Mucochloric Acid Research Articles

Further Utilization of Mucohalic Acids: Palladium‐Free, Regioselective Etherification and Amination of α,β‐Dihalo γ‐Methoxycarbonyloxy and γ‐Acetoxy Butenolides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Further Utilization of Mucohalic Acids: Palladium-Free, Regioselective Etherification and Amination of α,β-Dihalo γ-Methoxycarbonyloxy and γ-Acetoxy Butenolides

Palladium-free etherification and amination of mucohalic acid methyl carbonates 1e (3,4-dichloro-5-methoxycarbonyloxy-5H-furan-2-one) and 1f (3,4-dibromo-5-methoxycarbonyloxy-5H-furan-2-one) and mucochloric acid acetate 1h (3,4-dichloro-5-acetoxy-5H-furan-2-one) was achieved to afford gamma-functionalized alpha,beta-unsaturated gamma-butyrolactones in good to excellent yield. [reaction: see text]

Metal‐Mediated Allylation of Mucohalic Acids: Facile Formation of γ‐Allylic α,β‐Unsaturated γ‐Butyrolactones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Metal-mediated allylation of mucohalic acids: facile formation of γ-allylic α,β-unsaturated γ-butyrolactones

Mucohalic acids {mucochloric acid ( 1 , 3,4-dichloro-5-hydroxy-5 H-furan-2-one and mucobromic acid ( 2 , 3,4-dibromo-5-hydroxy-5 H-furan-2-one)} were employed as aldehydes in the indium- and tin-mediated Barbier-type allylation reactions and afforded γ-allylic α,β-unsaturated γ-butyrolactones in good to excellent yield.

First Direct Reductive Amination of Mucochloric Acid: A Simple and Efficient Method for Preparing Highly Functionalized α,β‐Unsaturated γ‐Butyrolactams.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Mucochloric Acid: A Useful Synthon for the Selective Synthesis of 4‐Aryl‐3‐chloro‐2(5H)‐furanones, (Z)‐4‐Aryl‐5‐[1‐(aryl)methylidene]‐3‐chloro‐2(5H)‐furanones and 3,4‐Diaryl‐2(5H)‐furanones

Abstract3,4‐Dichloro‐2(5H)‐furanone, which has been prepared efficiently from mucochloric acid, has been transformed selectively into 4‐aryl‐3‐chloro‐2(5H)‐furanones either by Suzuki‐ or Stille‐type reactions. These monochloro derivatives have been used as precursors either to (Z)‐4‐aryl‐5‐[1‐(aryl)methylidene]‐3‐chloro‐2(5H)‐furanones, including naturally occurring rubrolide M, or to unsymmetrical 3,4‐diaryl‐2(5H)‐furanones. Some 2(5H)‐furanone derivatives so prepared have been found to exhibit significant cytotoxic activity in vitro against the NCI three‐cell‐line panel, but limited cytotoxicity against the NCI human tumor 60 cell‐line panel. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Reinvestigation of Mucohalic Acids, Versatile and Useful Building Blocks for Highly Functionalized α,β‐Unsaturated γ‐Butyrolactones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

First direct reductive amination of mucochloric acid: a simple and efficient method for preparing highly functionalized alpha,beta-unsaturated gamma-butyrolactams.

[reaction: see text] The first direct reductive amination of mucochloric acid (1) has been accomplished. Reaction of 1 with various alkyl, aryl, and benzylamines, followed by reduction in the same pot, provides an efficient method of obtaining N-benzyl-3,4-dichloro-1,5-dihydro-pyrrol-2-one and N-aryl (or alkyl)-3,4-dichloro-1,5-dihydro-pyrrol-2-ones.

Reinvestigation of mucohalic acids, versatile and useful building blocks for highly functionalized alpha,beta-unsaturated gamma-butyrolactones.

[reaction: see text] Mucohalic acids (mucochloric acid (1, 3,4-dichloro-5-hydroxy-5H-furan-2-one) and mucobromic acid (2, 3,4-dibromo-5-hydroxy-5H-furan-2-one)) are inexpensive, commercially available starting materials with multiple functional groups. These compounds have been modified by way of reduction followed by Suzuki cross-coupling reactions involving arylboronic acids to afford highly functionalized alpha,beta-unsaturated gamma-butyrolactones in excellent yield. The synthetic utility of these building blocks was effectively demonstrated through preparation of the antiinflammatory drug Vioxx.

