Alkoxycarbonyl Group Research Articles

DBU-Promoted Cyclizations of Cyclopentyl-Substituted Oxazapolyenes to Cyclopentapyridones and Hydroxypyrroles: Experimental and DFT Study.

1,1-Di(alkoxycarbonyl)-4-cyclopentyl-2-azabuta-1,3-dienes react with DBU to form two types of heterocyclic products: 1H-cyclopenta[c]pyrid-1-ones and 3-hydroxy-1H-pyrroles. These previously unobserved transformations proceed through the formation of 1-azapentadienyl anion which undergoes 1,6-shift of the alkoxycarbonyl group to the cyclopentyl moiety followed by 1,6-cyclization to form the cyclopentapyridone (path a) and 1,5-cyclization accompanied by 1,3-shift of the methoxy group followed by dialkyl carbonate elimination to afford the hydroxypyrrole (path b). The mechanisms of the reactions were studied using DFT calculations. Pyridones can be synthesized in one pot in three steps via Rh(II)-catalyzed isomerization of 4-cyclopentylisoxazoles to 2H-azirines and their subsequent reaction with diazomalonic esters, followed by heating of the resulting 2-azabuta-1,3-dienes with DBU.

Alkoxycarbonyl Groups in Metalloesters Showing Oxocarbenium‐like Structure and Alkylating Reactivity

AbstractIn contrast to the well‐documented acylating reactivity, the alkylating reactivity of the alkoxycarbonyl group, as signified by its oxocarbenium‐like resonance structure, remains almost unexplored. Herein, the first series of Co/Ni dinuclear metalloesters exhibiting the novel oxocarbenium‐like alkoxycarbonyl groups were synthesized and characterized. In these deformed alkoxycarbonyl groups, the Ccarbonyl−Oalkoxyl bonds were contracted to 1.177(11)~1.191(9) Å with the elongations of the Ccarbonyl=Ocarbonyl bonds to 1.368(13)~1.441(9) Å. Meanwhile, the O−Calkyl bonds were also elongated to 1.522(11) ~1.607(15) Å, and were by far the longest O−Calkyl bonds reported for alkoxycarbonyl groups. As triggered by the long O−Calkyl distances, the alkylating reactivity of the oxocarbenium‐like methoxycarbonyl group towards a series of C/N/O‐nucleophiles via the rare BAL2 mechanism at ambient conditions was examined. Furthermore, the homo‐etherifications of alcohols mediated by the Co/Ni dinuclear metalloesters were investigated. The yields followed the trend ethanol≫n‐propanol≫n‐butanol ≈n‐pentanol, that closely related to the structure features of the alkoxycarbonyl groups in corresponding metalloesters: while the ethoxycarbonyl group showed the reactive oxocarbenium‐like framework, the n‐propoxycarbonyl group displayed the dioxocarbenium‐like skeleton with a shorter O−Calkyl bond; In comparison, the classical frameworks with unactivated alkyl moieties were observed for n‐butoxycarbonyl and n‐pentoxycarbonyl groups.

Alkoxycarbonyl Groups in Metalloesters Showing Oxocarbenium-like Structure and Alkylating Reactivity.

In contrast to the well-documented acylating reactivity, the alkylating reactivity of the alkoxycarbonyl group, as signified by its oxocarbenium-like resonance structure, remains almost unexplored. Herein, the first series of Co/Ni dinuclear metalloesters exhibiting the novel oxocarbenium-like alkoxycarbonyl groups were synthesized and characterized. In these deformed alkoxycarbonyl groups, the Ccarbonyl-Oalkoxyl bonds were contracted to 1.177(11)~1.191(9) Å with the elongations of the Ccarbonyl=Ocarbonyl bonds to 1.368(13)~1.441(9) Å. Meanwhile, the O-Calkyl bonds were also elongated to 1.522(11) ~1.607(15) Å, and were by far the longest O-Calkyl bonds reported for alkoxycarbonyl groups. As triggered by the long O-Calkyl distances, the alkylating reactivity of the oxocarbenium-like methoxycarbonyl group towards a series of C/N/O-nucleophiles via the rare BAL2 mechanism at ambient conditions was examined. Furthermore, the homo-etherifications of alcohols mediated by the Co/Ni dinuclear metalloesters were investigated. The yields followed the trend ethanol≫n-propanol≫n-butanol ≈n-pentanol, that closely related to the structure features of the alkoxycarbonyl groups in corresponding metalloesters: while the ethoxycarbonyl group showed the reactive oxocarbenium-like framework, the n-propoxycarbonyl group displayed the dioxocarbenium-like skeleton with a shorter O-Calkyl bond; In comparison, the classical frameworks with unactivated alkyl moieties were observed for n-butoxycarbonyl and n-pentoxycarbonyl groups.

