Bromo Ester Research Articles

An Easy Access to Construct Some New Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H)‐one (1) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4, 5, 6, which incorporating 1,2,4‐triazine moiety was achieved. Moreover, compound 1 was subjected to reaction either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3 or thiadiazine 7. However, while the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1. In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.

An Easy Access to Construct Some Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H)‐one (1) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4, 5, 6, which incorporating 1,2,4‐triazine nucleus was achieved. Moreover, compound 1 was subjected to react either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3, or thiadiazine 7. However, the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1. In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.

Dynamic Kinetic Resolution of L-Threonine-derived α-Bromo Esters for Asymmetric Synthesis of α-Amino Esters

Many chiral alcohols have successfully been used as a chiral auxiliary for the dynamic resolution of -halo esters in nucleophilic substitution. 1 L-Threonine is a proteinogenic -amino acid that bears a chiral alcohol group. However, so far L-threonine has not been used as a chiral auxiliary for the dynamic resolution of -halo esters. We herein report the first example of L-threonine-mediated dynamic kinetic resolution of -bromo esters in nucleophilic substitution with various amine nucleophiles. Treatment of N-acetyl L-threonine isopropyl ester with racemic -bromo phenylacetic acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) provided -bromo ester (RS)-1 in 70% yield with about 50:50 diastereomeric ratio (dr). When the mixture of (S)-1 and (R)-1 was treated with p-anisidine (1.2 equiv), tetrabutylammonium iodide (TBAI, 1.0 equiv) and diisopropylethylamine (DIEA, 1.0 equiv) in CH2Cl2 at room temperature for 12 h, amino ester 8a was produced in 63% yield with 84:16 dr as shown in Table 1, entry 1. Also, six different N-protection groups of L-threonine were examined for the substitution with p-anisidine as shown in entries 2-7. The reactions of 2, 3, 4, and 7 bearing N-pivaloyl, N-Boc, Nbenzoyl, and N,N-dibenzyl groups gave slightly better drs ranging from 88:12 to 86:14, while the reactions of 5 and 6 bearing N-p-methoxybenzoyl and N-2-pyridinylcarbonyl groups gave lower drs compared to the reaction of 1. The dr and yield of the substitutions in Table 1 imply that -bromo carbon center is configurationally labile with respect to the rate of substitution and L-threonine-derived -bromo esters

ChemInform Abstract: Rearrangement of 2-Azabicyclo(2.2.1)hept-5-en-3-ones: Synthesis of cis- 3-Aminocyclopentane Carboxylic Acid Derivatives.

The γ-lactam 4 was converted into the bromo ester 6 and the latter compound was transformed in five steps into the diester 10. Similarly the lactam 4 was converted into the hydroxy amide 17via the intermediacy of the dihalogeno compound 11. Compounds 10 and 17 are potential precursors of deoxycarbocyclic nucleosides. Unexpectedly, the lactam 4 furnished the addition product 25 on reaction with benzeneselenenyl bromide and a tentative rationale for the preferred reaction pathway is proposed.

Total syntheses and structural revision of alpha- and beta-diversonolic esters and total syntheses of diversonol and blennolide C.

Total syntheses and structural revision of alpha- and beta-diversonolic esters and total syntheses of diversonol and blennolide C.

Synthesis of ent‐Thallusin.

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Synthesis ofent-Thallusin

[reaction: see text] A three-step route from sclareol oxide (6) to bromo ester 4 in 53% overall yield was achieved using the efficient oxidation of an allylic bromide to an enal with bis(2,4,6-trimethylpyridine)silver(I) hexafluorophosphate in DMSO. Stille coupling of bromo ester 4 with stannylpyridine 5 gave the trimethyl ester of ent-thallusin in 54-92% yield by the stoichiometric conversion of 4 to a vinyl palladium intermediate prior to the addition of 5 to the reaction.

Organic/Inorganic Nanocomposite Star Polymers via Atom Transfer Radical Polymerization of Methyl Methacrylate Using Octafunctional Silsesquioxane Cores

A method was developed for atom transfer radical polymerization (ATRP) synthesis of a nanocomposite consisting of dispersed, nanosized hard particles in a thermoplastic matrix. Octafunctional cubic silsesquioxanes were used as a platform to synthesize 8-arm star poly(methyl methacrylate) (PMMA) via ATRP. The cubic silsesquioxane, octakis(hydridodimethylsiloxy)octasilsesquioxane (Q8M8H), was converted to either octakis(2-bromo-2-methylpropionoxypropyldimethylsiloxy)octasilsesquioxane (OBPS) or the octaethylbenzyl chloride analogue. The bromo ester was successfully employed as an ATRP initiator using CuCl as catalyst, leading to formation of PMMA arms with controlled molecular weights and hence to nanocomposites with essentially complete control of dispersion and solids loading. The catalyst and initiator concentrations were demonstrated to affect the molecular weight distribution and the occurrence of star−star coupling caused by inevitable termination reactions.

