6957-05-7Relevant academic research and scientific papers
Oxidative metabolism of 1-(2-chloroethyl)-3-alkyl-3-(methylcarbamoyl)triazenes: Formation of chloroacetaldehyde and relevance to biological activity
Rouzer, Carol A.,Sabourin, Michelle,Skinner, Tricia L.,Thompson, Erin J.,Wood, Thomas O.,Chmurny, Gwendolyn N.,Klose, John R.,Roman, John M.,Smith Jr., Richard H.,Michejda, Christopher J.
, p. 172 - 178 (1996)
(Methylcarbamoyl)triazenes have been shown to be effective cancer chemotherapeutic agents in a number of biological systems. Because of their chemical stability, it is likely that their activity in vivo is the result of a metabolic activation process. Previous studies have shown that 1-(2-chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM) and 1-(2-chloroethyl)-3-benzyl-3-(methylcarbamoyl)triazene (CBzM) are metabolized by rat liver microsomes in the presence of NADPH to yield the ((hydroxymethyl)carbamoyl)triazene analogs of the parent compounds. The present studies show that both compounds are also oxidized at the chloroethyl substituent to yield chloroacetaldehyde and a substituted urea. In the case of CBzM metabolism, 47% of the metabolized parent compound was recovered as benzylmethylurea, 8% was recovered as benzylurea, and 26% was recovered as the ((hydroxymethyl)carbamoyl)-triazene and carbamoyltriazene metabolites. These results suggest that the chloroethyl group is the favored initial site of metabolism. In reaction mixtures containing intitial concentrations of 300 μM. CBzM, 78 μM chloroacetaldehyde was produced, as compared to 58 μM chloroacetaldehyde produced from the metabolism of 300 μM CMM. The formation of chloroacetaldehyde, a known mutagenic DNA alkylating agent, may explain the biological activity of these compounds.
Stabilization of the hindered urea bond through de-tert-butylation
Yang, Yingfeng,Ying, Hanze,Jia, Yunchao,Chen, Yingying,Cheng, Jianjun
, p. 3812 - 3815 (2021/04/21)
We report the discovery of an acid-assisted de-tert-butylation reaction that can instantly “turn off” the dynamicity of hindered urea bonds (HUBs) and thus broaden their applications. The reaction is demonstrated to be widely applicable to different hindered urea substrates, leading to improved chemical stabilities and mechanical properties of HUB-containing materials.
Formamides as Isocyanate Surrogates: A Mechanistically Driven Approach to the Development of Atom-Efficient, Selective Catalytic Syntheses of Ureas, Carbamates, and Heterocycles
Bruffaerts, Jeffrey,Von Wolff, Niklas,Diskin-Posner, Yael,Ben-David, Yehoshoa,Milstein, David
supporting information, p. 16486 - 16493 (2019/10/14)
Despite the hazardous nature of isocyanates, they remain key building blocks in bulk and fine chemical synthesis. By surrogating them with less potent and readily available formamide precursors, we herein demonstrate an alternative, mechanistic approach to selectively access a broad range of ureas, carbamates, and heterocycles via ruthenium-based pincer complex catalyzed acceptorless dehydrogenative coupling reactions. The design of these highly atom-efficient procedures was driven by the identification and characterization of the relevant organometallic complexes, uniquely exhibiting the trapping of an isocyanate intermediate. Density functional theory (DFT) calculations further contributed to shed light on the remarkably orchestrated chain of catalytic events, involving metal-ligand cooperation.
A synthetic N, N '-di-substituted ureas method
-
Paragraph 0165-0168, (2016/11/17)
The invention discloses a method for synthesizing N,N'-disubstituent urea. The method comprises the following steps: adding N-substituent urea, a metal iridium, rhodium or ruthenium complex catalyst, an alkali, a compound alcohol and a solvent (or no solvent) to a reaction container; reacting at 90-130 DEG C for a plurality of hours and cooling the reaction mixture to room temperature; carrying out rotary evaporation to remove the solvent, and then separating through a column, so as to obtain a target compound. Compared with the prior art, N,N'-disubstituent urea which is obtained by regional selective alkylation reaction between commercial or easily synthesized N-substituent urea and the alcohol reflects and displays three significant advantages: 1) the alcohol which is nearly non-toxic is utilized as an alkylating reagent; 2) just water is generated as a by-product in the reaction, and harm to environment is not generated; 3) reaction atom economy is high. Therefore, the reaction accords with the requirements of green chemistry, and has a broad development prospect.
Bromodimethylsulfonium bromide (BDMS)-mediated Lossen rearrangement: Synthesis of unsymmetrical ureas
Yadav, Deepak K.,Yadav, Arvind K.,Srivastava, Vishnu P.,Watal, Geeta,Yadav, Lal Dhar S.
experimental part, p. 2890 - 2893 (2012/07/27)
Bromodimethylsulfonium bromide (BDMS) was found to be a very efficient reagent for Lossen rearrangement of hydroxamic acids to the corresponding isocyanates which were subsequently trapped in situ with various amines to afford unsymmetrical ureas in good to excellent yields (64-89%). The protocol is experimentally simple, mild, and represents valuable alternative to the existing methods for in situ activation of hydroxamic acids promoting Lossen rearrangement.
