Carbocyclic functionalization of quinoxalines, their chalcogen congeners 2,1,3-benzothia/selenadiazoles, and related 1,2-diaminobenzenes based on nucleophilic substitution of fluorine

Carbocyclic functionalization of quinoxalines, their chalcogen

congeners 2,1,3-benzothia/selenadiazoles, and related 1,2-

diaminobenzenes based on nucleophilic substitution of fluorine†

Tatiana F. Mikhailovskaya , Arkady G. Makarov^a^,^b^,^c, Natalia Yu. Selikhova , Alexander Yu.

a

b

a,b

c,d

a,c

e

Makarov , Elena A. Pritchina , Irina Yu. Bagryanskaya , Elena V. Vorontsova , Igor D.

Ivanov , Vera D. Tikhova , Nina P. Gritsan , Yuri G. Slizhov **, Andrey V. Zibarev^a^,^b^,^f^,*

e

a

d,f

b,

a

Institute of Organic Chemistry, Russian Academy of Sciences, 630090 Novosibirsk, Russia

b

Department of Chemistry, Tomsk State University, 634050 Tomsk, Russia

c

Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia

d

Institute of Chemical Kinetics and Combustion, Russian Academy of Sciences, 630090

Novosibirsk, Russia

e

Institute of Molecular Biology and Biophysics, Russian Academy of Sciences, 630117

Novosibirsk, Russia

f

Department of Physics, Novosibirsk State University, 630090 Novosibirsk, Russia

*

6

Corresponding author at: Institute of Organic Chemistry, Russian Academy of Sciences,

30090 Novosibirsk, Russia. Fax: +7 383 330 9752.

*

* Corresponding author at: Department of Chemistry, Tomsk State University, 634050 Tomsk,

Russia. Fax: +7 3822 423 944.

E-mail addresses: zibarev@nioch.nsc.ru (A.V. Zibarev), decan@xf.tsu.ru (Yu.G. Slizhov).

†

This work was performed under Agreement no. 79/12 between Institute of Organic Chemistry,

Russian Academy of Sciences, Novosibirsk, and Tomsk State University, Tomsk, and within

Joint Laboratory of the University and the Academy. The authors declare no competing financial

interest.

1

Graphical abstract

N

Nu

F

X

R_n

F

X

N

NH₂

[

H]

R_n

F

X = S

NH₂

-

X = CH=CH, S, Se; Nu = MeO , Me

2

NH; R = MeO, Me N; n = 1-4

2

Highlights



The title compounds were functionalized by nucleophilic substitution of 1-4 F atoms

The functions were MeO- or / and Me N-

Regioselectivity of the 1 : 1 substitution was explained with DFT calculations

Functionalized 2,1,3-benzothiadiazoles were reduced into 1,2-diaminobenzenes

2

ABSTRACT

Previously unknown mono-, di- and in some cases tri- and tetra- carbocycle-substituted

quinoxalines (2-8), 2,1,3-benzothiadiazoles (11, 12, 14-17) and 2,1,3-benzoselenadiazoles (20-

2

5) were synthesized by nucleophilic substitution of fluorine in 5,6,7,8-tetrafluoroquinoxaline

(1) and 4,5,6,7-tetrafluoro-2,1,3-benzothia/selenadiazoles (10 and 19, respectively) with

methoxide and dimethylamine. In the 1 : 1 reactions, the nucleophiles attacked selectively the

position 6 of 1 or the position 5 of 10 and 19. The regioselective nature of the 1 : 1 reactions was

confirmed by the DFT calculations at the M06-2X/6-31+G(d,p) level of theory. Disubstituted

quinoxaline (28), thia- (29) and selena- (30) diazoles bearing two different substituents, i.e.

MeO- and Me

3) were prepared by reduction of corresponding thiadiazoles (12, 14, 15) and isolated in the

form of hydrochlorides. Compound 33 was converted into a new quinoxaline (34) by reaction

with (PhCO) . Compounds 5, 7 and 14 were studied for cytotoxicity towards the human cancer

2

N-, were synthesized in a similar way. New substituted 1,2-diaminobenzenes (31-

3

2

cells and effects on the cytochrome P450 mRNA expression. They did not cause any significant

modulations in the expression of several cytochrome P450 genes, and 7 was weakly toxic for the

Hep2 (carcinoma) and U937 (leukemia) cells, particularly, apoptosis was observed.

Keywords: 1,2-diaminobenzenes, nucleophilic substitution, organofluorine, quinoxalines, 2,1,3-

benzothia/selenadiazoles

2

1

. Introduction

Organic heterocyclic compounds, both natural and synthetic, are of permanent interest to

1

,2

fundamental and applied biomedicine. Amongst them, aromatic and heteroaromatic derivatives

are especially important. In silico examination of virtual library of ~600 000 of mono-, bi- and

tri-cyclic heteroaromatic scaffolds based on current knowledge revealed that bioactivity is very

sparsely distributed and forms only several relatively small, well-defined islands around ~25

common 5- and 6-membered mono-cyclic and 5-6- and 6-6-membered bi-cyclic systems with N

2

and / or O atoms. A continued exploration of novel substituted bicyclic aromatic scaffolds is

hence guaranteed to yield new molecules of biological interest.

Functional derivatives of quinoxaline and its S and Se congeners, i.e. 2,1,3-

benzothia/selenadiazoles, are important for fundamental organic chemistry and its applications to

biomedicine (and also to materials science; relevant literature is too abundant to be cited

completely, for selected works see refs. 3 and 4 and references cited therein). Despite chemistry

of these substances is well-studied,⁵^,⁶there is a permanent demand for new methods of their

synthesis. In the field, most of recently suggested methods deal with hetero-ring formation⁶^,⁷

whereas those based on functionalization of the easily accessible parent compounds are also of

interest. One of efficient ways of functionalizing (hetero) arenes is nucleophilic substitution,

especially that of fluorine in (poly)fluorinated derivatives including regioselective substitution.⁸^-

1

At the same time smooth nucleophilic substitution of fluorine in some heteroarenes such as the

title quinoxalines and 2,1,3-benzothia/selenadiazoles is not a priori guaranteed in a general case

since nucleophilic addition to the hetero-ring of quinoxalines including that leading to ring-

contraction to give benzimidazoles,¹²as well as nucleophilic cleavage of 1,2,5-

1

3

chalcogenadiazole cycle, are known.

