Formylpyridines

In a synthesis of 2,3-di(hetero)arylpyrido[3,2 [l,4]thiazepines developed by Couture, 2-chloro-3-formylpyridine is reacted with arylmethylamines to form the imines. Deprotonation with LDA at -78 °C followed by treatment with non enolisable aryl thioesters gives the title compounds which may be further annulated by irradiation in benzene in the presence of iodine and propylene oxide <96S986> (Scheme 14). 

Bis(thiosemicarbazones) [89-97] and AT-heterocyclic thiosemicarbazones comprise two interesting series of experimental chemotherapeutic agents. 2-formylpyridine thiosemicarbazone, the first of the latter series to be examined for biological activity, showed mild antileukemic activity against 1-1210 tumor in mice [98]. However, it was found to be toxic at the therapeutic dose levels which led to synthesis of other aromatic and heterocyclic thiosemicarbazones as potential agents [80, 99, 100]. However, the only active anticancer compounds besides glyoxal bis(thiosemicarbazones) were the iV-heterocyclic thiosemicarbazones [101], 2 formyl-3-hydroxypyridine thiosemicarbazone [102] and... 

The E and Z isomers of 2-formylpyridine thiosemicarbazone, 5a, and 5b, respectively [123], as well as those of other heterocyclic thiosemicarbazones [124], have been separated and characterized. The difierentiation of stereochem-... 

Some early studies [126] on the S-methyldithiocarbazate of 2-formylpyridine, 6, showed it to form low spin iron(III) species, [Fe(6-H)2]C104 and [Fe(6-H)2] [FeCm. The Mossbauer spectrum of the latter showed the presence of two different iron centers, and the compound was a 1 1 electrolyte in nitromethane. 

There have been no reports of complexes of " JV-substituted thiosemicarbazones derived from 2-formylpyridine, but 2-acetylpyridine JV-methyl-thiosemicarbazone, 3a, formed [Fe(3a-H)2]C104 and [Fe(3a-H)2]FeCl4 [117]. The nature of these two species was established by partial elemental analyses, molar conductivities, magnetic moments, electronic, infrared, mass and electron spin resonance spectra. A crystal structure of a related selenosemicarbazone complex confirmed the presence of a distorted octahedral iron(III) cation coordinated by two deprotonated anions so that each ligand is essentially planar and the azomethine nitrogens are trans to each other the pyridyl nitrogen and selenium donors are both cis. 

While iron(III) complexes of thiosemicarbazones with different functional groups involving have been prepared from 2-acetylpyridine, substitution on the ring has been more popular with thiosemicarbazones derived from 2-formylpyridine. The only thiosemicarbazones in which the 2-acetylpyridine ring has been substituted are 15a and 15b, prepared from 6-methyl-2-acetyl-pyridine [120]. Both of these iron(III) complexes have rhombic spectra and values of g, are similar to those found for the 2-acetylpyridine thiosemicarbazones. Solution studies have been carried out on the iron(III) complex of 2,6-diacetylpyridine mono-thiosemicarbazone, but the solid complex was not isolated [143]. 

Iron(II) complexes are often included in studies when complexes are prepared from a large number of different metal ions. 2-formylpyridine thiosemicarbazone, 5, forms brown [Fe(5)2A2] (A = Cl, Br) when prepared in ethanol and [Fe(5-H)2] from aqueous alcohol solution [156], All of these complexes are diamagnetic. The resonance Raman and infrared spectra of [Fe(5-H)2] were examined in detail [130] and coordination occurs via the pyridyl nitrogen, azomethine nitrogen and thiol sulfur. There is appreciable d-d sulfur-to-iron(II) Jt-bonding. Solution studies of iron(II) complexes of some 5-substituted-2-formylpyridine thiosemicarbazones have been reported [157], but no solids... 

In aqueous solution the formation constants of Cu(5-H)", (5 is 2-formylpyridine thiosemicarbazone) have been studied in relation to the possible reaction of this ion with biological systems [166]. A pre-resonance Raman spectral study of... 

Early studies [170] of copper(II) complexes of thiosemicarbazones were 2-formylpyridine iV-methylthiosemicarbazone, 30, 6-methyl-2-formylpyridine Ai-methylthiosemicarbazone, 31, and 2-formylpyridine " JV-dimethylthiosemi-carbazone, 32. With copper(II) chloride and bromide, monomeric complexes of stoichiometry [Cu(L)A2] were isolated for each of these thiosemicarbazones. All six complexes had a band in the 14000-15000 cm spectral region, but their stereochemistry was not specified. 

Two copper(II) complexes of 2-acetylpyridine thiosemicarbazone, 8, were included in a study of complexes of 2-formylpyridine thiosemicarbazone [169]. [Cu(8-H)OAc] has a magnetic moment consistent with a monomeric copperfll) center and both it and [Cu(8)Cl2] have d,2-y2 ground state ESR spectra (Table 2). A d-d envelope and a magnetic moment of 1.68 B.M. have led others [178] to propose a distorted tetrahedral environment with metal-metal interaction for the brown complex, [Cu(8)Cl2]. 

A warmed alcoholic solution of cobalt(Il) nitrate and 2-formylpyridine S-methyldithiocarbazate, 6, yielded diamagnetic [Co(6-H)2]N03 [126]. However, cobalt(II) chloride, bromide and thiocyanate yielded complexes with cobalt(III) cations and cobalt(II) anions, [Co(9-H)2]2 [C0A4]. 

Although coordination of the heterocyclic nitrogen does not occur, two cobalt(II) complexes of 3-hydroxy-5-hydroxymethyl-2-methyl-4-formylpyridine have been isolated with stereochemistry [Co(34-H)A] 2H2O (A = NO3, OAc) [173], For both complexes coordination is ONS (deprotonated phenolic oxygen), but magnetic or electronic spectral data are not included. 

Both 2-formylpyridine and 6-methyl-2-formylpyridine N-methylthiosemi-carbazones, 30 and 31, respectively, form high spin NiLAj (A = Cl, Br, NCS) and [Ni(L)2]A2 (A = CIO4, NO3) [170]. The former complexes are 5- or 6-coordinate with bridging halogen or psuedohalogen ligands while the latter are octahedral with NNS coordination. 

With 2-formylpyridine S-methyldithiocarbazate, planar, diamagnetic nickel(II) complexes with stoichiometry [Ni(6-H)A], where A = Cl, Br, I, and NCS, have been isolated [126]. Also, paramagnetic, octahedral [Ni(6-H)2] has been prepared and spectrally characterized. These complexes have NNS coordination as does the related S-benzyldithiocarbazate, 24, in [Ni(31-H)A], A = Cl, Br [165]. 

Recently mononuclear ruthenium(II) and binuclear ruthenium(III) complexes of 5 and its iV-phenyl derivative have been isolated [214], Although many of the complexes were not soluble in the culture medium, both ruthenium(II) and ruthenium(III) complexes showed considerably more activity against E. coli than the uncomplexed thiosemicarbazones. Similar results were found for the oxovanadium(IV) complexes of the same ligands [VO(L)2Br]Br, where L is the deprotonated 2-formylpyridine N-phenylthiosemicarbazone, was the most potent inhibitory activity [215]. 

Several other organic and inorganic reaction intermediates have been studied using NMR methods. Trahanovsky et al. [12] reported a series of experiments in which they studied unstable molecules, such as benzocyclobutadiene, using flow NMR. Tan and Cocivera [13, 14] studied the reaction of 4-formylpyridine with amino acids, imidazole and D,L-alanylglycine using stopped-flow proton NMR. 

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