Rhodium-catalysed additive-free alkoxycarbonylation of indoles: 2,4,6-trimethylbenzoic acid-based carbonate anhydrides as a versatile alkoxycarboxyl source.

We report a CO-free approach to indole-2-carboxylic esters: rhodium-catalysed C(2)-alkoxycarbonylation of indoles with 2,4,6-trimethylbenzoic acid-based carbonate anhydrides. Selective C-O bond cleavage of the anhydrides facilitates the introduction of various alkoxycarbonyl groups. Control experiments suggest that merging a rhodium catalyst and KI promotes the in situ formation of the RhI species.

Synthesis and antiproliferative activity of thiazole-fused anthraquinones.

Heterocyclic derivatives of anthraquinone demonstrated a high potential for the development of new antitumor compounds. In this study, we report a scheme for the synthesis of thiazole-fused anthraquinones and the results of their antiproliferative activity. A convenient metal-free method for the thiolation of anthraquinone derivatives has been proposed for the preparation of the key intermediates. C-S bond formation upon nucleophilic substitution of the bromine atom in anthraquinone with 4-methoxybenzyl mercaptan readily occurs under mild conditions using t-BuOK as a base. This process was used for the preparation of anthra[2,3-d]thiazoles with various substituents at position 2, in particular the alkoxycarbonyl group. Study of the chemical properties resulted in the transformation of anthra[2,3-d]thiazole-2-carboxylic acid into a series of carboxamides. Screening the antiproliferative effect revealed moderate activity of compounds 12b and 12d against human cancer cells, showing weaker activity than anthra[2,3-d]thiophene analogs and indicating a crucial role of the heterocyclic nucleus in the antitumor potency of heteroareneanthraquinones.

Divergent synthesis of multi-substituted phenanthrenes via an internal redox reaction/ring expansion sequence.

We report an effective synthetic route to multi-substituted phenanthrenes via an internal redox reaction/ring expansion sequence. The interesting feature of the present system is that it allows for the divergent synthesis of the target skeleton depending on the selected Lewis acid catalyst. When benzylidene malonates with a cyclic structure at the ortho-position were treated with BF3·OEt2, three sequential processes (internal redox reaction/elimination of the alkoxy group/ring expansion) proceeded to give phenanthrene derivatives in which the alkoxycarbonyl (CO2R) group and the alkyl (R) group were in close proximity to each other, in good chemical yields. In sharp contrast, treatment with Bi(OTf)3 exclusively led to the formation of another type of phenanthrene, whose R group was positioned distal to the CO2R group.

Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis

Arginine, due to the guanidine moiety, increases peptides’ hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs.

Transformation of Highly Hydrophobic Triarylphosphines into Amphiphiles via Staudinger Reaction with Hydrophilic Trichlorophenyl Azide.

Owing to its hydrophobic properties and reactivity, triarylphosphines (PAr3 ) are promising precursors for the development of new amphiphiles. However, an efficient and reliable synthetic method for amphiphiles based on highly hydrophobic PAr3 is still required. Herein, a straightforward transformation of highly hydrophobic PAr3 into amphiphiles via the Staudinger reaction is reported. By simply mixing PAr3 and a hydrophilic trichlorophenyl azide containing two hydrophilic chains, amphiphiles bearing a N=P bond (i. e., an azaylide moiety) were quantitatively formed. The obtained azaylide-based amphiphiles were remarkably water-soluble, enabling their spontaneous self-assembly into 2 nm-sized micelles composed of 4-5 molecules in water with a low critical micelle concentration (up to 0.05 mM or less) due to the effective intermolecular interactions among the hydrophobic surfaces. Although the azaylide moiety is easily hydrolyzed in the presence of water, the azaylide in the amphiphiles displayed notable stability in water even at 60 h, which stems from the LUMO modulation induced by the presence of three electron-withdrawing chloro groups and two twisted alkoxycarbonyl groups, according to DFT calculations. An amphiphile having a large hydrophobic surface solubilized various hydrophobic organic dyes through efficient intermolecular interactions, resulting in the dyes exhibiting either monomer or excimer emissions in water.