In this paper we report on a functionalization of quinoxalines and 2,1,3-

benzothia/selenadiazoles using nucleophilic substitution of fluorine in tetrafluoro derivatives of

the archetypal compounds (1, 10, 19; Chart 1). The approach also covers 1,2-diaminobenzenes

since 2,1,3-benzothia/selenadiazoles are their well-known protected forms and can be easily

reduced into the diamines.¹⁴The latter are suitable starting materials for numerous further

preparations. Examples given in this paper (compounds 2-8, 11, 12, 14-17, 20-25, 28-34, Chart

1

) cover substitution with MeO- and Me N- functions only but the approach can potentially be

2

expanded onto many other substituents including pharmacophore ones.

It should be emphasized that in many cases hydrogen substitution by fluorine (mostly in

aliphatic moieties but also in aromatic ones) produces positive impact on ADME-toxicity of

3

compounds (in pharmacokinetics, ADME: absorption, distribution, metabolism and excretion),

and in some cases on their bioactivity, making low-fluorinated (and normally not high-

fluorinated; see, however, ref. 15) pharmaceuticals and agrochemicals to be of keen interest.¹⁶

Nowadays, fluorinated compounds are used increasingly in medicinal chemistry. Suggested

approach based on high-fluorinated starting materials allows synthesizing low-fluorinated and

variously functionalized final products.

Importantly, current interest to bioactivity of organochalcogen compounds is also

growing.¹⁷

Three of compounds synthesized, one low-fluorinated and two other non-fluorinated,

were tested for cytotoxicity and effects on the mRNA expression in a preliminary work before

further in-depths investigation.

2

. Results and discussion

Earlier, we described synthesis of compounds 1, 10 and 19 by reactions of corresponding

1

,2-diaminobenzene with glyoxal, SF

4

or (C

6

H

5

-SO

2

-N=)

2

S, and SeCl

4

or SeO

-N=S=N-SiMe

under the action of CsF.⁴^,¹⁸In this work, a new synthetic protocol for 10 was elaborated to be

based on interaction of the same 1,2-diamine with SOCl proceeding via N,N’-disulfinyl

2

, respectively,

and that of 10 also by the intramolecular nucleophilic ortho-cyclization of C

6

F

5

3

2

1

9

derivative (Scheme 1).

Previously, it was found that attack on 2,3,5,6,7,8-hexafluoroquinoxaline by methoxide

occurs readily at the positions 2 and 3 and, under forcing conditions, also at the position 6.¹⁰

Treatment of 1 with NaOMe in MeOH or its mixture with Me

2

SO; or with aqueous Me NH in

2

dioxane, DMF or N-methyl-2-pyrrolidone, gave previously unknown mono-, di-, tri- and tetra-

substituted derivatives of 1 (2-8, Scheme 2). Attempts to prepare compound 9 were unsuccessful

even under rather drastic reaction conditions. A minor amount of 9 was detected by GC-MS in

the reaction mixtures in preparation of 8 but was not isolated by silica-column chromatography

probably due to decomposition during work-up.

4

Similar treatment of 10 and 19 afforded earlier undescribed mono-, di-, tri- and tetra-

substituted derivatives of 10 (11-17, Scheme 3) and 19 (20-25, Scheme 4), respectively. In

1

19

preparation of 6-8, 17, 24 and 25, formation of their minor isomers was observed by H and F

NMR and GC-MS (see below) but they were not isolated. In experiments on preparation of 13

and 22, co-crystals 12 / 13, and 22 / 21 and 21 / 23, respectively, were obtained, in the first case

as major product and in the second as minor admixtures. Compound 13 was not isolated from the

co-crystal thus being observed in this work only in the form of 12 / 13. Attempted syntheses of

1

8, 26 and 27 were unsuccessful even under relatively drastic reaction conditions.

Overall with NaOMe, for all scaffolds 1, 10 and 19 tetra-substitution of fluorine was

achieved (compounds 5, 14 and 23). With Me NH, however, tetra-substituted derivatives 9, 18

2

and 27 were not obtained in all three cases, as well as tri-substituted derivative 26 in the

–

selenadiazole series. Dimethylamide Me

anions Alk

chalcogenadiazole ring¹³and interact with ether solvents at higher temperatures. Attempt to

obtain compound 26 from compound 19 and LiNMe generated in situ in DME led to a mixture

2

N is a stronger nucleophile but, as mentioned above,

N^–as some other charged nucleophiles are known to open the 1,2,5-

2

1

9

of compounds 20 and 24 in molar ratio 1.5 : 1 (GC-MS, NMR F), respectively, together with

unreacted 19.

1

19

According to H and F NMR and GC-MS of the reaction mixtures, in all 1 : 1 reactions

–

both MeO and Me

2

NH attacked selectively the position 6 of 1 or the position 5 of 10 and 19.

–

For these reactions, the regioselectivity was higher with MeO than with Me

2

NH, and with

quinoxaline 1 and selenadiazole 19 than with thiadiazole 10. Thus, in the 1 : 1 reactions between

Me NH and 1, 10 and 19 minor (~3 % for 1 and 19, and ~10 % for 10) isomers of the major

2

0

products 6, 15 and 24 were identified. In the corresponding 2 : 1 reaction total amount of minor

isomers of 7 and 25 reached ~10 % but their identification was complicated since, for example,

for compound 25 three minor isomers were observed. In the 3 : 1 reaction between Me

2

NH and

0, an isomer of compound 17 was observed in the reaction mixture at practically the same

abundance but, however, was isolated only in the form of non-crystallizable contaminated oil

20

1

19

contained 80 % of the target derivative (GC-MS, NMR H and F).

