S NH Reactions of ferrocenyllithium and azine N -oxides

A non-catalytic C-C coupling of ferrocenyllithium and heterocyclic N -oxides 2 was carried out for the first time using the reaction of nucleophilic substitution of hydrogen (S NH ) in azines.


Introduction
An interest in heterocyclic ferrocene derivatives is due first of all to their unique photophysical, 1 magnetic, 2 and redox 3 properties along with the possibility of their application in analytical 4 and medicinal 5 chemistry, and as efficient catalytic reagents in asymmetric synthesis. 6eteroarylferrocenes are often synthesized by means of a "building on" of a heterocyclic subunit on the ferrocene matrix using substituents introduced before in the ferrocene structure.The second method is a direct introduction of heterocycles in ferrocene.The applicability of the first method is limited by the necessity of obtaining the different starting ferrocene synthons.Various cross-couplings catalyzed with transition metals, such as Negishi, 7,8 Kumada, 9 Sonogashira 10 and Stille 11,12 reactions, have been examined as the second strategy.An aromatic halide is used as a substrate in the cross-couplings mentioned above.At the same time, the alternative C-C crosscouplings of azines and ferrocene are S N H reactions which do not require a preliminary introduction of either halogen or other nucleofuges in the azine structure.It is essential that these reactions proceed in the absence of transition metals as catalysts which usually contaminate the target product.
Recently the application of S N H reactions for the synthesis of a series of azinylferrocenes via the direct oxidative coupling of azine and ferrocenyllithium has been reported. 13We succeeded in the development of the simple, efficient approach of direct introduction of ferrocene subunit in azine structure, which made it possible to obtain mono-and 1,1'-diazinyl ferrocenes in good yields.
In this paper, we wish to report a new non-catalytic S N H C-C coupling of ferrocenyllithium and azines when N-oxide (an activated form of azine) is used as a substrate.
According to a generally accepted concept, the nucleophilic substitution of hydrogen in azaarenes proceeds in two stages. 14 Interaction of ferrocenyllithium with azine N-oxides is accompanied with the formation of heterocyclic ferrocene-containing products.The lithium derivative 1 was synthesized in the reaction of bromoferrocene and n-butyllithium for 15 min at room temperature under an argon atmosphere. 15Bright orange suspension of ferrocenyllithium was cooled to -78 °C, and a solution of the corresponding N-oxide in dry tetrahydrofuran was added.A reaction mixture was stirred for 10 min and then heated to room temperature.As the temperature increased, the color of the suspension changed to dark brown.In order to convert σ H -adducts 3-OLi into corresponding dihydro-compounds 3-OH, 1 mmol of water was added to the reaction mixture.4a-e and 4j

Scheme 1
When DDQ was used as an oxidant (THF solution of 1 equivalent) the oxidative type of aromatization S N H (AO) took place (PATHWAY 1, method 1).DDQ was chosen as an external oxidant because of good results obtained when it was used in aromatization of σ H -adducts of ferrocenyllithium and different azines.We succeeded in increasing the reaction yields up to 30-40% as compared with other oxidative reagents. 13The oxidant was added to the reaction mixture at room temperature.The suspension formed was immediately filtered through a layer of neutral aluminum oxide and subjected to alumina column chromatography.As a result, new heteroarylferrocene structures 4a-e and 4j were synthesized in 34-65% yields (Table 1).Moreover, the concomitant azinyl ferrocenes 5a-h were isolated from the reaction mixture in 4-14% yields by column chromatography.
It should be mentioned that in this case the N-oxide function remains in the structure of azaheterocyclic fragment.Compounds 4 cannot be obtained by other known methods, e.g., by oxidation of corresponding azinylferrocenes.Hydrogen peroxide in acetic acid as an oxidant is not applied in such cases because of the instability of the ferrocene moiety in these conditions.It should also be noted that in the case of pyrazine oxide 2g and 2,2'-bipyridyl oxide 2h we failed to isolate the corresponding ferrocenyl-containing N-oxides.It requires additional studies to account for these results.The spectroscopic characteristics and elemental analysis data for the obtained heteroarylferrocenes agreed well with proposed structures 4a-e and 4j.The peaks of the molecular ions were registered in mass spectra.The absorption bands corresponding to stretching vibrations of N-oxide group at v 1208-1275 cm -1 were observed in the IR spectra.The 1 H NMR spectra of compounds 4a-e and 4j showed the characteristic signals of monosubstituted ferrocene, viz.singlet (5H intensity) of unsubstituted cyclopentadienyl fragment of ferrocene at δ 4.02-4.24ppm and two multiplets (2H intensity) of the monosubstituted cyclopentadienyl fragment at δ 4.50-5.58ppm, as well as signals of the corresponding heteroaromatic fragments at δ 7.47-9.08ppm.
Most of the compounds were obtained in the crystalline state.The spatial structure of compound 4a was established by X-ray diffraction (Figure 1).Selected bond lengths and bond angles are listed in Table 2.The unsubstituted Cp (C(15)-C(19) atoms) and monosubstituted Cp (C(10)-C(14) atoms) cyclopentadienyl rings are coplanar (the angle is 1.60°).The oxidoquinoline ring is rotated relative to the Cp" ring by 5.42°.The Ct-Fe-Ct" angle is 179.39°,where Ct and Ct" are centers of Cp and Cp" rings, respectively.The Fe(1)-Cp and Fe(1)-Cp" distances are 1.656 and 1.635 Å, respectively.
In the case of pyridine N-oxide, 2f, the reaction product has acyclic structure 4f.According to literature data, opening of pyridine ring took place at the stage of the σ H -adduct formation when phenyl-, alkyl-, alkenyl-and alkynyl-Grignard reagents had been used as nucleophiles. 16,17Thus, intermediate 3f-OH was converted to 5-ferrocenylpenta-2,4-dienal oxime 4f.(Scheme 2).Derivative 4f is quite unstable and decomposed after four days at room temperature.