EFFICIENT SYNTHESIS OF A NEW PYRIMIDINE DERIVATIVE

ABSTRACT A ready preparation for a new pyrimidine derivative, 2-aminomethyl-5-chloropyrimidine, from s-methylthiouronium sulphate and mucochloric acid is reported.

The drinking water chlorination by-products 3,4-dichloro-5-hydroxy-2[5H]-furanone(mucochloric acid) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone do not induce preneoplastic or neoplastic intestinal lesions in F344 rats, balb/ca mice or C57bl/6J-min mice.

Epidemiological studies indicate an association between exposure to chlorinated drinking water and risk of intestinal cancer. In order to study this experimentally, we have examined the effects of 3,4-dichloro-5-hydroxy-2[5H]-furanone (mucochloric acid, MCA) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), mutagenic and genotoxic compounds in drinking water, on aberrant crypt foci and tumours in the intestines of male F344 rats and Balb/cA mice, and C57BL/6J-Min (multiple intestinal neoplasia)/+ mice of both sexes, in six independent experiments. In some experiments the effects of MCA and MX on aberrant crypt foci induced by the colon carcinogens 1,2-dimethylhydrazine or its metabolite azoxymethane were also studied. Neither MCA nor MX alone induced aberrant crypt foci or intestinal tumours when given in drinking water. With this route of exposure neither MCA nor MX, when given in combination with 1,2-dimethylhydrazine or azoxymethane, had any effect on the induction or growth of the aberrant crypt foci. Drinking water exposure of MX did not affect the number or growth of aberrant crypt foci or intestinal tumours in the Minl+ mice. When administered intrarectally MCA had a weak inducing effect on aberrant crypt foci in the colons of Balb/cA mice. Exposure to MCA and MX intrarectally apparently promoted the growth of aberrant crypt foci both in rats and mice, increasing the crypt multiplicity, aberrant crypts/aberrant crypt foci. Based on an overall evaluation of these experiments, the intestinal tract, at least in rats and mice, seems not to be a main target organ for effects of MCA or MX on preneoplastic or neoplastic development.

Arbuzov Reaction in the Series of Halogenocyclenes: New Synthetical and Mechanistical Variants

A new method of synthesis of phosphorylated furanones on the basis of tricoordinated phosphorus derivatives reaction with mucochloric acid and some of its derivatives is elaborated. The kinetic investigation of the reaction of phosphites (1, R = Me, Et, Pr, Bu, Ph) with mucochloric acid allowed to establish the reaction mechanism including competitive elimination of RCl or HCl from the obtaining intermediate. The ratio of these two possible reaction ways depends on the nature of substituents at phosphorus.

Arbuzov Reaction in the Series of Halogenocyclenes: New Synthetical and Mechanistical Variants

A new method of synthesis of phosphorylated furanones on the basis of tricoordinated phosphorus derivatives reaction with mucochloric acid and some of its derivatives is elaborated. The kinetic investigation of the reaction of phosphites (1, R = Me, Et, Pr, Bu, Ph) with mucochloric acid allowed to establish the reaction mechanism including competitive elimination of RCl or HCl from the obtaining intermediate. The ratio of these two possible reaction ways depends on the nature of substituents at phosphorus.

Formation of oxalo-substituted etheno derivatives in reactions of mucochloric acid with adenosine, guanosine and cytidine

Treatment of the nucleosides adenosine, guanosine and cytidine with mucochloric acid in slightly acid aqueous solutions at 37 °C affords oxalo-substituted etheno derivatives of nucleosides (2a, 3a and 4a). The derivatives are structurally characterised by UV, 1H and 13C NMR spectroscopy and mass spectrometry. In addition, all the long-range 1H–13C couplings are assigned in the base moieties of the products. A plausible mechanism is presented for the formation of the products.

Pyridazines. XV. Synthesis of 6‐aryl‐5‐amino‐3(2H)‐pyridazinones as potential platelet aggregation inhibitors

AbstractSeveral 3(2H)‐pyridazinones with amino groups at the 5‐position of the pyridazine nucleus have been prepared. The 6‐aryl‐5‐halo‐3(2H)‐pyridazinones obtained from mucochloric and mucobromic acid lead to the corresponding 5‐alkylamino‐3(2H)‐pyridazinones, which were tested as platelet aggregation inhibitors.