M06-2X/6-31+G(d,p) calculations performed with account for solvents confirmed

regioselective character of the mono-substitution reactions (Figure 1, Table 1; ESI, Tables S2-

–

S4; for generality, the calculations were also carried out for Me

2

N ). Figure 1 demonstrates that

the substitution in the position 6 of 1 (leading to compound 2) is both kinetically and

5

thermodynamically more attractive than that in the position 5. Slight thermodynamic

destabilization of 5-MeO isomer of 2 may be caused by the in-plane interaction between lone-

pair MOs of neighboring atoms O and N. Similar results were obtained for compounds 10 and 19

(Table 1), namely, substitution at position 5 for them is preferable. Overall, the major / minor

–

isomer ratio in the 1 : 1 reaction with MeO was predicted to be 99 / 1 in the case of 1, 82 / 18 in

the case of 10, and 94 / 6 in the case of 19. For compounds 1, 10 and 19, the free energies of

–

1

activation at the rate determining step of the reaction main route are within 0.7 kcalmol . This

is in agreement with comparable yields of products in their mono-substitution reaction with

MeONa in MeOH at ambient-temperature revealed by competitive experiment²¹although

experimental relative activities 1 > 19 > 10 contradict with theoretical prediction (Table 1). This

is quite understandable due to the small energy differences under discussion.

It should be noted that the regioselectivity of the discussed 1 : 1 reactions corresponds to

phenomenological rules for orientation of aromatic nucleophilic substitution in polyfluorinated

(hetero) arenes formulated by R.D. Chambers e. a. (for review, see ref. 11).

New disubstituted quinoxaline (28) and 2,1,3-benzothia/selenadiazoles (29, 30;

respectively) bearing two different substituents, i.e. MeO- and Me N-, were synthesized in a

2

similar way via two-step procedure (Scheme 5). The structure of final products did not depend

on the order of substitution.

New substituted 1,2-diaminobenzenes (31-33, Scheme 6) were synthesized by reduction

of corresponding thiadiazoles (12, 14, 15, Scheme 4). All diamines revealed high activity

towards oxidation and were isolated in the form of hydrochlorides. In the case of 33 even the

hydrochloride was highly unstable in the air and the compound was converted into derivative 34

(75 %) by reaction with 1,2-diphenylethane-1,2-dione (Scheme 7).

Structures of compounds 4, 7 (two polymorphs), 8, 11, 12, 14, 15, 17, 19 (racemic twin),

2

1, 25, and co-crystals 12 / 13, 22 / 21 and 21 / 23 (Figure 2, Table 2; ESI, Figure S1) were

characterized by single-crystal XRD (ESI, Table S5). Two polymorphs of compound 6 were

identified by powder XRD (ESI, Figure S2).

6

Overall, substitution in the carbocycles of 1, 10 and 19 with MeO- and Me

does practically not affect geometries of their hetero-rings. At the same time, propensity of

Me N-substituted quinoxalines 6 and 7 to form polymorphs was observed, as well as that of

2

N-groups

2

MeO-substituted thia/selenadiazoles to form co-crystals (S: 12 / 13; Se: 22 / 21, 21 / 23).

Together with the aforementioned lack of absolute regioselectivity of substitution (i.e.

observation of minor isomers in some cases), the propensity to form co-crystals reduces isolated

yields of the target products.

Compound 5, 7 and 14 were studied for cytotoxicity towards the human cancer cells

HepG2 (hepatocarcinoma), Hep2 (carcinoma) and U937 (leukemia) as well as effects on the

mRNA expression. Fluorine-less compounds 5 and 14 did not affect cellular viability whereas

fluoro-containing derivative 7 was weakly toxic for both the Hep2 and U937. It was found that 7

inhibits Hep2 and U937 cells at concentration of 125 µM. Therefore, cytotoxicity of 7 towards

Hep2 cells was examined through the induction of apoptosis (50%). U937 cells were more

sensitive to 7. With this compound, the growth of treated cells (625 µM) was reduced by 98%

compared to untreated cells (Figure 3; ESI, Figures S3-S5 and relevant text). At the same time,

compounds 5, 7 and 14 did not cause any significant modulations in the expression of several

cytochrome P450 genes, i.e. they are not xenobiotics (ESI, Figures S3-S5 and relevant text).

These studies will be continued.

3

. Conclusions

This work contributes to attracted much current attention applications of organofluorine

chemistry into heterocyclic chemistry.²²The approach was developed allowing with such

–

reagents as MeO and Me

2

NH synthesis of new and hardly accessible by other methods mono-,

di- and, with some exceptions, tri- and tetra- carbocycle-substituted quinoxalines (2-8), 2,1,3-

benzothiadiazoles (11, 12, 14-17) and 2,1,3-benzoselenadiazoles (20-25) based on nucleophilic

substitution of fluorine in 5,6,7,8-tetrafluoroquinoxaline (1) and 4,5,6,7-tetrafluoro-2,1,3-

benzothia/selenadiazoles (10 and 19, respectively). Previously unknown disubstituted

quinoxaline (28), thia- (29) and selena- (30) diazoles bearing two different substituents were

synthesized in a similar way. New substituted 1,2-diaminobenzenes (31-33) were prepared by

reduction of corresponding thiadiazoles (12, 14, 15). These compounds may be used in

7

numerous further preparations. As an example, diamine 33 was converted into quinoxaline 34 by

reaction with 1,2-diphenylethane-1,2-dione.

At the same time, full substitution of fluorine was not achieved in some cases with

neutral nucleophile Me NH even under rather drastic reaction conditions. One may think that

2

23

activation of C-F bonds with metal complexes might be useful in this context in the further

work.

It should be emphasized that the starting material in the synthesis of initial compounds 1,

1

0 and 19 was C

SiMe

.⁴^,¹⁸The nucleophilic substitution of fluorine in polyfluorinated (hetero) aromatics was

then used for CsF-induced cyclization of C -N=S=N-SiMe into thiadiazole 10 reduced further

into corresponding diamine followed by cyclization of the latter into quinoxaline 1 with glyoxal

and into selenadiazole 19 with SeCl or SeO

.⁴^,¹⁸This work reveals that the nucleophilic

6

F

5

-NH

2

subsequently functionalized into C

6

F

5

-N=S=O and C

6

F

5

-N=S=N-

3

6

F

5

3

4

2

substitution of fluorine, being the key step in the synthesis of the key compound of the

methodology under discussion, i.e. 10, can be exploited further until tetra-substituted, i.e.

fluorine-less, derivatives 5, 14, 23, and 31 are obtained. Suggested methodology of using C

6

5

F -

NH as starting material for synthesis of various polyfunctionalized derivatives, including

2

fluorine-less ones, via nucleophilic substitution can potentially be extended onto many other

nucleophiles bearing, particularly, pharmacophore groups. This will be direction of our further

research in the field.

