Synthesis of (Nitroaryl)chloromethanes via Vicarious Nucleophilic Substitution of Hydrogen

Mąkosza, Mieczysław; Bialecki, M.

doi:10.1055/s-1991-21979

Cited by 16 publications

(7 citation statements)

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“…A much more convenient method of introduction of chloromethyl substituent seems to be the VNS reaction of nitroheteroarenes with tert -butyl dichloroacetate , followed by one-pot hydrolysis−decarboxylation of the produced tert -butyl α -chloro(nitroaryl)acetate (Scheme 29) …”

Section: 3 Functionalized Alkyl Substituents331 α-Haloalkyl Substituentsmentioning

confidence: 99%

Nucleophilic Substitution of Hydrogen in Heterocyclic Chemistry

2004

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Section: 3 Functionalized Alkyl Substituents331 α-Haloalkyl Substituentsmentioning

confidence: 99%

Nucleophilic Substitution of Hydrogen in Heterocyclic Chemistry

2004

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“…The general synthetic plan follows from the route previously described, 15 i.e., displacement of the leaving group from a nitro(halomethyl)heterocycle with N-methyldiethanolamine, and conversion of the resulting quaternary salt diol to the mustard using SOCl 2 . In several cases the required (chloromethyl)-or (bromomethyl)heterocycles were known compounds: 5-(chloromethyl)-1-methyl-4-nitroimidazole 20 for the synthesis of 2, 2-(chloromethyl)-5-nitrothiophene 21 for the synthesis of 4, and 2-(bromomethyl)-3-nitrothiophene 22 for the synthesis of 7. In two other cases the (chloromethyl)- heterocycles were readily obtained from the corresponding aldehyde or acid: 1-methyl-5-nitropyrrole-2-carboxaldehyde 23 and 1-methyl-5-nitropyrazole-4-carboxylic acid 24 were each reduced to the hydroxymethyl analogues (NaBH 4 25 or BH 3 ‚DMS) and then converted to the chlorides with MsCl/Et 3 N, thus leading to the preparation of 3 and 5, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Mass spectra were obtained on a Varian VG 7070 mass spectrometer at nominal 5000 resolution. 20 (1.22 g, 6.9 mmol) and N-methyldiethanolamine (1.24 g, 10.4 mmol) in CH3CN (40 mL) was stirred at reflux for 18 h and then cooled to 20 °C and the supernatant decanted. The oily residue was crystallized from EtOH/Et2O to give N,N-bis(2-hydroxyethyl)-N-methyl-N-[(1methyl-4-nitro-5-imidazolyl)methyl]ammonium chloride as a cream solid (1.51 g, 74%): mp 177-178 °C; 1 H NMR [(CD3)2-SO] δ 8.13 (s, 1 H, H-2), 5.59 (t, J ) 4.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia-Selective Antitumor Agents. 16. Nitroarylmethyl Quaternary Salts as Bioreductive Prodrugs of the Alkylating Agent Mechlorethamine

et al. 2001

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Nitrobenzyl quaternary salts of nitrogen mustards have been previously reported as hypoxia-selective cytotoxins. In this paper we describe the synthesis and evaluation of a series of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of one-electron reduction potentials (from -277 to -511 mV) and substitution patterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, and all were more toxic under hypoxic than aerobic conditions, although the differentials were highly variable within the series. The most promising analogue, imidazole 2, demonstrated DNA cross-linking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecific nitrogen mustard release, and this has restricted further development of these compounds as hypoxia-selective cytotoxins.

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“…Pritzkow showed that 1,3dinitrobenzene reacts with 4-nitrobenzyl chloride in the presence of tBuOK to provide 2,4-dinitro-1-(4-nitrobenzyl)benzene. 9 Makosza and co-workers reported the synthesis of nitrobenzyl chlorides from nitrobenzenes and tert-butyl dichloroacetate in three steps (VNS, hydrolysis, and decarboxylation) 10 and VNS reaction of nitrobenzenes with diarylmethyl p-chlorophenyl sulfide (where p-chlorothiophenolate served as the leaving group). 11 The key nucleophilic reagent for direct VNS chloromethylation used in this study is dichloromethyllithium prepared by deprotonation of dichloromethane with n-butyllithium at a low temperature (approximately −100 °C) (Scheme 1B).…”

mentioning

confidence: 99%

“…Pritzkow showed that 1,3-dinitrobenzene reacts with 4-nitrobenzyl chloride in the presence of t BuOK to provide 2,4-dinitro-1-(4-nitrobenzyl)benzene . Makosza and co-workers reported the synthesis of nitrobenzyl chlorides from nitrobenzenes and tert -butyl dichloroacetate in three steps (VNS, hydrolysis, and decarboxylation) and VNS reaction of nitrobenzenes with diarylmethyl p -chlorophenyl sulfide (where p -chlorothiophenolate served as the leaving group) …”

mentioning

confidence: 99%