Acetate 1a Research Articles

The Comparative Nucleophilicity of Naphthoxide Derivatives in Reactions with a Fast-Red TR Dye. A Discovery-Oriented Capstone Project for the Second-Year Organic Laboratory

In this experiment, organic chemistry students perform reactions between three naphthyl acetate derivatives and the diazonium salt Fast-Red TR, under basic conditions. The three naphthyl acetate derivatives used in this study are 2-naphthyl acetate (1a), 6-bromo-2-naphthyl acetate (1b) and 1,6-dibromo-2-naphthyl acetate (1c). The two-step, one-pot reactions (ester hydrolysis followed by reaction with Fast Red TR) are screened for the formation of an orange–red diazo dye both visually and by UV–vis spectroscopy. Students discover that the hydrolysis and electrophilic aromatic substitution is the fastest with ester 1a and the slowest with ester 1c. This allows students to conclude that electrophilic aromatic substitution, rather than ester hydrolysis, is rate-limiting. This experiment is performed over a two-week period: during the first week students synthesize and purify compounds 1b and 1c, which are easily characterized through 1H NMR and IR spectroscopies. The ester hydrolysis and diazotization visual and UV–vis studies are performed during the second week of the experiment.

A new rearranged dolabellane diterpene from the soft coral Clavularia inflata

A new dolabellane type diterpene 1 has been isolated through its acetate 1a. The structure of 1a was elucidated by extensive 1D and 2D NMR spectroscopy and confirmed by mass spectrometry. The structure of 1 was deduced by comparison of its NMR spectral data with those of 1a, while its relative stereochemistry was deduced by NOESY. The absolute stereochemistry of C-7 was determined by analyses of 1 separately esterified with R and S O-mandelic acids.

Cyclooxygenase (COX)-1 and -2 Inhibitory Labdane Diterpenes from Crassocephalum mannii

Two new labdane diterpenes, 8alpha,19-dihydroxylabd-13 E-en-15-oic acid (1) and 13,14,15,16-tetranorlabdane-8alpha,12,14-triol (2), as well as an acetylated derivative, 8alpha-O-beta-D-glucopyranosyllabd-13 E-ene-15,19-diol-8alpha-2',3',4',6'-hexaacetate (3a), were isolated from the aerial parts of Crassocephalum mannii. The structures of 1, 2, and 3a were elucidated by spectroscopic data analysis. Selective inhibitory activity for 1 and 2 and their acetate derivatives, 1a and 2a, against cyclooxygenases (COX-1 and COX-2) was detected.

Regio- and stereoselectivity control in palladium-catalyzed allylic alkylation of 1-cycloalkenylmethyl acetates

Enantiomerically pure allylic acetates 1a and 1b were obtained by lipase-catalyzed acylation through kinetic resolution processes of the racemates. Palladium-catalyzed alkylation of 1a with dimethyl malonate was both regio- and stereoselective, showing that no isomerization of the acetate 1a or the intermediate π-allylic palladium complex took place under the conditions used. Alkylation of 1b was stereoselective but not regioselective. The regioselectivity could be partially controlled by the proper choice of a chiral ligand. Conditions were set up to perform both the alkylation of 1b and the decarbomethoxylation of the resulting product to afford 3-(cyclohex-1-enyl) butanoate in a one-pot, one-step process.

Synthesis of Some Novel 2,4-Disubstituted Thiazoles as Possible Antimicrobial Agents

A series of 4-aryl-2-(3-methyl-7-substituted quinoxaline-2-one-1-yl)-1,3-thiazoles ( 6a–l ) and 4-substituted alkyl-2-(3-methyl-7-substituted quinoxaline-2-one-1-yl)-1,3-thiazoles ( 8a–i ) were synthesized in good yield by condensing 2-(3-methyl-7-substituted l,2-oxoquinoxalin-1(2H)-yl)ethanethioamides ( 5a–c ) with substituted phenacyl bromide and dichloroacetone followed by treatment with secondary amines, respectively. The intermediates, 5a–c were conveniently obtained by reacting phosphorus pentasulphide with 2-(3-methyl-7-substituted-2-oxoquinoxalin-1(2H)-yl) acetamides ( 4a–c ) which in turn were synthesized from ethyl (3-methyl-7-substituted-2-oxoquinoxalin-1(2H)-yl) acetates ( 3a–c ) by aqueous ammonia treatment. The newly synthesized compounds were characterized by IR, 1 H NMR, 13 C NMR, and Mass spectral and elemental analyses. These compounds were screened for in vitro antibacterial activity against five pathogenic strains and antifungal activity against four fungi. Preliminary results revealed that some of the synthesized compounds showed promising antimicrobial activity.