Compounds 5, 7 and 14 were tested for cytotoxicity towards the human cancer cells and

effects on the mRNA expression. They were found to be low toxic. In addition 7 was found to

promote apoptosis without any significant modulation of cytochrome P450 expression. Further

studies of the biological activity of these compounds are under way.

4

. Experimental

4

.1. General

NMR spectra were measured with Bruker AV-300 ( H, 300 MHz; ¹⁹F, 282.4 MHz),

1

3

1

77

Bruker DRX-500 ( С, 125.76 MHz) and Bruker AV-600 ( H, 600.1 MHz; Se, 114.5 MHz)

1

spectrometers for solutions in CDCl

3

unless otherwise indicated. The standards were TMS ( H,

¹³С), CFCl

(¹⁹F) and Me

Se ( Se).

77

3

2

8

High-resolution mass-spectra (EI, 70 eV) were taken with a Thermo Electron Corporation

DFS mass-spectrometer. Gas-chromatography – mass-spectrometry (GC-MS) experiments were

performed with Hewlett-Packard G1800A instrument.

UV-Vis and fluorescent (FL) spectra were collected with Varian Cary 5000 and Varian

Cary Eclipse spectrophotometers, respectively, for heptane solutions unless otherwise indicated.

Elemental analyses for C, H, N and S were performed with Carlo Erba Model 1106

instrument. Analyses for F were carried out by standard spectrophotometric method with La

complex of alizarin complexone, analyses for Se by spectrophotometric method described in ref.

2

4, and those for O by classical Schutze-Unterzaucher method with Eurovector Model 1028

analyzer.

Starting materials 1, 10 and 19 were synthesized as described earlier,⁴^,¹⁸and 10 also by a

new approach suggested in this work. In the preparations described below, reaction solutions

were stirred, solvents distilled off under reduced pressure and sublimations performed in vacuo.

Tables 3-5 contain physical, analytical and NMR data of the compounds synthesized.

4

.2. X-ray diffraction

Single-crystal XRD data (ESI, Table S5) were collected on a Bruker Kappa Apex II CCD

diffractometer using φ,ω-scans of narrow (0.5°) frames with Mo Kα (λ = 0.71073 Å) radiation

with a graphite monochromator. The structures were solved by direct methods and refined by

2

full-matrix least-squares method against all F in anisotropic approximation using the SHELX-97

programs set.²⁵The H atoms positions were calculated with the riding model. Absorption

corrections were applied empirically using the SADABS programs.²⁶For compound 7 two

monoclinic polymorphs were observed, one with four crystallographically independent

molecules and another with two. Compound 19 was refined as a 0.52 : 0.48 racemic twin for

which C, F and N atoms were refined isotropically. The compounds 12 and 13, 21 and 22, and

2

1 and 23 form the co-crystal with 0.65 : 0.35, 0.25 : 0.75, and 0.77 : 0.23 occupation ratio,

respectively. For the co-crystals, atoms C and O of groups OCH were refined isotropically with

3

geometrical restrictions. The crystal structures obtained were analyzed for short contacts

between non-bonded atoms with the PLATON program.²⁷

CCDC 1408516 (4), 1408517 and 1408518 (7, two polymorphs), 1408519 (8), 1408520

(11), 1408521 (12), 1408522 (14), 1408523 (15), 1408524 (17), 1408525 (19), 1408526 (21),

9

1

408527 (22 / 21), 1408529 (21 / 23), and 1408528 (25) contain the supplementary

crystallographic data for this paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Powder XRD data (ESI, Figure S2) for two polymorphs of compound 6 were obtained at

2

00 K with a Bruker Kappa Apex II CCD diffractometer using Mo Kα radiation (λ = 0.71073 Å)

and a graphite monochromator, over the 2θ range 3-20º (R = 110 mm, cycle per  with 300 s on

the cycle,  = –30 and 30). The polycrystalline samples were ground with silicone grease prior

to measurement.

4

.3. Quantum chemical calculations

The geometries and harmonic vibrational frequencies of 1, 10 and 19 and species

–

involved in their reactions with MeO in MeOH and Me

2

NH or Me

2

N in DMF were calculated

2

8

29

at the M06-2X/6-31+G(d,p) level of theory with the Gaussian 09 suite of programs. All

stationary points on the potential energy surfaces were ascertained to be the minima or transition

states and the stability of the SCF solutions was tested. Calculations for MeOH and DMF

3

0

solutions were carried out using the polarizable continuum model (IEFPCM) with radii and

3

1

non-electrostatic terms of the SMD solvation model as implemented in the Gaussian 09.

4

.4. Preparations

Where needed, one-day experiments were performed with CaCl

2

protection from

atmospheric moisture whereas longer ones in an argon atmosphere. The diamines 31-33 were

synthesized and kept under argon until their conversion into hydrochlorides.

4

.4.1. Quinoxalines 2-8, 28

a) At ambient temperature, a solution of 0.202 g (1 mmol) of 1 and (a) 0.054 g (1 mmol),

(

or (b) 0.108 (2 mmol), of NaOMe in 6 ml of MeOH was (a) stirred for 24 h or (b) stirred for 24 h

and then refluxed for 8 h. The solvent was distilled off and the residue was (a) chromatographed

on silica column with ethyl acetate / CH

2

Cl 1 : 3 and recrystallized from hexane, or (b)

2

sublimed and recrystallized from hexane. Compound 2 (a) or 3 (b) was obtained in the form of

colorless crystals.

(b) A solution of 0.202 g (1 mmol) of 1 and 0.162 g (3 mmol) of NaOMe in 2 ml of

MeOH and 5 ml of Me SO was refluxed for 1 h, cooled to room temperature, diluted with 50 ml

2

1

0

of H

2

O and extracted with 3 × 20 ml of Et

2

O. The extract was dried with MgSO

4

, evaporated and

the residue chromatographed on silica column with hexane / ethyl acetate / CH

2

Cl 1 : 1 : 1. The

2

first colorless zone contained compound 3, the second and third pale-yellow zones contained

compounds 4 and 5 respectively. Evaporation of the eluate and recrystallization of the residue

from hexane gave compound 4 in the form of colorless crystals.