Microwave-induced Fast Synthesis and Optical Resolution of 9H-Carbazole-2-carboxylic Acids Enantiomers

Fast synthesis of a series 9H-carabzole-2-carboxylic acids enantiomers 9—13 by N-alkylation reaction of the carbazole and bromo ester under microwave irradiation is described using DMF as solvent. The HPLC optical resolution of these enantiomers were performed on amylose tris-(phenylcarbamate)-coated aminopropylated silica gel (ATPC) column.

(Z)- and (E)-2-((hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New nucleoside analogues with a broad-spectrum antiviral activity.

New nucleoside analogues 14-17 based on a methylenecyclopropane structure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (19) with adenine (18) led to bromoalkene 20, which was benzoylated to give N6,N6-dibenzoyl derivative 23. Attempts to convert 20 or 23 to bromocyclopropanes 21 and 22 by reaction with ethyl diazoacetate catalyzed by Rh2(OAc)4 were futile. By contrast, 2,3-dibromopropene (19) afforded smoothly (E)- and (Z)-dibromocyclopropane carboxylic esters 24 + 25. Alkylation of adenine (18) with 24 + 25 gave (E)- and (Z)-bromo derivatives 21 + 22. Base-catalyzed elimination of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropanecarboxylic esters 26 + 27. More convenient one-pot alkylation-elimination of adenine (18) or 2-amino-6-chloropurine (30) with 24 + 25 afforded (Z)- and (E)-methylenecyclopropane derivatives 26 + 27 and 31 + 32. The Z-isomers were always predominant in these mixtures (Z/E approximately 2/1). Reduction of 26 + 27 and 31 + 32 with DIBALH afforded (Z)- and (E)-methylenecyclopropane alcohols 14 + 16 and 33 + 34. The latter were resolved directly by chromatography. Compounds 14 + 16 were converted to N6-(dimethylamino)methylene derivatives 28 and 29 which were separated and deprotected to give 14 and 16. Reaction of 33 and 34 with HCO2H led to guanine analogues 15 and 17. The 1H NMR spectra of the Z-analogues 14 and 15 are consistent with an anti-like conformation of the nucleobases. By contrast, 1H NMR and IR spectra of bromo ester 21 are indicative of syn-conformation of adenine. Several Z-(hydroxymethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalovirus (HCMV and MCMV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and hepatitis B virus (HBV). Analogues 14, 15, and 33 were the most effective agents against HCMV (IC50 1-2.1, 0.04-2.1, and 0.8-5.6 microM), MCMV (IC50 2.1, 0.3, and 0.3 microM) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 microM) and Daudi cells (IC50 3.2, 5.6, and 1.2 microM). Adenine analogue 14 was active against HBV (IC50 2 microM), VZV (IC50 2.5 microM), and HHV-6 (IC50 14 microM). Synadenol (14) and the E-isomer (16) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer 16 was more reactive than Z-isomer 14. The deamination of 14 effectively stopped at 50% conversion. Synadenol (14) was also deaminated by AMP deaminase from aspergillus sp.

Reductive Carbonylation of gem-Dihalogenocyclopropanes by Pentacarbonyliron(0) in the Presence of Sodium Methoxide

Abstract The reaction of gem-dihalogenocyclopropanes derivatives with (tetracarbonyl)(methoxycarbonylato)ferrate(I−) has been investigated; gem-dibromocyclopropanes and gem-chlorobromocyclopropane derivatives are reduced and carbonylated. It could be shown that a bromo ester such as methyl 1-bromo-2-phenylcyclopropanecarboxylate is an intermediate in the transformation of 1,1-dibromo-2-phenylcyclopropane into methyl cis- and trans-2-phenylcyclopropanecarboxylates and dimethyl 2-phenyl-1,1-cyclopropanedicarboxylate.

Organic Reducing Agents: Some Radical Chain Reactions of Ketyl and 1,3-Dioxolanyl Radicals with Activated Bromides

The radical chain reduction of primary and secondary α-bromo esters by 2-propanol and 2-methyldioxolane has been shown to be a kinetically vi- able process with average chain lengths of >10 at temperatures between 30 and 60 o C. For electron-deficient bromides, these simple organic re- agents may effectively replace the more commonly used (and more expen- sive) organosilicon or tin hydides. Some mechanistic insights have been obtained from a combination of kinetic and thermodynamic measurements. The rate constants for the reaction of the 2-hydroxy-2-propyl and the 2-methyl-1,3-dioxolan-2-yl radicals with a primary bromo ester have been estimated to be 8×10 3 M -1 s -1 and 6×10 3 M -1 s -1 , respective- ly, at 30 o C in acetonitrile

A Total Synthesis of (±)-Tacamonine (Pseudovincamone I) through Radical Cyclization

The radical cyclization of the bromo ester (11), prepared from 2-hydroxymethylbutan-1-ol (7), giving the diastereoisomeric mixture of lactones (12) was examined under various conditions. Treatment of the bromo ester (17), derived from 7, with tris(trimethylsilyl)silane in the presence of 2,2-azoisobutyronitrile provided the epimeric mixture of lactams (18), convertible to (±)-tacamonine (pseudovincamone I) (1) in three steps

