Introducing Bis(5-(Trifluoromethyl)pyridin-2-yl)amine ...

Bis(pyridin-2-yl)amine (dpa) and its derivatives are flexible bidentate-ligands that are widely applied in supramolecular chemistry [ 1 3 ], catalysis [ 4 7 ] and ion sensing [ 8 10 ]. Metal complexes of bis(pyridin-2-yl)amine-based ligands demonstrate luminescent properties [ 11 ], possess cytotoxic activity and can bind with DNA molecules [ 12 15 ]. Introducing fluorine-containing groups to the molecule's structure is in demand because of the influence of such moieties on electronic properties, solubility, conformations and the lipophilicity of the compound [ 16 20 ]. Synthesis of dpa derivatives can be performed via-alkylation [ 1 ] or-arylation [ 2 3 ] of dpa or by-diarylation of amines with 2-halogenosubtituted pyridine [ 21 22 ].-diarylation of amines with 2-bromopyridine was reported by Buchwald's group during the first years after the discovery of the Pd-catalyzed amination reaction [ 23 ]. This way seems to be the most appropriate for the synthesis of the ligands containing substituents in the pyridine rings [ 21 ]. On the other hand, pyridine and other heterocycles can form complexes with palladium and interfere with the reaction, which may require careful optimization of the catalytic system [ 23 24 ]. Amination of commercially available 2-bromo-5-(trifluoromethyl)pyridine under Cu-, Ni- and Pd-catalyzed conditions was previously reported [ 25 30 ], but only a few examples of Pd-catalyzed-diarylation of amines with this substrate are reported. Thus,-diarylation of aliphatic amines is described for two examples [ 26 ]. The only example of-diarylation of aromatic amine with 2-bromo-5-(trifluoromethyl)pyridine is described in [ 31 ]; this protocol includes the use of a microwave reactor (120 °C), and the yield of the product is only 40%. In the present communication, we report a one-step synthesis of bis(5-(trifluoromethyl)pyridin-2-yl)amino-substituted arenes and heteroarenes from 2-bromo-5-(trifluoromethyl)pyridine via a Pd-catalyzed amination reaction. We consider these fluorine-containing ligands to be of interest for the synthesis of metal complexes and supramolecular structures for various applications.

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2. Results and Discussion

p

-anisidine 2a with 2-bromo-5-(trifluoromethyl)pyridine 1 was studied as a model reaction (

tert

-butoxide as a base, three equivalents of 1 were taken. The progress of the reaction and the yields of the product were monitored by 1H NMR spectroscopy using internal standard.

Diarylation of-anisidinewith 2-bromo-5-(trifluoromethyl)pyridinewas studied as a model reaction ( Scheme 1 ). The reaction was performed under an argon atmosphere in boiling 1,4-dioxane in the presence of sodium-butoxide as a base, three equivalents ofwere taken. The progress of the reaction and the yields of the product were monitored byH NMR spectroscopy using internal standard.

2/DavePhos (4/4.5 mol%) catalytic system (dba = dibenzylideneacetone, DavePhos = 2-dicyclohexylphosphino-2'-(

N

,

N

-dimethylamino)biphenyl), which was previously reported to be effective for the amination of 2-bromo-5-(trifluoromethyl)pyridine [2a was observed after 24 h, but the yields of amination products 3a and 4a were quite poor because of numerous side reactions (3a and 4a in yields of 32 and 17%, respectively (

rac

-BINAP ligand (

rac

-BINAP =

rac

-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene) provided an increase in the selectivity of the

N,N

-diarylation reaction (3a (71%) was achieved in the presence of Pd(dba)2/

rac

-BINAP (8/9 mol%) catalytic system (

We started our investigation from Pd(dba)/DavePhos (4/4.5 mol%) catalytic system (dba = dibenzylideneacetone, DavePhos = 2-dicyclohexylphosphino-2'-(-dimethylamino)biphenyl), which was previously reported to be effective for the amination of 2-bromo-5-(trifluoromethyl)pyridine [ 26 ]. Full conversion of the aminewas observed after 24 h, but the yields of amination productsandwere quite poor because of numerous side reactions ( Table 1 , entry 1). The increase in the catalyst loading to 8/9 mol% led to the formation of productsandin yields of 32 and 17%, respectively ( Table 1 , entry 2). Using-BINAP ligand (-BINAP =-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene) provided an increase in the selectivity of the-diarylation reaction ( Table 1 , entry 3). The highest yield of the target product(71%) was achieved in the presence of Pd(dba)-BINAP (8/9 mol%) catalytic system ( Table 1 , entry 4).