(c) A solution of 0.202 g (1 mmol) of 1 and 0.270 g (5 mmol) of NaOMe in 3 ml of

o

MeOH and 5 ml of Me

2

SO was kept at 100 C for 3 h, cooled to room temperature, diluted with

5

ml of H

2

O and extracted with 4 × 10 ml of Et

2

O. The extract was dried with MgSO ,

4

evaporated and the residue sublimed and recrystallized from hexane. Compound 5 was obtained

in the form of yellow crystals.

(

d) A solution of 0.202 g (1 mmol) of 1 and 0.450 g (4 mmol) of 40% aqueous Me NH in

2

o

9

ml of dioxane was kept at 60 C for 7 h, cooled to room temperature, diluted with equal volume

of H

2

O and extracted with 4 × 10 ml of CHCl

3

. The extract was dried with MgSO , evaporated

4

and the residue sublimed and recrystallized from hexane. Crystallization at ambient temperature

o

(

1 h) and at 7 C (16 h) gave different polymorphs of compound 6 with melting points 78-79 and

o

8

6-87 C, respectively, in both cases in the form of bright yellow crystals.

(e) In sealed glass tube placed in steel cylinder, a solution of 0.202 g (1 mmol) of 1 and

o

0

.900 g (8 mmol) of 40% aqueous Me

2

NH in 3 ml of DMF was kept at 150 C for 6 h. The

reaction mixture was cooled to room temperature, solvents were distilled off and the residue was

sublimed and recrystallized from hexane. Compound 7 was obtained in the form of yellow

о

needles of polymorph with m. p. 113-114 С; for the second polymorph of 7, see entry (f).

(f) In sealed glass tube placed into steel cylinder, a solution of 0.202 g (1 mmol) of 1 and

o

1

.35 g (12 mmol) of 40% aqueous Me

2

NH in 3 ml of N-methyl-2-pyrrolidone was kept at 230 C

for 22 h. The reaction mixture was cooled to room temperature, diluted with 40 ml of H

2

O and

extracted with 7 × 40 ml of hexane. The extract was dried with CaCl

2

and evaporated to dryness.

1

19

The residue contained compounds 7, 8 and 9 in ratio 3 : 8 : 2 ( H and F NMR, GC-MS)

together with non-identified minor admixtures. This product was chromatographed on a silica

column with 10 : 1 chloroform / ethyl acetate. The first yellow zone contained mixture of

unidentified compounds and the second yellow-orange zone compound 7 and 8. Compound 9

was not isolated from the column on further elution with ethyl acetate and then MeCN.

Compounds 7 and 8 were separated by repeated chromatography on a silica column with hexane

/

ethyl acetate 5 : 1. The first orange zone corresponded to compound 8 and the second yellow

one to compound 7. Eluates were evaporated and residues were recrystallized from hexane.

1

Compound 8 was obtained in the form of orange crystals and compound 7 in that of greenish-

о

yellow crystals of a polymorph with m. p. 115-116 С.

(g) A solution of 0.114 g (0.5 mmol) of 6 and 0.054 g (1 mmol) of NaOMe in 6 ml of

о

MeOH was kept at 65 С for 8 h. The reaction mixture was cooled to room temperature, poured

in water, acidified with HCl to рН ~6-7 and extracted with 6 × 10 ml of Et

was dried with MgSO and evaporated. The residue was sublimed and recrystallized from

hexane. Compound 28 was obtained in the form of yellow crystals.

2

O. The Et O solution

2

4

.4.2. Thiadiazoles 10-17, 29

a) Under argon, a mixture of 0.458 g (2.5 mmol) of 3,4,5,6-tetrafluoro-1,2-

(

1

8

diaminobenzene and 1 ml of SOCl

2

was refluxed for 1 h, the excess of SOCl was distilled off

2

1

9

and extremely moisture sensitive N,N’-disulfinyl-3,4,5,6-tetrafluoro-1,2-diaminobenzene was

obtained. This product was (a) dissolved in 2 ml of absolute pyridine and the solution was heated

o

at 100 C for 4 h; or (b) dissolved in 5 ml of toluene, 0.333 g (2.5 mmol) of freshly sublimed

AlCl

3

was added, and the mixture refluxed for 6 h. The solvents were distilled off and the residue

18

sublimed. Compound 10 was obtained in the form of white needles.

(b) A solution of 0.208 g (1 mmol) of 10 and 0.059 g (1.1 mmol) of NaOMe in 10 ml of

MeOH was kept at ambient temperature for 4 h. Then aqueous HCl was added to pH ~3, solvent

was distilled off and the residue recrystallized from hexane. Compound 11 was obtained in the

form of yellowish needles.

(c) A solution of 0.208 g (1 mmol) of 10 and 0.113 g (2.1 mmol) of NaOMe in 1 ml of

MeOH and 9 ml of THF was kept at ambient temperature for 60 h, solvents were distilled off and

the residue sublimed in vacuo and recrystallized from hexane. Compound 12 was obtained in the

form of yellow needles.

(d) A solution of 0.208 g (1 mmol) of 10 and 0.207 g (3.7 mmol) of NaOMe in 6 ml of

o

MeOH and 10 ml of dioxane was kept at 95 C for 90 h, solvents were distilled off and the

residue sublimed and recrystallized from pentane. Yellow co-crystals of compounds 12 and 13,

0

.65 : 0.35 (GC-MS and XRD), were obtained in the yield of 0.022 g (10 %). They were not

separated into individual 12 and 13.

(e) A solution of 0.208 g (1 mmol) of 10 and 0.259 g (4.8 mmol) of NaOMe in 2 ml of

MeOH and 10 ml of dioxane was refluxed for 9 h, cooled to room temperature, solvents were

1

2

distilled off and the residue sublimed and recrystallized from hexane. Compound 14 was

obtained in the form of yellow needles.

(

f) A solution of 0.208 g (1 mmol) of 10 and 0.450 g (4 mmol) of 40% aqueous Me NH

2

in 5 ml of THF was kept at ambient temperature for 3 h, solvents were distilled off and the

residue sublimed and recrystallized from hexane. Compound 15 was obtained in the form of red

crystals.

(g) In sealed glass tube placed into steel cylinder, a solution of 0.072 g (0.35 mmol) of 10

o

and 0.175 g (1.56 mmol) of 40% aqueous Me

2

NH in 0.5 ml of DMF was kept at 150 C for 7 h.