ChemInform Abstract: Synthesis of Isochroman and Tetrahydroisoquinoline Derivatives from Baylis—Hillman Adducts by Radical Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Isochroman and Tetrahydroisoquinoline Derivatives from Baylis-Hillman Adducts by Radical Cyclization

Recently we were interested in radical cyclizations of modified Baylis-Hillman adducts. We reported the synthesis of various heterocyclic compounds including 2,3dihydrobenzofuran derivatives using radical cyclization process. Meantime we reasoned that six-membered heterocyclic compounds such as isochroman and tetrahydroisoquinoline derivatives could be prepared by radical cyclization from suitably modified Baylis-Hillman adducts (vide infra, Scheme 1). Isochroman and tetrahydroisoquinoline derivatives are important backbone in many biologically interesting substances and their synthesis have been studied extensively. Especially, appropriately substituted tetrahydroisoquinolines are an important class of natural and synthetic compounds, which exhibit various biological activities including antitumor, antibacterial, antiplasmodial and β-adrenergic receptor antagonism. As an initial trial we examined the synthesis of isochroman derivative 4a as shown in Scheme 1. The starting material 3a was synthesized from the reaction of BaylisHillman acetate 1a and 2-bromobenzyl alcohol (2a) in good yield (82%). With this compound 3a in our hand we examined the radical cyclization under the influence of nBu3SnH/AIBN in benzene and we obtained desired 4,4disubstituted isochroman derivative 4a in 89% yield (Scheme 1). We did not observe the formation of sevenmembered ring compound or reduction product. Most of the radical cyclizations of aryl radical toward tethered unsaturated ester occurred at the β-position of unsaturated moiety. However, we observed the selective formation of sixmembered ring compound 4a presumably due to the special stability of the intermediate benzylic radical as in our previous synthesis of 2,3-dihydrobenzofuran. Encouraged by the results we prepared starting materials 3b-f (vide infra, Table 1 and Scheme 2) and carried out radical cyclizations under the same conditions, and the results are summarized in Table 1. As shown we prepared three isochroman derivatives 4a-c (entries 1-3) and two tetrahydroisoquinolines 4d and 4e (entries 4 and 5) in good yields (85-89%). However, unfortunately, radical cyclization was not completed in the case of nitrile derivative 3f and we isolated isochroman 4f and reduction compound 5 together (1:1 mixture based on H NMR) as a mixture. The separation of 4f and 5 was very difficult by column chromatography due to their same mobility on TLC. At this stage the reason for low yield of cyclized compound 4f is not clear. Synthesis of starting materials 3a-e required somewhat different synthetic approaches depending upon the substrates as shown in Scheme 2. Synthesis of 3a and 3b was carried out by the reaction of Baylis-Hillman acetate 1a and 2bromobenzyl alcohol (2a) in the presence of K2CO3 in acetonitrile (79-82%). The compound 3c was synthesized from cinnamyl alcohol 1b and 5-bromo-6-bromomethyl1,3-benzodioxole (2b) in moderate yield (56%) by using potassium tert-butoxide in DMF. The compounds 3d and 3e were prepared from the reaction of rearranged aza-BaylisHillman adduct 1c and 2b or 2-bromobenzyl bromide (2c) in the presence of K2CO3 in DMF in good yields (81-91%). Nitrile derivative 3f was prepared by the reaction of 2a and the corresponding Baylis-Hillman acetate in 79% yield by following the same procedure for the synthesis of 3a. In summary, we disclosed the synthesis of some isochroman and tetrahydroisoquinoline derivatives by the radical cyclization process starting from the Baylis-Hillman adducts.

