 87%. m.p. 97–98оC. 1H NMR (400 MHz, DMSO) δ 1.21 (t, J = 7.1 Hz, 3H, OEt), 3.76 (s, 3H, OMe), 4.11 (q, J = 7.1 Hz, 2H, OEt), 4.34 (d, J = 5.3 Hz, 2H, CH2), 6.96 (d, J = 8.7 Hz, 2H, HAr), 7.20 (d, J = 8.7 Hz, 2H, HAr), 8.00 (s, 1H, NH), 10.10 (s, 1H, NH). 13C{1H} NMR (101 MHz, DMSO) δ 14.2, 48.6, 55.4, 60.6, 114.5 (2C), 126.6 (2C), 130.8, 157.5, 169.6, 180.1. 77Se NMR (76 MHz, CDCl3) δ 217.01. FTIR (ZnSe, cm-1): 552, 633, 710, 781, 829, 874, 955, 1026, 1126, 1172, 1238, 1255, 1298, 1373, 1405, 1444, 1459, 1512, 1443, 1591, 1716, 1761, 2837, 2988, 3230, 3336, 3358. HRMS (FTMS+cESI) m/z: [М+H]+ Calcd for C12H16N2O3Se 317.0399; Found 317.0394. Representative procedure for the synthesis of (Z)-5-(4-ethoxybenzylidene)-3-(4-methoxyphenyl)-2-selen-oxoimidazolidin-4-one 5{1,1}. A corresponding ethyl ethyl 2-(3-(4-methoxyphenyl)selenoureido)acetate (3{1}, 1 mmol) was added to a 2% solution of potassium hydroxide in ethanol. The resulted mixture was stirred for 10 minutes followed by the addition of corresponding aldehyde (4, 1,1 mmol). The reaction was stirred at least for another 2 h at ambient room temperature. Then it was quenched by an aqueous solution of ammonium chloride and the product was extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate, then filtered, the solvent was evaporated and the crude product 5{1,1} was purified by flashchromatography (eluent dichloromethane). Yellow solid. Yield: 301 mg, 75%. m.p. 224–225оC. 1H NMR (400 MHz, DMSO) δ 1.35 (t, J = 7.0 Hz, 3H, OEt), 3.81 (s, 3H, Me), 4.10 (q, J = 6.9 Hz, 2H, OEt), 6.77 (s, 1H, CH), 6.98 – 7.05 (m, 4H, HAr), 7.28 (d, J = 8.8 Hz, 2H, HAr), 7.85 (d, J = 8.6 Hz, 2H, HAr), 12.99 (s, 1H, NH). 13C{1H} NMR (101 MHz, DMSO) δ 14.6, 55.5, 63.5, 114.1 (2C), 114.9, 115.0 (2C), 124.8, 124.9, 126.8, 130.2 (2C), 132.7 (2C), 159.4, 160.1, 163.8, 178.5. 77Se NMR (76 MHz, DMSO) δ 388.57. FTIR (ZnSe, cm-1): 569, 596, 625, 681, 700, 736, 753, 802, 818, 837, 895, 920, 952, 1033, 1048, 1079, 1112, 1171, 1192, 1246, 1308, 1419, 1453, 1514, 1599, 1643, 1725, 2937, 2977, 3208. HRMS (FTMS+cESI) m/z: [М-H]- Calcd for C19H18N2O3Se 401.0410; Found 401.0412. Representative procedure for the synthesis of (Z)-4-(4-ethoxybenzylidene)-1-(4-methoxyphenyl)-2-(phenyl-selanyl)-1Himidazol-5(4H)-one 7{1,1,1}. To a solution of corresponding (Z)-5-(4-ethoxybenzylidene)-3-(4-methoxyphenyl)-2-selenoxoimidazolidin-4-one (5{1,1}, 0,25 mmol) in 1,2-dichloroethane (1 ml) copper acetate monohydrate (0,275 mmol, 1,1 equiv) and 1,10-phenanthroline (0,55 mmol, 2,2 equiv) was added. The resulted mixture was stirred 15 minutes followed by the addition of corresponding boronic acid (6{1}, 1 mmol, 4 equiv). The reaction was stirred at least for another 2 h at room temperature. After completion of the reaction according to TLC, it was quenched by a 4M aqueous solution of disodium EDTA and the product was