Formation of bromohydrins and epoxides from 4-hydroxy-2-oxabicyclo[3.3.0]oct-7-en-3-one and 9-hydroxy-7-oxabicyclo[4.3.0] non-4-en-8-one

The hydroxy lactone 1 and the silylated derivative 8 react selectively with HOBr to give access to polyfunctional bicyclic systems such as the bromo ester 10. The lactone 3 or the corresponding derivative 20 react less selectively to give mixtures of compounds 16, 17, 18, 19, 21, 22. The hydroxybicyclo[4.3.0]nonenones 2 and 4 behave in a similar fashion to the lactone 3, reacting non-selectively with HOBr and m-chloroperbenzoic acid to produce a plethora of highly substituted bicyclo compounds 23–31, 33–39, 41 and 42. X-Ray crystal structures were obtained for four compounds, the diacetates 25 and 37 and the epoxides 26 and 27.

Fluorinated acetylenes. Part 12. Reaction of 3,3,3-trifluoropropynyl-lithium with benzil and α-haloacetophenones

Treatment of 3,3,3-trifluoropropynyl-lithium ( 4) with benzil (2:1 molar ratio) in diethyl ether at −50 °C, followed by addition of an excess of benzoyl chloride, affords 1-benzoyl-5-benzoyloxy-5-phenyl-2,3-bis(trifluoromethyl)cyclopenta-1,3-diene ( 11) (61%) and the 1,4-dialkynyl ester (CF 3CC) 2CPhO 2CPh ( 1b) (8%). Similar reaction of the salt 4 with α-chloroacetophenone (2:1 molar ratio) in diethyl ether at −50 °C, followed by addition of a slight excess of benzoyl chloride, gives the ester CF 3CCPh(CH 2Cl)O 2CPh ( 14a) (55%) and a compound considered to be 2,5-diphenyl-2,5-bis(3,3,3-trifluoropropynyl)-1,4-dioxan ( 15) (30%). Under the same conditions, α-bromoacetophenone yields the corresponding bromo ester CF 3CCCPh(CH 2Br)O 2CPh ( 14b) (39%), 2-phenyl-2-(3,3,3-trifluoropropynyl)oxirane ( 16) (25%) and the dialkynyl ester ( 1b) (7%). The oxirane 16, conveniently prepared (51%) by treatment of salt 4 with the bromoketone (1:1 molar ratio) in THF at −60 °C, on reaction with lithium phenylacetylide followed by addition of benzoyl chloride ( c. 1:1:1 molar ratio) in THF at −60 °C gives a compound identified as 2-phenyl-2-(1-phenyl-5,5,5-trifluoropent-3-en-1-yn-3-yl)oxirane ( 17) or possibly 2-phenyl-2-(3-phenylprop-2-yn-1-yl)-3-(2,2,2-trifluoroethylidene)oxirane ( 18) in 28% yield.

A simple synthetic approach to Cbz-Phe-Ψ-(Ch 2)-Gly-Pro-OMe and related Peptide Isosteres

A new approach to ketomethylene and hydroxymethylene peptide isosteres has been developed which is simple, direct, and highly convergent. A key feature is construction of the central bond of a ≥-keto ester by alkylation of a t-butyl β-keto ester with an ∠-bromo ester.

Rearrangement of 2-azabicyclo[2.2.1]hept-5-en-3-ones: synthesis of cis-3-aminocyclopentane carboxylic acid derivatives

The γ-lactam 4 was converted into the bromo ester 6 and the latter compound was transformed in five steps into the diester 10. Similarly the lactam 4 was converted into the hydroxy amide 17via the intermediacy of the dihalogeno compound 11. Compounds 10 and 17 are potential precursors of deoxycarbocyclic nucleosides. Unexpectedly, the lactam 4 furnished the addition product 25 on reaction with benzeneselenenyl bromide and a tentative rationale for the preferred reaction pathway is proposed.

ChemInform Abstract: Cephalotaxine Analogues: Stereospecific Synthesis of Spiro‐Fused 3‐Benzazepine and 1,3‐Benzodiazepine Derivatives.

AbstractThe spirolactam (I) is coupled with the bromo ester (II), further transesterificated, and reduced to give the aldehyde (III).

ChemInform Abstract: Potential Antisecretory Antidiarrheals. Part 2. α2‐Adrenergic 2‐((Aryloxy)alkyl)imidazolines.

AbstractThe bromo ester (I) is coupled with the phenols (II) to produce the corresponding α‐phenoxy esters (III) which are transformed into the imidazolines (V) mentioned in the title by cyclocondensation with the diamines (IV).

ChemInform Abstract: Stereoisomeric Flavor Substances. Part 31. Tetrahydro‐2‐methylthiophen‐3‐ol ‐ Structure and Properties of the Stereoisomers.

AbstractStarting from the bromo ester (I), the title compound (V) is prepared as diastereomeric racemic mixture and separated into its four optically active stereoisomers via 1. separation into the racemic cis and trans isomers by liquid chromatography and 2. optical resolution of the cis and trans isomers using (S)‐tetrahydro‐5‐oxo‐2‐furancarboxylic acid chloride.