Synthesis of 2,4,5-Trisubstituted Pyrimidines from Baylis-Hillman Adducts and Amidines

The pyrimidine moiety is one of the most widespread heterocycles in biologically occurring compounds, such as nucleic acids and vitamin B1, and is an important constituent of numerous drug molecules in many therapeutic areas. Although various procedures for the synthesis of pyrimidine derivatives have been developed, it is convenient to synthesize substituted pyrimidines by the reaction of amidine or guanidine derivatives with a variety of 1,3-dielectrophilic three-carbon units such as α,β-unsaturated carbonyl compounds. During the continuous studies on the chemical transformation of Baylis-Hillman adducts our recent interest was focused on the synthesis of oxygen and nitrogen-containing heterocyclic compounds. In addition, we were interested in the reaction of Baylis-Hillman adducts and 1,3-dinucleophile like as 1,3-dinitroalkanes and dimethyl 1,3acetonedicarboxylate. In these respects we presumed that we could synthesize trisubstituted pyrimidine derivatives 3 by using some amidine derivatives 2 as shown in Scheme 1. In the reaction, Baylis-Hillman acetates 1 act as 1,3dielectrophilic component and amidine derivatives 2 served the role of 1,3-dinucleophile. The reaction of the Baylis-Hillman acetate 1a and benzamidine hydrochloride (2a) in tert-butanol in the presence of K2CO3 produced desired compound 3a in 91% isolated yield (entry 1 in Table 1). Similarly we prepared 2,4,5-trisubstituted pyrimidines 3b-h in 27-92% yields from the reaction of Baylis-Hillman acetates 1a-f and amidine derivatives 2a and 2b, and the results are summarized in Table 1. As shown in Table 1, the reaction of acetamidine hydrochloride (2b) gave relatively lower yields than the cases of 2a (see entries 1&2, entries 6&7) presumably due to low solubility of 2b in tert-butanol. The Baylis-Hillman acetates containing ester moiety (entries 1-5) or acetyl group (entries 6 and 7) showed moderate to good reactivity, however, nitrile-containing substrate 1f showed very low reactivity (entry 8). The reaction of 1a and 1,3-diphenyl guanidine (2c) gave the corresponding 2-aminopyrimidine derivative 3i in moderate yield (entry 9). Initially we examined the reaction of BaylisHillman adduct itself and benzamidine hydrochloride (2a), however, we could not obtain the desired product 3a directly. In summary, we synthesized some 2,4,5-trisubstituted pyrimidines from the reaction of Baylis-Hillman acetates and amidine derivatives in a one-pot reaction in moderate yields.

Synthesis of 2,3‐Disubstituted Benzofurans and Indoles by π‐Lewis Acidic Transition Metal‐Catalyzed Cyclization of ortho‐Alkynylphenyl O,O‐ and N,O‐Acetals.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis and molecular structure of ethyl [N-tosyl-(R)-prolyloxy]-2(S)-[4-cyano-8,8-ethylenedioxy-5-oxo-5,6,7,8-tetrahydroindolizin-3-yl] acetate, a key intermediate in the total synthesis of (20S)-camptothecins.

The synthesis of optically active [N-tosyl-(R)-prolyloxy]-2(S)-[4-cyano-8,8-ethylenedioxy-5-oxo-5,6,7,8-tetrahydroindolizin-3-yl] acetate (4a), a key intermediate for the total asymmetric synthesis of 20(S)-camptothecin anticancer drugs, is described. Its structure was characterized by 2D-NMR techniques and the absolute configuration was further confirmed for the first time by X-ray crystal structure analysis.

Enantioselective allylic substitution on Pd/Al 2O 3 modified by chiral diphosphines

The allylic substitution of ( E)-1,3-diphenylallyl acetate ( 1a) with dimethyl malonate was investigated on Pd/Al 2O 3 modified by ( R)- and ( S)-BINAP, ( S , S )-Chiraphos, ( R)-C 3-Tunephos, and ( R)-Solphos. Stable performance of Pd/Al 2O 3 required its reduction in hydrogen before the allylic substitution reaction, which was carried out under Ar. The enantioselectivity of the Pd/Al 2O 3-BINAP system [58–60% ee to ( S)- 2] was independent of the reaction temperature (60 and 120 °C), and only 300 ppm BINAP related to 1a was required. According to UV–vis analysis, only a small fraction of BINAP was adsorbed on Pd/Al 2O 3. At 120 °C, full conversion and 94% chemoselectivity were achieved in 6 h. For comparison, analogous soluble Pd–BINAP complexes were poorly efficient and afforded low ee to the opposite enantiomer of the product at 60 °C or above. Electron microscopy could detect no restructuring of Pd in Pd/Al 2O 3 during the reaction. Surprisingly, the addition of BINAP induced a significant rate acceleration (by a factor of almost 7 at 60 °C) and also improved the chemoselectivity of Pd/Al 2O 3. Among the diphosphine ligands tested, ( R)-Solphos was the most effective (67% ee). An important advantage of the Pd/Al 2O 3–BINAP system is that it can transform not only the allyl acetate 1a, but also the corresponding allyl alcohol 1b without the application of any additive.