Cyanuric chloride: an efficient reagent for the Lossen rearrangement
Hamon, Florian,Prié, Gildas,Lecornué, Frédéric,Papot, Sébastien
experimental part, p. 6800 - 6802 (2010/04/27)
An efficient method for the Lossen rearrangement that uses 2,4,6-trichloro-1,3,5-triazine (TCT) as a promoter is reported. This procedure allowed the preparation of various carbamates, thiocarbamates, and ureas in good yields directly from the correspondi
Preparation of mono-, di-, and trisubstituted ureas by carbonylation of aliphatic amines with S,S-dimethyl dithiocarbonate
Artuso, Emma,Degani, Iacopo,Fochi, Rita,Magistris, Claudio
, p. 3497 - 3506 (2008/09/19)
General procedures are reported to prepare N-alkylureas, N,N′-dialkylureas (both symmetrical and unsymmetrical), and N,N,N′-trialkylureas by carbonylation of aliphatic amines, employing S,S-dimethyl dithiocarbonate (DMDTC) as a phosgene substitute. All reactions were carried out in water. Symmetrical disubstituted ureas were prepared directly working at 60°C with a molar ratio of DMDTC:amine = 1:2, preferably under nitrogen. Unsymmetrical ureas were prepared in two steps via S-methyl N-alkyl-thiocarbamate intermediates, which are formed selectively in the first step at room temperature. These intermediates react in the second step with ammonia or various aliphatic amines, both primary and secondary, at temperatures varying between 50 and 70°C. All the target ureas were obtained in high yields (28 examples, average yield 94%) and with very high purity (generally >99.2%). Also to be noted is the recovery of a co-product of industrial interest, methanethiol, in an amount of two moles for each mole of DMDTC, with complete exploitation of the reagent. Georg Thieme Verlag Stuttgart.
Comparison of DNA lesions produced by tumor-inhibitory 1,2- bis(sulfonyl)hydrazines and chloroethylnitrosoureas
Penketh, Philip G.,Shyam, Krishnamurthy,Sartorelli, Alan C.
, p. 283 - 291 (2007/10/03)
1,2-Bis(sulfonyl)hydrazine derivatives, designed to generate several of the electrophilic species classically believed to be responsible for the alkylating (chloroethylating) and/or carbamoylating activities of the chloroethylnitrosoureas (CNUs), were compared with respect to the cross- linking and nicking of T7 DNA to that caused by 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1-(2-chloroethyl)-3-(4-trans-methylcyclohexyl)-1-nitrosourea (MeCCNU). In the case of BCNU, a large proportion of T7 DNA strand nicking was found to be due to the generation of 2-chloroethylamine, produced from the hydrolysis of 2- chloroethylisocyanate, in turn formed during the decomposition of the parental nitrosourea. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (compound 1) gave a greater yield of DNA cross-links than the CNUs. Compound 1, as well as its derivatives that were incapable of generating 2- chloroethylisocyanate, did not produce detectable levels of strand nicking, indicating that N7-alkylation of guanine did not occur to a significant extent with these agents. Since compound 1 and its derivatives are believed to generate chloronium and chloroethyldiazonium ions, it would appear that these species could not be significantly involved in the N7-alkylation of guanine caused by the CNUs. The relatively low level of N7-alkylation of guanine residues and the relatively high yield of cross-links generated by some of the 1,2-bis(sulfonyl)-1-(2-chloroethyl)hydrazine derivatives implies that they are more exclusive O6-guanine chloroethylating agents than the CNUs. O6-Guanine chloroethylation is believed to be the therapeutically relevant event produced by the CNUs; therefore, compound 1 derivatives represent promising new cancer chemotherapeutic agents, since they appear to generate lower quantities of therapeutically unimportant, yet carcinogenic lesions, and more of the therapeutically relevant O6-guanine chloroethylation than the CNUs.
A novel synthesis of disubstituted ureas using titanium(IV) isopropoxide and sodium borohydride
Armstrong III, Joseph D.,Wolfe, Chad N.,Keller, Jennifer L.,Lynch, Joseph,Bhupathy,Volante,De Vita, Robert J.
, p. 1531 - 1532 (2007/10/03)
This paper describes a high yield preparation of unsymmetrically disubstituted ureas by a titanium(IV) isopropoxide/sodium borohydride mediated reductive amidation of aromatic aldehydes with monosubstituted ureas.
1,3-Dialkyl-3-acyltriazenes: Products and Rates of Decomposition in Acidic and Neutral Solutions
Smith, Richard H.,Wladkowski, Brian D.,Herling, Julie A.,Pfalzgraff, Timothy D.,Pruski, Brunon,et al.
, p. 654 - 661 (2007/10/02)
The products and mechanism of hydrolytic decomposition of a series of 1,,3-dialkyl-3-acyltriazenes were studied in both acidic and neutral buffers.In the acidic region, the products are alkyl alcohols derived from the N(1) alkyl group and amides derived from the intact N(3) portion of the molecule.The solvent deuterium isotope effect (kH2O/kD2O)) is less than 1.0.The mechanism is specific acid catalyzed, involving rapid reversible protonation of the 3-acyl group followed by scision of the N(2)-N(3) bond to generate an amide and an alkyl diazonium ion.The (2-hydroxyethyl)diazonium ion gives ethylene glycol and acetaldehyde, while the (2-chloroethyl)diazonium ion yields 2-chloroethanol.In the neutral region, the products are similar to those found in acidic buffers, alkyl alcohols, and amides.At this pH the (2-chloroethyl)diazonium ion produces ethylene glycol and acetaldehyde in addition to 2-chloroethanol.The solvent deuterium isotope effect (kH2O/kD2O) is greater than 1.0.The mechanism involves unimolecular heterolylsis of the N(2)-N(3) bond to form an amide anion and an alkyldiazonium ion.The methyldiazonium ion leads to incorporation of deuterium in the methyl group of the products, indicating the existence of an equilibrium between the metastable methyldiazonium ion and diazomethane.