Einige ungewöhnliche Umsetzungen des Dinatrium-2-oxo-1,3-dithiol-4,5-dithiolats mit Biselektrophilen

Some Unusual Reactions of Disodium 2-Oxo-1,3-dithiole-4,5-dithiolates with Biselectrophiles Reaction of disodium 2-oxo-1,3-dithiole-4,5-dithiolate (3) with dichloro-maleic anhydride (4), Mucobromic acid (7) and its pseudoester 9 leads to the formation of the 1,3-dithiolo[4,5-b]-1,4-dithiins 6, 8 and 10. 3 condenses with cis-3,5-dibromo-cyclopentene (15) to yield the tricyclic compounds 16 and 17. 3 is silylated by trimethylsilyltriflate (19) to give the unstable bis(trimethylsilyl)-thioether 20 which reacts with aldehydes and ketones to furnish the 1,3-dithiolo[4,5-d]-1,3-dithiole-2-ones 22a–c.

Kinetic Investigation of Unusual Arbuzov Reaction

Abstract 3,4-Dichloro-5-hydroxyy-2(5H)furanone (mucochloric acid) (I), which may exist in two (cyclic and acyclic) forms, reacts with trialkylphosphites under mild conditions to form two products, one and the most interesting of which is (II). Kinetic study if this process has shown the following reaction mechanism which is an unusual Arbuzov reaction with the elimination of HCl (but not RCl) from the intermediate (A):

Reaction of mucochloric and mucobromic acids with adenosine and cytidine: formation of chloro- and bromopropenal derivatives.

Mucochloric (MCA) and mucobromic acid (MBA)--bacterial mutagens and water disinfection byproducts--were reacted with adenosine, cytidine, and guanosine in N,N-dimethylformamide (DMF). In the MCA reaction with adenosine and cytidine and in the MBA reaction with adenosine one major product was formed. In the reactions of MBA with cytidine and in the reactions of MCA and MBA with guanosine only trace levels of products could be detected, and these were not further characterized. The products from the adenosine and cytidine reactions were isolated by preparative chromatography on octadecylsilane columns and structurally characterized by UV absorbance, 1H and 13C NMR spectroscopy, and mass spectrometry. The products were identified as 3-(N6-adenosinyl)-2-chloro-2-propenal (MClA), 3-(N6-adenosinyl)-2-bromo-2-propenal (MBrA), and 3-(N4-cytidinyl)-2-chloro-2-propenal (MClC). The yields of MClA, MBrA, and MClC were 19, 4 and 7 mol %, respectively. These halopropenal derivatives were formed also in reactions carried out in aqueous solutions at pH 7.4 and 37 degrees C at low yields, about 5 x 10(-3)%. The mechanism of formation of the halopropenal derivatives and of the previously identified etheno and ethenocarbaldehyde derivatives was elucidated by reacting 13C-3 labeled MCA with adenosine in DMF and in water. The location of the labeled carbon in the products was determined from the 13 C NMR spectra. It was concluded that the halopropenal derivatives were formed by mechanisms that differ completely from the one responsible for the formation of the propenal adducts (M1A and M1C) previously reported to be formed in reactions of malonaldehyde with adenosine and cytidine.

Identification of adducts formed in reaction of adenosine with 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone, a bacterial mutagen present in chloride disinfected drinking water.

3-Chloro-4-methyl-5-hydroxy-2(5h)-furanone, MCF, a genotoxic hydroxyfuranone present in chlorine disinfected drinking water, was reacted with adenosine, guanosine, and cytidine in aqueous solutions. HPLC analyses of the reaction mixtures showed that only in the reaction of MCF and adenosine clearly detectable products were formed. The two major products were isolated by C18 column chromatography and characterized by UV absorbance, 1H and 13C NMR spectroscopy, and mass spectrometry. The products were identified as 4-(N6-adenosinyl)-3-formyl-3-butenoic acid (I) and 5-(N6-adenosinyl)-3-chloro-4-methyl-2(5H)-furanone (II). The yield of I and II in reactions performed at pH 7.4 and 37 degrees C was 0/8% and 0/5%, respectively. Reaction of adenosine with 13C-3-labeled MCF was employed to elucidate the mechanism of formation of I. It was found that the product was formed by a nucleophilic attack of the exocyclic amino group in adenosine on the carbon in the 4-methyl group of MCF. These adducts appear to be novel and not structurally related to those previously identified in the reaction of adenosine with mucochloric acid, another genotoxic hydroxyfuranone.

ChemInform Abstract: Synthesis of Chlorinated 5‐Hydroxy‐4‐methyl‐2(5H)‐furanones and Mucochloric Acid.

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