Upon cooling to room temperature, the reaction mixture was diluted with 10 ml of H

extracted with 5 × 10 ml of hexane. Solvent was distilled off and the residue was

chromatographed on silica column. Elution with CH Cl gave yellow zone of compound 16.

Further elution with CH Cl / ethyl acetate 10 : 1 gave orange zones containing compound 17, its

2

O and

2

1

19

isomer and an isomer of compound 16 along with unidentified compounds ( H and F NMR and

GC-MS). The yellow zone was evaporated and the residue recrystallized from hexane.

Compound 16 was obtained in the form of orange crystals.

(h) In sealed glass tube placed into steel cylinder, a solution of 0.390 g (1.9 mmol) of 10

o

and 2.270 g (16 mmol) of 40% aqueous Me

2

NH in 3 ml of Me

2

SO was kept at 170 C for 35 h.

Upon cooling to room temperature, the reaction mixture was diluted with 20 ml of H O and

2

extracted with 5 × 20 ml of chloroform. Solvents were distilled off and the residue was sublimed

and chromatographed on silica plates (200 × 200 × 1 mm) with hexane / ethyl acetate 10 : 1. The

bright-yellow zone was extracted with MeCN, solvent distilled off and the residue recrystallized

from MeOH. Compound 17 was obtained in the form of yellow crystals. The orange zone was

worked-up in the same way, the residue was dark-red oil contained 80 % (GC-MS) of 6-F isomer

of 17.²⁰

(i) A solution of 0.105 g (0.45 mmol) of 15 and 0.024 g (0.45 mmol) of NaOMe in 1 ml

o

of MeOH and 5 ml of dioxane was kept at 70 C for 24 h, cooled to room temperature and the

solvents were distilled off. The residue was recrystallized from hexane and sublimed. Compound

2

9 was obtained in the form of yellow crystals.

4

.4.3. Selenadiazoles 20-25, 30

(a) A solution of 0.250 g (1 mmol) of 19 and 0.054 g (1 mmol) of NaOMe in 2 ml of

MeOH and 5 ml of THF was kept at 50 ºС for 5 h and cooled to room temperature. The

1

3

precipitate was filtered off, sublimed and recrystallized from EtOH. Compound 20 was obtained

in the form of crystalline yellow solid.

(b) A solution of 0.250 g (1 mmol) of 19 and 0.108 g (2 mmol) of NaOMe in 2 ml of

o

MeOH and 5 ml of dioxane was kept at 85 C for 8 h, cooled to room temperature and solvents

were distilled off. The residue was recrystallized from toluene / hexane 1 : 1 and sublimed.

Compound 21 was obtained in the form of yellow crystals.

(c) A solution of 0.250 g (1 mmol) of 19 and 0.162 g (3 mmol) of NaOMe in 2 ml of

o

MeOH and 5 ml of dioxane was kept at 85 C for 16 h, cooled to room temperature and passed

though alumina column (d = 25, h = 50 mm) which was additionally washed with 150 ml of

CH

2

Cl

2

. The combined solution was evaporated and the residue (0.174 g) was sublimed to give 1

1

19

:

5 : 1 ( H and F NMR, GC-MS) mixture of compounds 21, 22 and 23. The mixture was

separated by fractional sublimation controlled by GC-MS. The fraction contained 74% of 22 was

chromatographed on alumina column with hexane followed by hexane / ethyl acetat 3 : 1.

Compound 22 was obtained in the form of yellow crystals. Additionally, two minor fractions

were isolated from the column to be co-crystals 22 / 21 and 21 / 23 (XRD).

(

d) A solution of 0.250 g (1 mmol) of 19 and 0.216 g (4 mmol) of NaOMe in 2 ml of

MeOH and 5 ml of Me SO was refluxed for 8 h, cooled to room temperature and passed though

alumina column (d = 35, h = 25 mm) which was additionally washed with 150 ml of CH Cl .

2

Combined solution was evaporated under reduced pressure and the residue recrystallized from

EtOH. Compound 23 was obtained in the form of yellow crystals.

(e) A solution of 0.160 g (0.63 mmol) of 19 and 0.215 g (4.7 mmol) of 40% aqueous

Me

2

NH in 5 ml of dioxane was kept at ambient temperature for 5 h, solvents were distilled off

and the residue was sublimed and recrystallized from EtOH. Compound 24 was obtained in the

form of yellow crystals.

(

f) In sealed glass tube placed in steel cylinder, a mixture of 0.255 g (1 mmol) of 19 and

.900 g (8 mmol) of 40% aqueous Me NH in 7 ml of Me SO was kept at 175 ºС for 12 h and

cooled to room temperature. The reaction mixture was passed through alumina column (d = 25, h

45 mm) which was additionally washed with 200 ml of CH Cl . Combined solution was

0

2

=

2

evaporated and the residue recrystallized from toluene / hexane 2 : 1. Compound 25 was

obtained in the form of yellow crystals.

1

4

(g) A solution of 0.100 g (0.36 mmol) of 24 and 0.019 g (0.36 mmol) of NaOMe in 1 ml

o

of MeOH and 5 ml of dioxane was kept at 65 C for 7 h, cooled to room temperature and

solvents were distilled off. The residue was recrystallized from toluene / hexane 1 : 1 and

sublimed. Compound 30 was obtained in the form of brick-red crystals.

4

.4.4. Diamines 31-33 and quinoxaline 34

o

(

a) At 0 C, a solution of 0.100 g (0.4 mmol) of compound 14 in 5 ml of THF was added

to suspension of 0.204 g (5.3 mmol) of LiAlH

4

in 10 ml of THF. The reaction mixture was kept

Cl was carefully added. The reaction

O. The filtrate was

added to solution of NaOH in methanol (pH ~11), the solvents were distilled off and the residue

was sublimed. Sublimed product was dissolved in a mixture of 3 ml of Et O and 1 ml of MeOH

and 2 ml of Me SiCl was added. The resulting white precipitate was filtered off and washed

twice with Et

o

at 0 C for 1 h and 5 ml of saturated water solution of NH

4

mixture was filtered under argon and the filter washed with 2 × 10 ml of Et

2

3

2

O. Compound 31·2HCl was obtained in the form of colorless crystals.

o

(

b) At 0 C, 0.177 g (4.7 mmol) of LiAlH

4

was added to a solution of 0.153 g (6.6 mmol)

o

of compound 12 in 15 ml of THF. The reaction mixture was kept at 0 C for 1 h and 1 ml of

methanol was carefully added. The solvents were distilled off and the residue was extracted with

3

× 5 ml of benzene. The extract was evaporated to dryness, the residue sublimed and the

sublimate dissolved in mixture of 5 ml of Et O with 1 ml MeOH. Then 2 ml of Me SiCl was

added to the solution, the precipitate was filtered off and washed twice with Et O. Compound

2·2HCl was obtained in form of white powder.

