Pyridine hydrazides

As far as synthetic agents were concerned, isoniazid (a pyridine hydrazide structure) was found to be effective against human tuberculosis in 1952, and in 1962 nalidixic acid (Fig. 10.74) (the first of the quinolone antibacterial agents) was discovered. A second generation of this class of drugs was introduced in 1987 with ciprofloxacin (Fig. 10.74). 

Curtius reaction, conversion of a pyridine hydrazide to a pyridine amide, 362 Cyanoacetamide, 602, 620 Cyanoacetic acid, 601 Cycloalkano-2-pyridones, preparation from 2- (2-cymo-ethyl) cycloalkanones, 729 a-Cyano-2-butenolc acids, 601... 

The conversion of esters to hydrazides and of hydrazides to the sulfonyl derivatives occurs in good yield in the McFadyen-Stevens synthesis, but the decomposition of sulfonyl derivatives gives low yields of the desired products, for example, thiazole hydrazide (28) with 10% excess of PhSOjCl in pyridine gave a 75% yield of l-phenylsulfonyl-2-(4-methyl-5-thiazo ecarbonyl)hydrazine (29) (66). The Newman-Caflish modification of the McFadyen-Stevens synthesis gave 37% 4-methyl-5-thiazole-carboxaldehyde (30) (Scheme 27). 

See also Isomcotimc hydrazide.) [PYRIDINE AND PYRIDINE DERIVATIVES] (Vol 20)... 

Acylation of pyridazinones and related compounds in the presence of weakly basic catalysts such as pyridine or sodium acetate produces IV-acylated products, while O-acylated products are obtained under strongly basic conditions. However, the reaction between 6-chloropyridazin-3(2//)-one with chlorocarbonates and that of maleic hydrazide with unsaturated acid chlorides or chloromethylsulfonyl chloride gives preferentially N-substituted products. 

Reactions involving quinoline hydrazide derivatives have been noted in the pyridazino-[4,3-c]- (64MI21500), -[4,5-f ]- (31M(58)238) and -[4,5-c]-quinoline (71CB3341) series, whilst the double cyclization of (358) to the pyridazino[4,5-f ]quinoline (359) (80CPB3457) and related cyclizations in the same series (80H(14)267) are of a basically similar type. A lone cyclization of this type from cinnoline intermediates involves the o-acetonylcarboxamide type formation of the pyridine ring to give the pyrido[3,4-c]cinnoline (360) (76JCS(Pl)592). 

In the other extreme, ethyl 3-oxohexanoate 75 required fusion with 3-pyridyl-hydrazide 73a or 3-hydrazinocarbonyl-pyridine-l-oxide 73b at 120°C in order to give the corresponding pyrazol-3-ones 76a,b (92AF1350) (Scheme 22). Depending on the reaction conditions, the reaction of ethyl 3-oxo-3-phenylpropanoate 77 and cyanomethylhydrazide 78 gave different products. Thus, fusion at 140°C gave pyrazol-3-one 79 and N,A -bis(cyanoacetyl)hydrazine 80, while heating in ethanol... 

Hydrazides of isonicotinic acid have been used as antidepressant agents by virtue of their monoamine oxidase-inhibiting activity the pyridine ring has been shown to be replaceable by an... 

Analogous reactions have been carried out with hydrazide ions (R2NNH A mixture of NO2 and O3, with excess NaHS03, converted pyridine to 3-aminopyri-dine. ° For other methods of aminating aromatic rings, see 11-6. 

Prostaglandins 195—197, 242 — 244, 273, 274,376, 411,413, 430, 438 Protocol form example 133 Prunasin 179,181 Psychopharmaceuticals 364 Purines 44, 266, 438, 439 Pyrazolidine derivatives 426 Pyrethroid insecticides 359 Pyridine alkaloids 66 4-Pyridinecarboxylic acid hydrazide reagent 318... 

Aryl hydrazide-based linker 79 was developed as a traceless handle that released products under mild oxidative conditions (Scheme 42) [91]. Polymeric bound p-iodophenylhydrazide was subjected to a variety of Pd°-catalyzed coupling reactions (Heck, Suzuki, Sonogashira, and Stille). Oxidation with Cu(OAc)2 in MeOH and pyridine released the final products in 50-96% yield. 

A series of mixed-ligand thiosalicylato complexes of the type PtL(PPh3)Y2] (Y2 = thiosalicylate L = pyridine, 4-methylpyridine, picolinic acid hydrazide, imidazole) have been prepared by the reaction of [PtCl2(COD)] with PPh3, thiosalicylic acid, and A-donor ligand in MeOH solution.375 The X-ray structure of the pyridine derivative (162) was determined, the first example of where a platinum atom is coordinated to a N, O, P, and S donor atom set. 

Numerous other complexes of beryllium with organic ligands such as alloxides (276-280), /6-diketonates (90, 281-297), SchifF bases (64, 298-301), thiols (302), pyridines (303), bipyridyl (304), phthalocya-nine (305), hydroxyquinolines (306, 307), tropolones (308, 309), pyra-zolylborates, (94, 310), phosphinates (311), hydrazides (312), phenyl-hydrazonocarboxylates (313), dinaphthofuchsonedicarboxylates (314),... 

A. t-Butyl hydrazodiformate. A solution of 28.6 g. (0.2 mole) of /-butyl azidoformate and 26.4 g. (0.2 mole) of /-butyl carba-zate in 60 ml. of pyridine (Note 1) is allowed to stand at room temperature for 1 week and is then diluted with 500 ml. of water. The snow-white microciystalline powder that separates is removed by filtration and is washed with two 50-ml. portions of water. The yield of air-dried hydrazide, m.p. 124-126°, is 35.5-37 g. (77-80%). i,The product is pure enough for most applications but may be purified by recrystallization from a 1 1 mixture of benzene and ligroin (60-90°) from which it separates as small white needles, m.p. 124—125.5°. The recovery is 92%. 