extracted two times with dichloromethane. The solvent was evaporated and the crude product 7{1,1,1} was purified by column chromatography (eluent – dichloromethane). Yellow solid. Yield: 59 mg, 49%. m.p. 179–180оC. 1H NMR (400 MHz, CDCl3) δ 1.43 (t, J=6.9 Hz, 3H, OEt), 3.87 (s, 3H, OMe), 4.06 (q, J=6.8 Hz, 2H, OEt), 6.77 (d, J=8.3 Hz, 2H, HAr), 6.95 (s, 1H, CH), 7.02 (d, J=8.7 Hz, 2H, HAr), 7.30 (d, J=8.7 Hz, 2H, HAr), 7.42 – 7.51 (m, 3H, HAr), 7.76 (d, J=7.9 Hz, 2H, HAr), 7.90 (d, J=8.4 Hz, 2H, HAr). 13C{1H} NMR (101 MHz, CDCl3) δ 14.9, 55.7, 63.7, 114.6 (2C), 115.0 (2C), 124.8, 125.8, 125.9, 127.25, 128.8 (2C), 129.4 (2C), 129.5, 134.2 (2C), 136.5 (2C), 136.9, 160.25, 160.4, 160.75, 169.2. FTIR (KBr, cm-1): 566, 594, 635, 659, 685, 704, 734, 755, 811, 837, 901, 941, 1024, 1047, 1068, 1112, 1153, 1179, 1210, 1254, 1299, 1312, 1350, 1361, 1391, 1425, 1442, 1470, 1496, 1509, 1563, 1598, 1628, 1715, 2935, 2973, 3076, 3212, 3423. HRMS (FTMS+cESI) m/z: [М+H]+ Calcd for C25H22N2O3Se 479.0868; Found 479.0871. Representative procedure for the synthesis of (Z)-1-(4-chloropyridin-2-yl)-4-(4-ethoxybenzylidene)-2-(p-tolylselanyl)-1Himidazol-5(4H)-one 8. To a solution of (5{1,1}, 0,25 mmol) in 1,2-dichloroethane (1 ml), cat. (1,1 equiv, Scheme 1) and 1,10phenanthroline (0,55 mmol, 2,2 equiv, or base Scheme 1) was added. The resulted mixture was stirred 15 minutes followed by the addition of corresponding boronic acid (6{1}, 1 mmol, 4 equiv). The reaction was stirred at least for another 2 h at room temperature. After completion of the reaction according to TLC, it was quenched by a 4M aqueous solution of disodium EDTA and the product was extracted two times with dichloromethane. The solvent was evaporated and the crude product 8 was purified by column chromatography (eluent – dichloromethane). Yellow solid. Yield: 80 mg, 69%. m.p. 164–165оC. 1H NMR (400 MHz, CDCl3) δ 1.45 (t, J=6.7 Hz, 3H, OEt), 3.62 (t, J=7.6 Hz, 2H, CH2), 3.85 (s, 3H, OMe), 4.02 (t, J=8 Hz, 2H, CH2), 4.11 (q, J=6.6 Hz, 2H, OEt), 6.95 – 7.03 (m, 5H, CH + HAr), 7.25 (d, J=8.7 Hz, 2H, HAr), 8.17 (d, J=8.1 Hz, 2H, HAr). 13C{1H} NMR (101 MHz, CDCl3) δ 14.9, 28.1, 42.9, 55.7, 63.7, 114.9 (2C), 115.0 (2C), 125.5, 125.9, 127.1, 128.6 (2C), 134.2 (2C), 136.6, 159.0, 160.3, 161.0, 169.1. FTIR (KBr, cm-1): 560, 594, 620, 663, 701, 738, 756, 834, 948, 1025, 1043, 1072, 1108, 1154, 1174, 1211, 1256, 1303, 1351, 1423, 1511, 1566, 1600, 1637, 1707, 2933, 2976. HRMS (FTMS+cESI) m/z: [М+H]+ Calcd for C21H21ClN2O3Se 465.0479; Found 465.0475. Representative procedure for the synthesis of (4Z,4'Z)-2,2'-diselanediylbis(4-(4-ethoxybenzylidene)-1-(4-methoxyphenyl)-1Himidazol-5(4H)-one) 9. To a solution of (5{1,1}, 0,25 mmol) in dry dichloromethane (5 ml) a solution of sulfuryl chloride (1,2 equiv) in dry dichloromethane (20 ml) was added dropwise. The reaction was stirred for 2 h and then the solvent was evaporated. The crude diselenide 9 was purified by column chromatography (eluent dichloromethane-ethanol (99:1)). The current method is a modification of the oxidation procedure illustrated by Leino and co-workers33. The desired compound 9 was obtained as a yellow solid. 