2

3

2

3

(

c) A mixture of 0.146 g (0.6 mmol) of compound 15, 0.780 g (3.5 mmol) of SnCl

and 6 ml of conc. HCl was refluxed for 1 h, cooled to room temperature, neutralizated with

aqueous NaOH to pH ~8, and extracted with 6×20 ml of Et O. The extract was dried with

MgSO , filtered, concentrated to a volume of ~2 ml. and treated by solution of 0.1 ml of MeOH

2

·2H O

2

4

and 0.3 ml of Me

powder.

3

SiCl in 2 ml of Et O. Compound 33·2HCl was obtained in the form of white

2

In all cases, free bases for spectral measurements were recovered by the action of Et

suitable solvent.

3

N in

(d) A mixture of 0.457 g (0.16 mmol) of 33·2HCl and 0.336 g (0.16 mmol) of

PhCOCOPh in 6 ml of MeOH was refluxed for 4.5 h, cooled to room temperature and the

1

5

solvent was distilled off. The residue was chromatographed on silica column with toluene, bright

yellow fraction was evaporated to dryness and the residue recrystallized from pentane.

Compound 34 was obtained in the form of bright yellow powder.

4

.4.5. Competitive interaction of compounds 1, 10 and 19 with methoxide

At ambient temperature, a solution of 0.05 mmol of NaOMe in 1 ml of MeOH was

slowly added with syringe to a solution of equimolar (0.05 mmol) mixture of 1, 10 and 19 in 15

1

9

21

ml of MeOH. After 48 h the reaction mixture was studied by F NMR and GC-MS.

4

.4.6. Reaction of compound 19 with LiNMe

2

o

At –30 C and under argon, 1.8 ml of 1.7 M hexane solution of BuLi (3.0 mmol) were

added to a suspension of 0.123 g (1.5 mmol) of Me

2

NH·HCl in 10 ml of DME. After 30 min, a

solution of 0.127 g (0.5 mmol) of compound 19 in 5 ml of DME was added during 15 min.

1

9

Reaction mixture was slowly (~3 h) warmed to ambient temperature. According to NMR F and

GC-MS data, the reaction mixture contained compounds 19, 20 and 24 in molar ratio 1 : 1.5 : 1,

respectively.

4

.5. Determination of cytotoxicity and effects on the mRNA expression

For compounds 5, 7 and 14, cytotoxicity and effects on the mRNA expression were

investigated. The studied cell lines included HepG2, Hep2 (human carcinoma) and U937 (human

leukemia). All reagents for cell cultures were purchased from Thermo Scientific. The HepG2 and

Hep2 cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented

with 10% (v/v) fetal bovine serum (FBS). The U937cell lines were cultured in RPMI

supplemented with 10% (v/v) FBS. All cell lines were cultured at 37 °C in a 5% CO humidified

2

incubator. For the full data obtained and their discussion, see ESI (section Bioactivity studies,

Figure S3).

To determine the effects of compounds 5, 7 and 14 on the mRNA expression CYP1a1,

CYP1A2, CYP4a11, CYP3A4 and TNF-alfa, HepG2 and U937 cells were treated with low

toxicity concentration of the compounds (25 µM) for 16 h. The compounds were dissolved in

Me

2

SO, the concentration of Me

2

SO in treated cells did not exceed 0.1% (v/v). Control cells

were treated with Me

2

SO (50% v/v) to yield a final concentration of 0.1% (v/v). After 16 h of

treatment, either the total RNA was isolated using Tri Reagent according to the standard

protocol. The purity of each RNA preparation was evaluated by the ratio of the absorbance at

1

6

2

60 nm to that at 280 nm. RNA was transcribed using High Capacity cDNA Reverse

Transcription Kit (Applied Biosystems). Reaction was stopped by heating the mixture at 85 °C

for 5 min and storing at −20 °C until subsequent analysis. The primer sets was designed using

GenBank database: GAPDH, CYP1a, CYP1a2, CYP2a1, CYP3a4 and TNF-alfa (for details, see

ESI: Section Bioactivity studies). The quantitative real-time reverse-transcription polymerase

chain reactions (RT-PCRs) were performed using qPCRmix-HS SYBR (Eurogen) and a

o

LightCycler instrument (Roche Diagnostics). Reactions conditions were: preheating at 95 С,

o

3

00 s; amplification, 45 cycles; 95 С, 12 s; 58 С, 15 s; 72 С, 20 s; detection, respectively.

Melting point analysis was carried out by heating the DNA synthesis product from 65 °C to 95

C and a characteristic melting point curve was obtained. All PCR reactions were performed in

°

triplicates. Calibration curve was constructed by plotting the cross point (Ct) against a serial

dilution with cDNA produced from heart total RNA extracts using 1 : 4 dilution steps The Ct is

the cycle number at which the fluorescence signal is greater than a defined threshold, one in

which all the reactions are in the logarithmic phase of amplification. Negative control samples

contained water instead of cDNA; occasionally dimer production was seen being easily

distinguished by melting point analysis. The effect of compounds 5, 7 and 14 on the Cytochrome

P450 (CYP) induction of HepG2 and U937 cells was determined. The non-toxic concentrations

of 5, 7 and 14 (more than 90% viability) used for mRNA expression study of HepG2 and U937

cells were 25 μM. The change in expression of CYP mRNA by 5, 7 and 14 was interpreted in

fold induction pattern. The inducing effect of 5, 7 and 14 for CYPs 1A1, 1A2, 3A4 and 4A11

mRNA was fairly low in that almost all of the fold induction was in the range of only 1- to 2-

fold. Therefore, the compounds were unlikely to potentiate the CYP induction of the inducers.

For CYP1A1, it was the only gene that could be greater induced in HepG2 cells by compound 5

to about 4-fold, but not remarkable as compared with such classic inductor as benzopiren.