The reaction of 2-ethylthioxazolo[4,5- ]pyridine 279 with phenyl hydrazide and thiosemicarbazide gives compounds 280 which, after refluxing in DMF, afford the oxazolotriazoles 69 in good overall yields <2000SC3423> (Scheme 27). 

Closure of the triazole ring can be achieved either by oxidative formation of the N-N bond, or condensation of an fV-aminopyridone. The latter was formed by iV-amination of pyridines with mesitylhydroxylamine (MSH), or by forming the pyridine ring, starting from cyanoacetic hydrazide with malononitrile or 2-cyanoacrylates. 

Condensation of active methylene compounds with cyanoacetic hydrazide-derived hydrazones led to a one-pot formation of pyridine and triazole rings. 

By analogy with the conversion of 1,2-dialkylpyridinium salts into 2-alkylaminopyridines known as the Kost-Sagitullin rearrangement, the pyridinium salt 252 was treated with two different hydrazides (Equation 33). The [l,2,4]triazolo[4,3-tf]-pyridines 253 with Y = 4-pyridyl and NH2 were obtained with 35% and 38% yields, respectively <2003CHE275>. 

Metal-free initiators, 14 258-259 Metal fullerenes, 2 718-719 Metal-halogen exchange, in pyridine chemistry, 22 107-108 Metal hydrazides, 23 567 Metal hydrides, 23 611-613 amines by reduction, 2 493 hydrogen storage and, 23 851 nitriding, 27 206-207 storage of, 23 786... 

Bromonaphthalene has been reduced to naphthalene in good yield by hydrogenation over Raney nickel in methanolic potassium hydroxide, by triphenyltin hydride in benzene, by magnesium in isopropyl alcohol, by sodium hydrazide and hydrazine in ether, and by copper(I) acetate in pyridine. ... 

The first inhibitors of flavin-dependent MAO that were developed for clinical use were hydrazines and hydrazides. The chance discovery that the antitubercular drug, 4-pyridine carboxylic acid hydrazide (isoniazid, 40), was also a potent MAO inhibitor led to the development of the related drug, iproniazid (41), used for the treatment of depressive illness. Although this compound demonstrated remarkable antidepressant action, its clinical value was seriously compromised by side effects [19]. 

Methyl-3,3 -bipyridine has been oxidized by permanganate to 3,3 -bi-pyridine-4-carboxylic acid. " 3,3 -Bipyridine carboxylic acids are easily decarboxylated and have been esterified and converted to amides, hydrazides, and acylazides. The Hofmann degradation, of the diamide of 3,3 -bipyridine-2,2 -dicarboxylic acid affords the expected 2,2 -diamino-3,3 -bipyridine, but some of the tricyclic system 108 is formed as well. A 2,2 -bis(acylazide) is converted to a similar tricyclic system with ethanol via the intermediate isocyanate, and several related reactions have been described. The simultaneous dehydration... 

Pyridine reacts with sodium hydrazide in the presence of hydrazine to yield 2-hydrazinopyridine in the absence of free hydrazine a hydrazo compound is formed (Scheme 88) (64AG(E)342). A difference between hydrazination and amination is the formation of 1,4-adducts which cannot be rearomatized even on heating. This is reflected in the behaviour of quinoline, which gives only a 0.5% yield of a -hydrazino product, whereas 4-methylquino-line is hydrazinated in 76% yield (64AG(E)342). Acridine behaves differently with sodium hydrazide/hydrazine, 9,10-dihydroacridine is formed almost quantitatively, but reaction in the absence of hydrazine yields 9-aminoacridine (65%). An even higher yield of 9-amino-acridine is obtained when sodium Af.AC-dimethylhydrazide is used (Scheme 89). Good evidence for intermediacy of (151) comes from the isolation of (152) on hydrolysis of (151). 

In a rearrangement reaction, 2-hydroxy-2-phenyl-2-(3-pyridinyl)acetic hydrazide, 102, reacts with methanesulfonyl chloride to generate a mixture of pyrrolo[2,3-. ]pyridine derivatives (Equation 42) <1998JHG145>. The proposed mechanism for the rearrangement involves intramolecular attack of compound 102 on a reactive pyridinium intermediate formed during the reaction. 

Methode 2,65 g (11 mmol) 4-Chlorcarbonyl-3,5-dioxo-4-aza-tricyclo[5 2.1.02-6]dec-8-cn lost man in 20 ml THF und kiihlt auf 0° ab. Zu dieser Losung wird bei 0° miter Riihren ein Gcmisch aus 10 mmol Carbonsaure-hydrazid, 30-50 ml THF, 869 mg (11 mmol) Pyridin und 3,66 mg (0,03 mmol) 4-Dimethyl-amino-pyridin (DMAP) zugetropft. Danach riihrt man 1 h bei 0 und 3 b bei 20". Nach Eincngen der Reaktionsmischung versetzt man mit 30 ml Wasser, riihrt 10 min, saugt ab und kristallisiert aus Ethanol um. 

Bei dieser Reaktion konnen allerdings auch Kohlensaure-bis-hydrazide entstehen. So cyclisiert l-Amino-2-oxo-4,6-diphenyl-l,2-dihydro-pyridin mit Kohlensaure-bis-imidazolid zu 5,7-Di-phenyl-(pyridio[2,l-b]-l,3,4-oxadiazolium )-2-olat innvA 37%iger AusbeutelS0(vgl. S. 533, 535). AuBerdem wird 1,3-Bis-[4,6-diphenyl-2-oxo-l, 2-dihydro-pyrido -harnstoff (45%) gebildet. 

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