43 mg 43% yield. m.p. 190–191оC. 1H NMR (400 MHz, CDCl3) δ 1.45 (t, J=7.0 Hz, 6H, OEt), 3.86 (s, 6H, OMe), 4.11 (q, J=7.0 Hz, 4H, OEt), 6.95 (d, J=8.8 Hz, 4H, HAr), 7.01 (d, J=8.8 Hz, 4H, HAr), 7.22 (d, J=8.8 Hz, 4H, HAr), 7.24 (s, 2H, CH), 8.11 (d, J=8.7 Hz, 2H, HAr). FTIR (ZnSe, cm-1): 560, 598, 638, 663, 684, 737, 756, 800, 814, 830, 909, 929, 964 ,1027, 1046, 1067, 1114, 1158, 1178, 1216, 1251, 1305, 1318, 1352, 1424, 1441, 1472, 1511, 1524, 1599, 1644, 1723, 2852, 2925, 2983. LCMS (ESI) m/z: [М+H]+ Calcd for C38H34N4O6Se2 803.08; Found 803.00. General procedure for cytotoxicity test. Results of cytotoxicity test in vitro. Human breast cancer cell line MCF7, and human lung adenocarcinoma cell line A549 were kindly provided by dr. S. Dmitriev, immortalized human fibroblasts cell line VA13 were kindly provided by dr. M. Rubtsova, human embryonic kidney HEK293T cell line were kindly provided by dr. E. Knyazhanskaya. MCF7, VA13, A549 and HEK293T cell lines were maintained in DMEM/F-12 (Thermo Fisher Scientific, USA) culture medium containing 10% fetal bovine serum (Thermo Fisher Scientific, USA), 50u/ml penicillin and 0.05 mg/ml streptomycin at 37°С (Thermo Fisher Scientific, USA) in 5% СО2. Medium F-12 (Paneco LLC, Russia) containing 10% fetal bovine serum (Thermo Fisher Scientific, USA), 50u/ml penicillin, 0.05 mg/ml streptomycin (Thermo Fisher Scientific, USA) was used instead of DMEM/F-12 in some cytotoxicity assays. Cell cultures were tested for the absence of mycoplasma



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ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental procedures, additional experimental data, and compound characterization data (PDF)

Accession Codes CCDC 1874216 and 1874217 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] ORCID Alexander V. Finko: 0000-0002-1334-9485 Yan A. Ivanenkov: 0000-0002-8968-0879

ACKNOWLEDGMENT The authors are thankful to Thermo Fisher Scientific Inc., Textronica AG group (Moscow, Russia), and personally to Professor A. Makarov for providing Orbitrap Elite mass spectrometer for this work. The authors thank Dr. V. P. Dyadchenko and Dr. B. N. Tarasevich for valuable input to this work. Mass spectra were recorded in Department of Structural Studies, N. D. Zelinsky Institute of organic Chemistry RAS under the guidance of Ph.D. D. Eremin. This study was fulfilled using a STOE STADI VARI PILATUS100K diffractometer purchased by MSU Development Program and personally to Leading researcher Andrei V. Mironov. This work was supported by Russian Science Foundation № 17-74-10065.