Suppression of alpha-carbon racemization in peptide synthesis based on a thiol-labile amino protecting group

In conventional solid-phase peptide synthesis (SPPS), α-amino groups are protected with alkoxycarbonyl groups (e.g., 9-fluorenylmethoxycarbonyl [Fmoc]). However, during SPPS, inherent side reactions of the protected amino acids (e.g., α-C racemization and aspartimide formation) generate by-products that are hard to remove. Herein, we report a thiol-labile amino protecting group for SPPS, the 2,4-dinitro-6-phenyl-benzene sulfenyl (DNPBS) group, which is attached to the α-amino group via a S–N bond and can be quantitatively removed in minutes under nearly neutral conditions (1 M p-toluenethiol/pyridine). The use of DNPBS greatly suppresses the main side reactions observed during conventional SPPS. Although DNPBS SPPS is not as efficient as Fmoc SPPS, especially for synthesis of long peptides, DNPBS and Fmoc are orthogonal protecting groups; and thus DNPBS SPPS and Fmoc SPPS can be combined to synthesize peptides that are otherwise difficult to obtain.

Ring‐Opening Cyclization of Spirocyclopropanes with Stabilized Phosphorus Ylides: Access to Indane and Azulene Skeletons

AbstractIn this study, regio‐ and diastereoselective ring‐opening cyclization of spirocyclopropanes with phosphorus ylides stabilized by electron‐withdrawing groups were developed. The reaction of various cyclohexane‐1,3‐dione‐2‐spirocyclopropanes with phosphorus ylides bearing alkoxycarbonyl groups proceeded smoothly without any additives to provide the corresponding 6,7‐dihydroindan‐4‐ones in 32–87% yields. Cycloheptane‐1,3‐dione‐2‐spirocyclopropanes were also used in this reaction, producing the corresponding products 1,2,3,6,7,8‐hexahydroazulen‐4‐ones in 52–67% yields. The resulting [5.6]‐ and [5.7]‐fused carbocyclic products were readily converted into highly substituted indanes and azulenes, respectively, by oxidation.

Self-Assembly-Directed Exciton Diffusion in Solution-Processable Metalloporphyrin Thin Films.

The study of excited-state energy diffusion has had an important impact in the development and optimization of organic electronics. For instance, optimizing excited-state energy migration in the photoactive layer in an organic solar cell device has been shown to yield efficient solar energy conversion. Despite the crucial role that energy migration plays in molecular electronic device physics, there is still a great deal to be explored to establish how molecular orientation impacts energy diffusion mechanisms. In this work, we have synthesized a new library of solution-processable, Zn (alkoxycarbonyl)phenylporphyrins containing butyl (ZnTCB4PP), hexyl (ZnTCH4PP), 2-ethylhexyl (ZnTCEH4PP), and octyl (ZnTCO4PP) alkoxycarbonyl groups. We establish that, by varying the length of the peripheral alkyl chains on the metalloporphyrin macrocycle, preferential orientation and molecular self-assembly is observed in solution-processed thin films. The resultant arrangement of molecules consequently affects the electronic and photophysical characteristics of the metalloporphyrin thin films. The various molecular arrangements in the porphyrin thin films and their resultant impact were determined using UV-Vis absorption spectroscopy, steady-state and time-resolved fluorescence emission lifetimes, and X-ray diffraction in thin films. The films were doped with C60 quencher molecules and the change in fluorescence was measured to derive a relative quenching efficiency. Using emission decay, relative quenching efficiency, and dopant volume fraction as input, insights on exciton diffusion coefficient and exciton diffusion lengths were obtained from a Monte Carlo simulation. The octyl derivative (ZnTCO4PP) showed the strongest relative fluorescence quenching and, therefore, the highest exciton diffusion coefficient (5.29 × 10−3 cm2 s−1) and longest exciton diffusion length (~81 nm). The octyl derivative also showed the strongest out-of-plane stacking among the metalloporphyrins studied. This work demonstrates how molecular self-assembly can be used to modulate and direct exciton diffusion in solution-processable metalloporphyrin thin films engineered for optoelectronic and photonic applications.

New indoline spiropyrans with highly stable merocyanine forms

New spiropyrans with chromene and indoline cores bearing alkoxycarbonyl group and cationic π-acceptor in the chromene moiety were synthesized in one step from 1,2,3,3-tetramethylindolinium and isophthalic dialdehyde derivatives. The appending of a 8′-positioned conjugated cationic fragment causes a significant red-shift of the photoinduced isomers absorption maxima and provides them with extremely long lifetimes up to 75 min. The obtained spiropyrans exhibit both positive and negative photochromism in solutions, demonstrating the properties of ‘photochromic balance’.