3b'd under optimized conditions (

N

-phenyl derivative 3b was obtained in a 71% yield, while quinoline- and 1,10-phenanthroline-based ditopic ligands 3c and 3d were afforded in very good yields (90 and 83%, respectively). The obtained yields are superior to those previously reported for a similar reaction, which gives a 40% yield and proceeds under more stringent conditions (120 microwave reactor, sealed ampoule), which limits its scaling. Thus, the procedure can be applied for the synthesis of various ligands from corresponding amino substituted arenes and heteroarenes.

In the next step, we undertook the synthesis of a representative series of bis(5-(trifluoromethyl)pyridin-2-yl)amine-based ligandsunder optimized conditions ( Scheme 2 ). The-phenyl derivativewas obtained in a 71% yield, while quinoline- and 1,10-phenanthroline-based ditopic ligandsandwere afforded in very good yields (90 and 83%, respectively). The obtained yields are superior to those previously reported for a similar reaction, which gives a 40% yield and proceeds under more stringent conditions (120 microwave reactor, sealed ampoule), which limits its scaling. Thus, the procedure can be applied for the synthesis of various ligands from corresponding amino substituted arenes and heteroarenes.

1H NMR spectra of the products can be easily attributed to the protons in the structure basing on their chemical shifts, coupling constants and relative integral values. A typical 1H NMR spectrum (compound 3c) is shown in

All the compounds obtained were characterized by NMR and IR spectroscopies and mass spectrometry. The signals inH NMR spectra of the products can be easily attributed to the protons in the structure basing on their chemical shifts, coupling constants and relative integral values. A typicalH NMR spectrum (compound) is shown in Figure 1 , and the full spectra of the products are given in the Supplementary Materials

Three characteristic signals of the double intensity, which correspond to 2-amino-5-(trifluoromethyl)pyridine moiety, are observed in the 1H spectra in all the products (3a'd). The upfield doublet (7.17 ppm, 3

J

= 8.8 Hz) corresponds to the protons at the

ortho

-position to the amino group, a doublet of doublets (7.80 ppm, 3

J

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= 8.8 Hz, 4

J

= 2.4 Hz) corresponds to the protons at position 4 of the pyridine rings, and a downfield broadened multiplet is assigned to the protons at position 6. In the case of 3c, a characteristic doublet of doublets (7.42 ppm, 3

J

= 8.4 Hz, 3

J

= 4.3 Hz) was attributed to the proton at position 3 of quinoline, the downfield doublet of doublets (8.93 ppm, 3

J

= 4.3 Hz, 4

J =

1.7 Hz) can be assigned to the proton at position 2 of quinoline, and the downfield doublet of doublets (8.07 ppm, 3

J

= 8.4 Hz, 4

J =

1.7 Hz) corresponds to the proton at position 4. It should be noted that the signals of the protons at positions 5 and 7 (7.54 and 7.67 ppm, 4

J

= 2.3 Hz) are in a lower field compared to the signals of the corresponding protons in 6-aminoquinoline, which is due to the electron-withdrawing effect of 5-(trifluoromethyl)pyridine moieties. This is also observed in the spectra of other products. The 8.19 ppm doublet (3

J

= 9.0 Hz) corresponds to the proton at position 8. One can observe characteristic quadruplets in 13C{1H} NMR spectra with (1

JCF

= 271.4 Hz, 2

JCF

= 33.6 Hz, 3

JCF

= 4.1 and 3.1 Hz), which can be attributed to the CF3 group and carbon atoms at positions 5, 6 and 4 of the pyridine core, respectively. The characteristic signals of the CF3 group ('61.9 ppm) are observed in the 19F NMR spectra of the products.

3c, a crystal of satisfactory quality was obtained, and its structure was additionally proved by X-ray analysis (3c forms crystals of a monoclinic system with P21 symmetry. In the crystal, molecules are assembled by parallel displaced π-π interactions between the quinolinyl moieties (

a

axis are grafted together by several C-H-π contacts, forming thick layers in the

0ab

plane. The layers are packed along the

c

axis by van der Waals interactions.

For product, a crystal of satisfactory quality was obtained, and its structure was additionally proved by X-ray analysis ( Figure 2 a). Productforms crystals of a monoclinic system with P2symmetry. In the crystal, molecules are assembled by parallel displaced π-π interactions between the quinolinyl moieties ( Figure 2 b). The resulting stacks passing along theaxis are grafted together by several C-H-π contacts, forming thick layers in theplane. The layers are packed along theaxis by van der Waals interactions.

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