REFERENCES (1) Mudit, M.; Khanfar, M.; Muralidharan, A.; Thomas, S.; Shah, G. V.; Soest, R. W.M.; El Sayed, K.A. Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products. Bioorg. Med. Chem. 2009, 17, 17311738. (2) Stilz, H. U.; Guba, W.; Jablonka B.; Just, M.; Klingler, O.; Konig, K.; Wehner, V.; Zoller, G. Discovery of an Orally Active NonPeptide Fibrinogen Receptor Antagonist Based on the Hydantoin Scaffold. J. Med. Chem. 2001, 44, 1158-1176. (3) Peyman, A.; Wehner. V.; Knolle, J.; Stilz, H. U.; Breipohl, G.; Scheunemann, K-H.; Carniato, D.; Ruxer, J-M.; Gourvest, J-F.; Gadek, T. R.; Bodary, S. RGD Mimetics containing a central hydantoin scaffold: αvβ3 vs αllbβ3 selectivity requirements. Bioorg. Med. Chem. Lett. 2000, 10, 179-182. (4) Subtel’na, I.; Atamanyuk, A.; Szymańska, E.; Kieć-Kononowicz, K.; Zimenkovsky, B.; Vasylenko, O.; Gzella, A.; Lesyk, R. Synthesis of 5-arylidene-2-amino-4-azolones and evaluation of their anticancer activity. Bioorg. Med. Chem. 2010, 18, 5090-5102. (5) Ivanenkov, Y. A.; Veselov, M. S.; Rezekin, I. G.; Skvortsov, D.A.; Sandulenko, Y. B.; Polyakova, M. V.; Bezrukov, D. S.; Vasilevsky, S. V.; Kukushkin, M. E.; Moiseeva, A. A.; Finko, A. V.; Koteliansky, V. E.; Klyachko, N. L.; Filatova, L. A.; Beloglazkina, E. K.; Zyk, N. V.; Majouga, A. G. Synthesis, isomerization and biological activity of novel 2-selenohydantoin derivatives. Bioorg. Med. Chem. 2016, 24, 802-811. (6) Steklov, M.Y.; Chernysheva, A.N.; Antipin, R.L.; Majouga, A.G.; Beloglazkina, E.K.; Moiseeva, A.A.; Strel’tsova, E.D.; Zyk, N. V. Synthesis and coordinating properties of 5-phenyl- and 5-pyridylmethylidene-substituted 2-selenohydantoines and 2-selenoimidazol-4ones. Russ. Chem. Bull. 2012, 61, 1182-1192. (7) Merino-Montiel, P.; Maza, S.; Martos, S.; López, Ó.; Maya, I.; Fernández-Bolaños, J.G. Synthesis and antioxidant activity of Oalkyl selenocarbamates, selenoureas and selenohydantoins. Eur. J. Pharm. Sci. 2013, 48, 582-592. (8) Hemantha, H. P.; Sureshbabu, V. V. Isoselenocyanates derived from amino acid esters: an expedient synthesis and application to the assembly of selenoureidopeptidomimetics, unsymmetrical Selenoureas and selenohydantoins. J. Pept. Sci. 2010, 16, 644-651. (9) Kuznetsova, O.Yu.; Antipin, R.L.; Udina, A.V.; Krasnovskaya, O.O.; Beloglazkina, E. K.; Terenin, V. I.; Koteliansky V. E., Zyk, N. V.; Majouga, A. G. An Improved Protocol for Synthesis of 3‐Substituted 5‐Arylidene‐2‐thiohydantoins: Two‐step Procedure Alternative to Classical Methods. J. Het. Chem. 2016, 53, 1570-1577. (10) (a) Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E. Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold. Chem. Rev. 2017, 117, 13757-13809. (b) Koketsu, M.; Takahashi, A.; Ishihara, H. A facile preparation of selenohydantoins using isoselenocyanate. J. Het.. Chem. 2007, 44, 79-81. (11) Dlin, E. A.; Averochkin, G. M.; Finko, A. V.; Vorobyeva, N. S.; Beloglazkina, E. K.; Zyk, N. V.; Ivanenkov, Y.A.; Skvortsov D. A.; Koteliansky, V. E.; Majouga, A. G. Reaction of arylboronic acids with 5-aryl-3-substituted-2-thioxoimidazolin-4-ones. Tetr. Lett. 2016, 57, 5501-5504. (12) Carreaux, F. Imidazaolone derivatives, preparation thereof and biological use of same. U.S. Patent 2010, 2010216855 A1. (13) Reddy, P. V.; Kumar, A. V.; Rao, R. K. Unexpected C−Se Cross-Coupling Reaction: Copper Oxide Catalyzed Synthesis of Symmetrical Diaryl Selenides via Cascade Reaction of Selenourea with Aryl Halides/Boronic Acids. J. Org. Chem. 2010, 75, 8720-8723. (14) (a) Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. J.; Lloyd-Jones, G. C. Base-Catalyzed Aryl-B(OH)2 Protodeboronation Revisited: From Concerted Proton Transfer to Liberation of a Transient Aryl Anion. J. Am. Chem. Soc. 2017, 139, 13156-13165. (b) Cao, Y.-N.; Tian, X.-C.; Chen, X.-X.; Yao, Y.-X.; Gao, F.; Zhou, X.-L. Rapid Ligand-Free Base-Accelerated CopperCatalyzed Homocoupling Reaction of Arylboronic Acids. Synlett 2017, 28, 601-606. (15) Raghuvanshi, D. S.; Gupta, A. K.; Singh, K. N. Nickel-Mediated N-Arylation with Arylboronic Acids: An Avenue to Chan–Lam Coupling. Org. Lett. 2012, 14, 4326-4329. (16) Hu, G.; Chen, W.; Fu T.; Peng Z.; Qiao H.;, Gao, Y.; Zhao, Y. Nickel-Catalyzed C–P Cross-Coupling of Arylboronic Acids with P(O)H Compounds. Org. Lett. 2013, 15, 5362-5365. (17) Hügel, H. M.; Rix, C. J.; Fleck, K. Comparison of Copper(II) Acetate Promoted N-Arylation of 5,5-Dimethyl Hydantoin and Other Imides with Triarylbismuthanes and Aryl Boronic Acids. Synlett 2006, 14, 2290-2292. (18) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. New N- and O-arylations with phenylboronic acids and cupric acetate. Tetr. Lett. 1998, 39, 2933-2936. (b) Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of diaryl ethers through the copper-promoted


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arylation of phenols with arylboronic acids. An expedient synthesis of thyroxine. Tetr. Lett. 1998, 39, 2937-2940. (c) Lam, P. Y. S.; Clark, C. G.; Saubernt, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation. Tetr. Lett. 1998, 39, 2941-2944. (19) King, A. E.; Brunold, T. C.; Stahl, S. S. Mechanistic Study of Copper-Catalyzed Aerobic Oxidative Coupling of Arylboronic Esters and Methanol: Insights into an Organometallic Oxidase Reaction. J. Am. Chem. Soc. 2009, 131, 5044-5045. (20) (a) Vantourout, J. C.; Law, R. P.; Isidro-Llobet, A.; Atkinson, S. J.; Watson, A. J. B. Chan–Evans–Lam Amination of Boronic Acid Pinacol (BPin) Esters: Overcoming the Aryl Amine Problem. J. Org. Chem. 2016, 81, 3942-3950. (b) Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.; Watson, A. J. B. Spectroscopic Studies of the Chan–Lam Amination: A Mechanism-Inspired Solution to Boronic Ester Reactivity. J. Am. Chem. Soc. 2017, 139, 4769-4779. (21) Xu, H.-J.; Zhao, Y.-Q.; Feng, T. Feng, Y.