Synthesis of the Novel 4 , 4 ’-and 6 , 6 ’-Dihydroxamic-2 , 2 ’-Bipyridines and Improved Routes to 4 , 4 ’-and 6 , 6 ’-Substituted 2 , 2 ’-Bipyridines and MonoN-Oxide-2 , 2 ’-Bipyridine

Neste trabalho relatamos a preparação, por métodos mais eficientes e práticos, de derivados da 2,2’-bipiridina, que são importantes precursores para outros, tais como: 4,4’-dicarbóxi-2,2’-bipiridina (I), 6,6’-dicarbóxi-2,2’-bipiridina (II), 6,6’-dicarbotiamida 2,2’-bipiridina (III), 4,4’-dinitroN,N’-dióxido-2,2’-bipiridina (IV) e mono-N-óxido-2,2’-bipiridina (VII). A síntese dos ligantes inéditos 4,4’-diácido hidroxâmico-2,2’-bipiridina (V) e 6,6’-diácido hidroxâmico-2,2’-bipiridina (VI) é também relatada.


Introduction
2,2'-Bipyridinyls continue to attract attention as important ligands of great interest for chelation of transition metals 1 due to their ability to form very stable complexes with many cations and to their remarkable anti-tumoral [2][3][4][5] , catalytic 6 , electrocatalytic 7,8 and photochemical 9 properties.Nevertheless, the methods available for the synthesis of new or even well-known symmetrical and unsymmetrical derivatives of 2,2'-bipyridines are usually not practical, and present low yields.2,2'-Bipyridinyls can be prepared by three principal routes: i) from the cyclization of appropriately substituted precursors 10a,b ; ii) by coupling reactions of pyridines 10c,11 , iii) from the functionalization of the heteroaromatic ring of 2,2'-bipyridine through electrophilic and nucleophilic aromatic substitution reactions.
We have also been studying new derivatives of 6,6'-dicarbothioamide-2,2'-bipyridine (IV) which have shown anti-tumoral activity 4,5 , as well as their metal complexes (with Fe(II)).We are studying the complexation with other metals such as Fe(III), Ni(II), Ru(II), Pd(II) and Pt(II).It is noteworthy that in the last step of a previously reported synthesis 3,4 of IV, the conversion of the 6,6-dicyano-2,2'bipyridine XIII to the dithiocarbamide IV is very complicated (48 h, using liquid ammonia and gaseous H2S) and with only moderate yield (65%yield).We have devised a much easier and faster method 17 using thioacetamide with HCl on a steam bath for 30 min (71% yield) (Scheme 4).The 4,4'-dihydroxamic-2,2'-bipyridine (V) and 6,6'dihydroxamic-2,2'-bipyridine (VI) were prepared starting from their carboxylic acid analogues, I and II prepared as mentioned before, going through the diacyl dichloride (formed with SOCl2) and followed by direct reaction with hydroxylamine hydrochloride in the presence of dried triethylamine 18 (Schemes 5 and 6).The IR spectrum shows the characteristic bands of the hydroxamic group (C=ON-HOH) and the 1 H-and 13 C-NMR spectra showed the occurrence of (E-Z) isomerism in accordance with the studies of Brown and co-workers 19 .
The mono-N-oxide-2,2'-bipyridine (VII) is the main precursor for the synthesis of unsymmetrical mono-substituted 2,2'-bipyridines due to the higher reactivity of the mono-N-oxide ring.The synthesis of unsymmetrical bypiridines has received attention, even recently 20 , due to their potential as precursors of unsymmmetrical heterocycles.Nevertheless, the mono-N-oxide VII is usually made using peracetic acid prepared in situ (3 h, 49% yield) 5 , or by using meta-chloro perbenzoic acid (MCPBA) (15h, 79%) 21 .We prepared the mono-N-oxide VII in 80% yield using a new, and more selective oxidant named magnesium monoperoxyphthalate (MMPP) (XIV), in glacial acetic acid for 6 h at 85 °C (Scheme 7).Oxidations with MMPP + -  afford N-oxides, sulfoxides and epoxides in good yields using mild conditions.

Experimental
Melting points were determined on a Mettler apparatus and were uncorrected. 1H-and 13 C-NMR spectra were recorded on an AC-80 (80 MHz) Bruker instrument.FT-IR spectra were recorded on a Mattson instrument model Galaxy 3000.The microanalysis were performed on a Perkin-Elmer 240B elemental analyser.

4,4'-Dicarboxy-2,2'-bipyridine (I)
To a solution of 3.14 g (9.7 mmol) of Na2Cr2O7 in 10.6 mL of concentrated sulfuric acid, was slowly added, under magnetic stirring, 0.80 g (4.3 mmol) of 4,4'-dimethyl-2,2'bipyridine (VII).The resultant orange slurry became dark green after a while and reaction was complete after 30 min.The reaction mixture was then poured into 100 mL of cold water forming a light yellow precipitate.After filtration and drying, the solid was dissolved in an alkaline 10% NaOH aqueous solution followed by slow acidification (pH = 2) with 10% aqueous HCl solution.This recrystallization afforded the desired compound free of Cr(+3) ions.After a second filtration compound I was dried under vacuum (P2 O5 as drying agent) to provide a white solid (0.90 g, 85 %) with m.p. > 300 °C.All spectroscopic and physical data were in full agreement with those obtained for a commercial sample.

4,4'-Dihydroxamic-2,2'-bipyridine (V)
a) Preparation of 2,2'-bipyridine-4.4'-dicarboxylicacid dichloride:To 0.86 g (3.5 mmol) of 4,4'-dicarboxy-2,2'bipyridine (I) was added 9.0 mL (124 mmol) of thionyl chloride (SOCl2), under magnetic stirring .The mixture was heated for 3 h under reflux.After cooling the solution was evaporated in the presence of anhydrous benzene (30 mL) for total elimination of SOCl2 and the crude dichloride was directly submitted to the following reaction: b) A solution of 0.58 g (8.4 mmol) of hydroxylamine hydrochloride and 2.3 mL of triethylamine (16.8 mmol) in 7.0 mL of chloroform was added to a 25 mL round bottom flask equipped with a magnetic stirrer, dropping funnel and reflux condenser containing the crude acid dichloride in 7 mL of dry chloroform.The mixture was stirred for 48 h at room temperature and after filtration and drying 0.82 g (86%) of a light brown solid was obtained with m.p. = 202-204 °C.

Mono-N-oxide-2,2'-bipyridine (VII)
To a solution of 1.0 g (6.4 mmol) of 2,2'-bipyridine (XI) in 10 mL of glacial acetic acid, in a round bottom flask equipped with magnetic stirrer and reflux condenser, was slowly added 0.80 g (1.6 mmol) of magnesium monoperphtalate (MMPP).After 6 h of heating at 80 °C, the solution was cooled and evaporated in a desiccator, with sodium hydroxide, under vacuum.Then the mixture was dissolved in chloroform (20 mL) and washed with a 5% sodium bicarbonate aqueous solution.The organic phase was then dried with anhydrous magnesium sulfate, filtered and evaporated to afford 0.88 g (80%) of a gray solid, m.p. = 56-58 °C (Lit 4 m.p. = 57-58 °C); IR (KBr, cm