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a– h, 6a, b, 8a– n, 10a– g, and 16a, b, and (pyrimidin-4-yl)acetonitriles 13a– g has been delineated by base catalyzed ring transformation of suitably functionalized 2 H-pyran-2-ones 1a– h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.

Synthesis of Acid-Degradable Poly(amidoamine)s

A new class of acid-degradable polymers with poly(amidoamine) backbones was synthesized. Reaction of N-(2-hydroxyethyl)phthalimide (1) with acetal 2a or ketal 2b provided intermediate 3, which was deprotected with NaOH and further reacted with acryloyl chloride (4) to afford monomer 5. Michael addition of piperazine monomer (6) to 5 provided the desired poly(amidoamine)s 7, which were characterized by NMR spectroscopy and GPC. The hydrolysis rate constants and half-lives of the polymers were also obtained from the hydrolysis kinetic studies. The data suggested the potential usefulness of polymer 7 in the field of polymer therapeutics and drug delivery.

Identification of antibacterial and antiviral activities of novel fused 1,2,4-triazine esters

The in vitro biological activities of novel derivatives of methyl and ethyl 2-(4-oxo-8-aryl-2 H-3,4,6,7-tetrahydroimidazo[2,1- c][1,2,4]triazin-3-yl)acetates ( 3a, 3d–j) have been evaluated and are reported. The final heterobicycles ( 3a–j) were obtained from monocyclic 1-aryl-2-hydrazonoimidazolidines ( 2a–f) by addition and cyclization reaction with fumaric acid esters. In particular, compounds 3d and 3e were found to exhibit comparable antibacterial potencies in vitro as that of ampicillin. Heterobicycles of the 3e, 3g and 3j type were screened for their antiviral activities against the selected viruses’ DNA (human adenovirus type 5-Ad-5) and RNA (human enterovirus-Echo-9). Simultaneously, their cytotoxicities towards HEK-293 and GMK cells were established. In particular, heterobicycle 3j, completely non-toxic for GMK cells, was found to exhibit virucidal properties against Echo-9 virus justifying its further investigation as the potential antiviral agent.

Synthesis of 2,3-disubstituted benzofurans and indoles by π-Lewis acidic transition metal-catalyzed cyclization of ortho-alkynylphenyl O, O- and N, O-acetals

The PtCl 2-catalyzed cyclization reaction of ortho-alkynylphenyl acetals 1 in the presence of COD (1,5-cyclooctadiene) produces 3-(α-alkoxyalkyl)benzofurans 2 in good to high yields. For example, the reaction of acetaldehyde ethyl 2-(1-octynyl)phenyl acetal ( 1a), acetaldehyde ethyl 2-(cyclohexylethynyl)phenyl acetal ( 1c), and acetaldehyde ethyl 2-(phenylethynyl)phenyl acetal ( 1f) in the presence of 2 mol % of platinum(II) chloride and 8 mol % of 1,5-cycloocatadiene in toluene at 30 °C gave the corresponding 2,3-disubstituted benzofurans 2a, 2c, and 2f in 91, 94, and 88% yields, respectively. Moreover, the reaction of N-methoxymethyl-2-alkynylanilines 3 was catalyzed by PdBr 2, affording the corresponding 2,3-disubstituted indoles 4 in moderate yields. For example, the reaction of N-methoxymethyl-2-(1-pentynyl)- N-tosylaniline ( 3a) and N-methoxymethyl-2-(phenylethynyl)- N-tosylaniline ( 3b) in the presence of 10 mol % of PdBr 2 in toluene at 80 °C gave 3-methoxymethyl-2-propyl-1-tosylindole ( 4a) and 3-methoxymethyl-2-phenyl-1-tosylindole ( 4b) in 33 and 33% yields, respectively.

Novel derivatives of methyl and ethyl 2-(4-oxo-8-aryl-2 H-3,4,6,7-tetrahydroimidazo[2,1- c][1,2,4]triazin-3-yl)acetates from biologically active 1-aryl-2-hydrazinoimidazolines: Synthesis, crystal structure and antiproliferative activity