-S. Chan–Lam-Type S-Arylation of Thiols with Boronic Acids at Room Temperature. J. Org. Chem. 2012, 77, 2878-2884. (22) Didehban, K.; Vessallya, E.; Hosseinian, A.; Edjlali, L.; Khosroshahi, E. S. Nanocatalysts for C–Se cross-coupling reactions. RSC Adv. 2018, 8, 291–301. (23) Saba, S.; Botteselle, G. V.; Godoi, M.; Frizon T. E. A.; Galetto, F. Z.; Rafique, J.; Braga, A. L. Copper-Catalyzed Synthesis of Unsymmetrical Diorganyl Chalcogenides (Te/Se/S) from Boronic Acids under Solvent-Free Conditions. Molecules 2017, 22, 1367. (24) Taniguchi, N. Convenient Synthesis of Unsymmetrical Organochalcogenides Using Organoboronic Acids with Dichalcogenides via Cleavage of the S−S, Se−Se, or Te−Te Bond by a Copper Catalyst. J. Org. Chem. 2007, 72, 1241–1245. (25) Kumar, A.; Kumar, S.; A convenient and efficient copper-catalyzed synthesis of unsymmetrical and symmetrical diaryl chalcogenides from arylboronic acids in ethanol at room temperature. Tetrahedron 2014, 70, 1763-1772. (26) Wang, L.; Wang, M.; Huang, F. A Simple Copper Salt-Catalyzed Synthesis of Unsymmetrical Diaryl Selenides and Tellurides from Arylboronic Acids with Diphenyl Diselenide and Ditelluride. Synlett 2005, 13, 2007-2010. (27) Zheng, B.; Gong, Y.; Xu, H.-J. Copper-catalyzed C–Se coupling of diphenyl diselenide with arylboronic acids at room temperature. Tetrahedron 2013, 69, 5342-5347. (28) Beletskaya, I. P.; Anannikov, V. P. Transition-Metal-Catalyzed C−S, C−Se, and C−Te Bond Formation via Cross-Coupling and Atom-Economic Addition Reactions. Chem. Rev. 2011, 111, 1596-1636. (29) Luo, D.; Wu, G.; Yang, H.; Liu, M.; Gao, W.; Huang, X.; Chen, J.; Wu, H. Copper-Catalyzed Three-Component Reaction for Regioselective Aryl- and Heteroarylselenation of Indoles using Selenium Powder. J. Org. Chem. 2016, 81, 4485-4493. (30) Nakanishi, W.; Yoshitsugu, Y. Studies on Long-range Couplings between 77Se and 13C in Some Aryl Selenides, Dichlorides, and Selenoxides. The Inverse Effect on Couplings in the Selenoxide Formation. Bull. Chem. Soc. Jpn. 1983, 56, 1661-1664. (31) Krief, A.; Derock, M. Condition-Driven Selective Syntheses of Dialkyl Diselenides Involving Elemental Selenium and Sodium Borohydride. Synlett 2005, 6, 1012-1014. (32) Khalili, D.; Iranpoor, N.; Firouzabadi, H. 4,4′-Azopyridine as an easily prepared and recyclable oxidant for synthesis of symmetrical disulfides from thiols or alkyl halides(tosylates)/thiourea. J. Sulf. Chem. 2015, 36, 544-555. (33) Leino, R.; Lӧnnqvist, J.-E. A very simple method for the preparation of symmetrical disulfides. Tetr. Lett. 2004, 45, 8489-8491. (34) Tsedilin, A.M.; Fakhrutdinov, A.N.; Eremin, D.B.; Zalesskiy, S.S.; Chizhov, A.O.; Kolotyrkina, N.G.; Ananikov, V.P. How sensitive and accurate are routine NMR and MS measurements? Mend. Comm., 2015, 25, 454-456. (35) Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 1983, 65, 55 – 63.


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