Scheme 2
A peak of 4f molecular ion was registered in mass spectra.The absorption bands corresponding to stretching vibrations of C=N and O-H groups were observed at v 1610 and 3264 cm -1 , respectively, in the IR spectrum.The 1 H NMR spectrum of oxime 4f showed characteristic proton signals of the monosubstituted ferrocene fragment at δ 4.08-4.49ppm, as well as the proton signals of polyene substituent at δ 5.91-8.27ppm and O-H group at δ 10.81 ppm.
When acetic anhydride was added as dehydrating agent to intermediate 3-OLi (Scheme 1), aromatization process proceeded according to the eliminative type (PATHWAY 2) and was accompanied by removal of an acetic acid molecule from 3-OAc.The reaction mixture was heated to a room temperature, and then treated with acetic anhydride.The suspension obtained was stirred for 15 min, a solvent was evaporated, and the residue was subjected to alumina column chromatography.As a result, we obtained the known azinylferrocenes 5a-d, 5f and 5h.Characteristics of the obtained derivatives agreed to the literature data. 13Moreover, we synthesized the previously unknown phthalazine and pyrazine derivatives, 5e and 5g.Yields of azinylferrocenes 5a-h were 35-55% (Table 3).It has been found that the aromatization process of intermediate 3-OH could proceed spontaneously in the presence of atmospheric oxygen (Scheme 1); however, the selectivity is essentially decreased in this case.The reaction products comprised a mixture of N-oxidoazinylferrocenes 4 (23-55% yield) and derivatives 5 (15-30% yield) without N-oxide fragment in the azine moiety (PATHWAY 1, method 2).

Conclusions
Thus, the use of S N H methodology makes it possible to obtain a series of heterocyclic ferrocene containing derivatives 4 and 5, the reaction products' type depends on the starting heteroaryl Noxides, and conditions of the aromatization stage of σ H -adducts.For the first time, ferrocenylcontaining heterocyclic N-oxides 4 were synthesized.Such a type of compounds were not known before.However, it should be recognized that for the synthesis of azinylferrocenes it is necessary to use coupling of ferrocenyllithium and heterocycles, 13 since we failed to increase yields of the compounds 5 previously synthesized, as we planned at the beginning of our research.

Experimental Section
General Procedures.Solvents were purified according to standard procedures.The course of the reactions was monitored and the purity of the reaction products was checked by TLC on Polygram Alox N/UV-254 plates.Column chromatography was performed on Sigma-Aldrich neutral aluminum oxide (activated, neutral, Brockmann I, STD grade, approx.150 mesh, 58 Å).

Synthesis of N-oxido-azinylferrocenes 4a-e and 4j.
To the previously obtained suspension of 3, a solution of DDQ (220 mg, 1.0 mmol) in THF (5 mL) was added, and the mixture was stirred for 15 min.Finally, the reaction mixture was filtered through neutral alumina and subjected to alumina column chromatography to give a mixture of bromoferrocene and ferrocene (hexane as the eluent), and the reaction product (Et 2 O or EtOAc, or a mixture of n-hexane and EtOAc as the eluent) as a slowly eluting compound.The eluate was concentrated to dryness in vacuo and the residue was recrystallized from an appropriate solvent.
At the first step the nucleophilic reagent 1 forms a σ H -adduct 3-OLi with aza-heterocyclic N-oxide 2, at the second stage the aromatization of intermediates 3-OH or 3-OAc to S N H products 4 or 5 takes place.There are two possible ways for the aromatization stage.The oxidation of S N H (AO) intermediate 3-OH (Scheme 1) predominantly results in the reaction products 4 with the retention of N-oxide function during the aromatization process.We used DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) (PATHWAY 1, method 1) or atmospheric oxygen (PATHWAY 1, method 2) as oxidants.In this case a mixture of products 4 and 5 is formed.Deoxygenative aromatization (PATHWAY 2) is realized according to the addition-elimination S N H (AE) scheme, and compounds 5 without N-oxide function can be obtained.

Table 1 .
Yields of compounds 4a-e and 4j

Oxido-phthalazin-1-yl)-ferrocene (4e). Yield
22eld 214 mg (65%), dark purple powder, mp 185 °C (n-hexane: benzene, 8: 2).R f = 0.45 (eluent Et 2 O).To the previously obtained of 3 0.08 mL (1.0 mmol) of acetic anhydride was added, and the mixture was stirred for 15 min.Then solvent was removed under reduced pressure and the oily residue subjected to alumina column chromatography to obtain a mixture of bromoferrocene and ferrocene (hexane as the eluent) and the reaction product (Et 2 O or EtOAc, or a mixture of n-hexane and EtOAc as the eluent) as a slow eluting compound.The suitable crystals of compound 4a were obtained by slow crystallization from benzene at room temperature.The crystallographic data were collected with an Xcalibur 3 CCD diffractometer.The relevant crystallographic data and structure refinement are given in Table4.The structure was solved21by direct methods and refined22by anisotropic full-matrix least-squares technique.Perspective view and the numbering of the atoms are depicted in Figure1.The hydrogen atoms were refined isotropically in idealized positions riding on the atom to which they are attached.Atomic coordinates, bond lengths, bond angles and thermal parameters were set at Cambridge Crystallographic Data Centre (CCDC), deposition number 720051.These data can be obtained free of charge on www.ccdc.cam.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, England; fax: +44 1223 335 033; or deposit@ccdc.cam.ac.uk).Any request to the CCDC should contain full literature quotation and CCDC reference numbers.

Table 4 .
Crystal and experimental data for compound 4a