The 1-aryl-2-hydrazinoimidazolines ( 2a– h) were directly obtained from appropriate 1-aryl-2-methylthioimidazolines ( 1a– h) by condensation reaction with hydrazine hydrate. Antimicrobial activities of two 1-aryl-2-hydrazinoimidazolines ( 2b and 2e) are presented. Their chemical structures were confirmed by IR, 1H NMR, EI-MS and elemental analysis. The susceptibility of Gram-positive and Gram-negative bacterial strains, mould and yeast-like fungi strains to synthesized compounds and the MIC values against two reference strains of bacteria were determined. The strongest antibacterial activity for compound 2b in relation to reference Gram-negative Escherichia coli ATCC 25922 bacterial strain with minimal inhibitory concentration (MIC) value of 3.91 μg mL −1 was found. Compound 2b showed superior activity (MIC) to ampicillin and comparable to chloramphenicol. A novel compound 2e was found to be effective against E. coli ATCC 25922 and Staphylococcus aureus ATCC 25923 at concentrations of 7.81 μg mL −1 and 15.62 μg mL −1, respectively. Compound 2e revealed antibacterial activity against E. coli ATCC 25922, superior to ampicillin and inferior to chloramphenicol. Against S. aureus ATCC 25923 strain tested, compound 2e demonstrated MIC value inferior to ampicillin and chloramphenicol. Moreover, the synthesis, crystal structure and antiproliferative activity of novel derivatives of methyl and ethyl 2-(4-oxo-8-aryl-2 H-3,4,6,7-tetrahydroimidazo[2,1- c][1,2,4]triazin-3-yl)acetates ( 3a– f and 3g– j) are presented. These compounds were obtained from 1-aryl-2-hydrazinoimidazolines ( 2a– f) by the addition and cyclization reactions with fumaric acid esters. Molecular structures of these compounds were confirmed by elemental analysis, IR, 1H NMR, 13C NMR, EI-MS and by X-ray crystallography (for 3g). The tested imidazotriazines 3e, 3i and 3j exhibited anticancer activities towards the following cancer cells: LS180 (ECACC 87021202, human Caucasian colon adenocarcinoma cells), SiHa (ECACC 85060701, uterus cancer cells), and T47D (ECACC 85102201, human breast carcinoma cells). Compounds 3i and 3j having comparable GI values (above 50%) towards uterus cancer cell line (SiHa) at both examined concentrations (10 μg mL −1 and 50 μg mL −1) were found to be the most effective against this cancer cell line; their GI factors were 53%, 51% and 62%, 55%, respectively, in both examined concentrations (10 μg mL −1 and 50 μg mL −1). Furthermore, the distinctly marked lower cytotoxicity of tested imidazotriazines 3i and 3j against normal cell lines (HSF, human skin fibroblast cells and Vero African Green Monkey Kidney cells, GMK clone) and almost 2-times higher against the majority of cancer cell lines was confirmed.

β-Alkyl-α-allylation of Michael Acceptors through the Palladium-Catalyzed Three-Component Coupling between Allylic Substrates, Trialkylboranes, and Activated Olefins

The palladium-catalyzed three-component beta-alkyl-alpha-allylation reaction of activated olefins has been achieved. For example, in the presence of 5 mol % of Pd(PPh3)4, the reaction of benzylidenemalononitrile 1a with Et3B and allyl acetate 2a in THF proceeded smoothly at 40 degrees C to give the corresponding beta-ethyl-alpha-allylated product 3a in 81% yield.

Synthesis of 2,3‐Disubstituted Benzofurans by Platinum—Olefin‐Catalyzed Carboalkoxylation of o‐Alkynylphenyl Acetals.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Stereoselective Synthesis of Methyl (Z)‐(4,4‐Difluoro‐2,3,4,5‐tetrahydro‐1H‐1‐benzazepin‐5‐ylidene)acetate Using a Dianion Horner—Wadsworth—Emmons Reagent.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 2,3-Disubstituted Benzofurans by Platinum−Olefin-Catalyzed Carboalkoxylation of o-Alkynylphenyl Acetals

The PtCl2-catalyzed cyclization reaction of o-alkynylphenyl acetals 1 in the presence of 1,5-cyclooctadiene produces 3-(alpha-alkoxyalkyl)benzofurans 2 in good to high yields. For example, the reaction of acetaldehyde ethyl 2-(1-octynyl)phenyl acetal (1a), acetaldehyde ethyl 2-(cyclohexylethynyl)phenyl acetal (1c), and acetaldehyde ethyl 2-(phenylethynyl)phenyl acetal (1f) in the presence of 2 mol % of platinum(II) chloride and 8 mol % of 1,5-cyclooctadiene in toluene at 30 degrees C gave the corresponding 2,3-disubstituted benzofurans 2a, 2c, and 2f in 91, 94, and 88% yields, respectively.