According to the result, more obvious change in the U937 cells was seen in CYP1A1 mRNA

expression for compound 14. It should be noted that TNF-alfa (a major marker of inflammation)

was slightly elevated in U937 cells treated with 14 than in control cells. For the full data obtained

and their discussion, see ESI (section Bioactivity studies, Figures S4 and S5).

Acknowledgments

The authors thank the Collective Service Center of Siberian Branch of the Russian Academy of

Sciences for spectral and analytical measurements, and the Siberian Supercomputer Center for

computational facilities. Financial support from the Ministry of Education and Science of the

Russian Federation (project of Joint Laboratories of Siberian Branch of the Russian Academy of

1

7

Sciences and National Research Universities) is gratefully acknowledged. The authors affiliated

with Tomsk State University are grateful to the Foundation named after D.I. Mendeleev for

support of their work.

Appendix A. Electronic supplementary information

Electronic supplementary information (ESI) associated with this article and containing

XRD and DFT data, chemical names of compounds, and details of the cytotoxicity and effects on

the mRNA expression studies can be found, in the online version, at http://

1

8

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20] NMR, δ: 5-Dimethylamino-6,7,8-trifluoroquinoxaline (minor isomer of 6): Н: 8.86,

1

9

8

.84, 3.13; F: –152.9 (m, 2F), –154.0 (t, 1F). 4-(Dimethylamino)-5,6,7-trifluoro-2,1,3-

benzothiadiazole (minor isomer of 15): H: 3.21; ¹⁹F: –147.8, –154.0, –156.1. 4-

1

Dimethylamino-5,6,7-trifluoro-2,1,3-benzoselenadiazole (minor isomer of 24): Н: 3.14;

¹⁹F: –147.8, –154.3, –154.8. 4,5,7-Tris(dimethylamino)-6-fluoro-2,1,3-benzothiadiazole

1

19

(

isomer of 17): Н: 3.03; F: –129.2. For compounds 6, 15, 17 and 24, see Table 5.

[

21] Relative yields of products 2, 11 and 20 in the reaction of an equimolar (0.5 mmol each)

mixture of 1, 10 and 19 with MeONa (0.5 mmol) in MeOH were 3.0 : 1.0 : 2.2 according

1

9

to F NMR, and 2.8 : 1.0 : 1.3 according to GC-MS, respectively. Some discrepancy

between the data may be caused by different sensitivity of the GC-MS detector towards

different types of the heterocycles.

[

22] (a) Fluorine in Heterocyclic Chemistry, V. Nenajdenko (Ed.), Springer (2014);

(b) A. Gakh, K.L. Kirk, Fluorinated Heterocycles, Oxford University Press (2008).

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(

b) J. Burdeniuc, B. Jedicka, R.H. Crabtree, Chem. Ber. 130 (1997) 145 –154;

c) J.L. Kiplinger, T.G. Richmond, C.E. Osterberg, Chem. Rev. 94 (1994) 373–431.

(

[

24] V.P. Fadeeva, D.O. Panin, O.N. Nikulicheva, V.D. Tikhova, J. Analyt. Chem. 69 (2014)

32–437.

4

[

25] G.M. Sheldrick, Acta Crystallogr. A 64 (2008), 112–122.

26] SADABS, Version 2008-1, Bruker AXS, Madison, WI, USA (2008).

2

3

[

27] (a) A.L. Spek, PLATON, A Multipurpose Crystallographic Tool, Version 10M, Utrecht

University, The Netherlands (2003);

(b) A.L. Spek, J. Appl. Crystallogr. 36 (2003) 7–13.

[

28] Y. Zhao, N.E. Schultz, D.G. Truhlar, J. Chem. Theory Comput. 2 (2006) 364–382.

29] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G.

Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li,

H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M.

Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,

H. Nakai, T. Vreven, J.A. Montgomery, J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd,

E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari,

A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M.

Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E.

Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin,

K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich,

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30] (a) J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 105 (2005) 2999–3093;

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[

31] A.V. Marenich, C.J. Cramer, D.G. Truhlar, J. Phys. Chem. B 113 (2009) 6378–6396.

32] Compound 6 was isolated in the form of two polymorphs having identical elemental

analysis but different melting points and powder X-ray diffraction patterns (Figure S2,

ESI). Two polymorphs of compound 7 were characterized by XRD (Figure 2; Table 2;

ESI, Table S4).

2

4

–1

Figure 1. Relative Gibbs free energies (ΔGrel, kcal.mol ) of the stationary points on the potential

–

energy surface for the reaction of quinoxaline 1 with MeO in MeOH calculated by the M06-

2

X/6-31+G(d,p) method for T = 298 K, the solvent was taken into account using polarized

continuum model. Color code: C – black, H – white, N – blue, O – red, F – green.

2

5

4

7

8

11

1

2

14

1

5

17

2

6

1

9

21

2

25

Figure 2. XRD molecular structures (displacement ellipsoids at 30%) of compounds (22 from 3 :

co-crystal with 21). For selected bond lengths and angles, see Table 2.

1

2

7

Figure 3. Treatment of Hep2 and U937 cells with different concentrations (from 1 to 625 µM) of

compound 7 for 72 hours. The percentage of apoptotic cells was determined by staining with

Hoechst 33342 and percentage of dead cells was determined by using propidium iodide. The data

represent the mean ± S.D. of three independent experiments.

2

8

F

N

1

F

OMe

F

N

MeO

N

MeO

N

MeO

N

MeO

OMe

2

3

4

5

F

NMe₂

F

N

Me N

N

Me N

N

Me2N

N

2

Me N

N

2

F

NMe₂

NMe2

6

7

8

9

F

N

S

F

1

0

F

OMe

F

MeO

N

S

N

MeO

F

OMe

11

12

13

14

F

NMe₂

F

Me N

N

2

N

Me2N

2

N

S

Me N

2

F

NMe₂

15

16

17

18

2

9

Article Doi

Carbocyclic functionalization of quinoxalines, their chalcogen congeners 2,1,3-benzothia/selenadiazoles, and related 1,2-diaminobenzenes based on nucleophilic substitution of fluorine

DOI: 10.1016/j.jfluchem.2016.01.009

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Article abstract of DOI:10.1016/j.jfluchem.2016.01.009

Full text of DOI:10.1016/j.jfluchem.2016.01.009

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