New indoline spiropyrans with highly stable merocyanine forms

New spiropyrans with chromene and indoline cores bearing alkoxycarbonyl group and cationic π-acceptor in the chromene moiety were synthesized in one step from 1,2,3,3-tetramethylindolinium and isophthalic dialdehyde derivatives. The appending of a 8′-positioned conjugated cationic fragment causes a significant red-shift of the photoinduced isomers absorption maxima and provides them with extremely long lifetimes up to 75 min. The obtained spiropyrans exhibit both positive and negative photochromism in solutions, demonstrating the properties of ‘photochromic balance’.

Synthesis, characterization, and their field-effect properties of azaisoindigo-based conjugated polymers with versatile alkoxycarbonyl substituents

In this study, versatile alkoxycarbonyl substituents were incorporated onto the azaisoindigo (AIID)-based polymeric π-skeleton, affording two novel polymers PAZPT and PAZPTEt. The PAZPT has the alkoxycarbonyl groups substituted on its thiophene unit, whereas the PAZPTEt has both the thiophene and thieno[3,2-b]thiophene units substituted with alkoxycarbonyl groups. As result, PAZPT has more planar conjugated backbone conformation than that of PAZPTEt. Experimental characterization results indicated that alkoxycarbonyl substituents can effectively pull down the frontier molecular orbital energy levels and optimize the solubility and molecular packing mode of conjugated polymers. All the field-effect transistors based on the two polymers showed ambipolar carrier transport characteristics. Such results show that introducing alkoxycarbonyl substituents on polymeric π-skeleton might be a potential approach in fine-tuning the semiconducting properties of conjugated polymers.

Orthoamide und Iminiumsalze, CII. Umsetzungen eines Orthoamids der Phenylpropiolsäure mit tertiären CH-aciden Verbindungen

AbstractThe orthoamide derivative of phenylpropiolic acid reacts with tertiary CH-acidic compounds as alkylmalonic acid dialkylesters under formation of 1,1-diamino-allenes wich rearrange to give 2-alkoxycarbonyl-1,1-diamino-1,3-butadienes by migration of an alkoxycarbonyl group. Perchloric acid transforms these butadienes to amidinium perchlorates. The crystal structure of an amidinium perchlorate derived from cinnamic acid has been determined.

Orthoamide und Iminiumsalze, CII. Umsetzungen eines Orthoamids der Phenylpropiolsäure mit tertiären CH-aciden Verbindungen

Abstract The orthoamide derivative of phenylpropiolic acid reacts with tertiary CH-acidic compounds as alkylmalonic acid dialkylesters under formation of 1,1-diamino-allenes wich rearrange to give 2-alkoxycarbonyl-1,1-diamino-1,3-butadienes by migration of an alkoxycarbonyl group. Perchloric acid transforms these butadienes to amidinium perchlorates. The crystal structure of an amidinium perchlorate derived from cinnamic acid has been determined.

Взаимодействие замещенных 6-оксоциклогексан-1,3-дикарбоксамидов с гидроксиламином

Functionalized cyclohexanones are multifunctional highly reactive available substrates. They are convenient for the synthesis of new compounds, including practically significant ones. The presence of a 1,3-dicarbonyl fragment in their composition makes it possible to obtain various heterocyclic systems in reactions with binucleophilic reagents: indazoles, benzisoxazoles, and diazepines. The interaction of cyclohexanones functionalized with acetyl or alkoxycarbonyl substituents with hydroxylamine was previously studied. It was shown that, depending on the nature of the substituents, the reaction can proceed with the formation of the corresponding oximes, or give products of heterocyclization – benzisoxazoles. The interaction of cyclohexanones containing amide groups in an alicycle with hydroxylamine has not been studied. We studied the reaction of unsubstituted 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamides with hydroxylamine hydrochloride in the presence of an equivalent amount of alkali. When boiling in ethanol in the absence of a catalyst, new 2-aryl-4-hydroxy-6-(hydroxyimino)-4-methylcyclohexane-1,3-dicarboxamides were obtained. Cyclization with the formation of benzisoxazoles does not occur in this case due to a lower positive charge on the carbon atom of the amide group compared to the carbon atom of the acetyl or alkoxycarbonyl groups. The structure of the synthesized compounds was established based on the data of IR, 1H NMR and 13C NMR spectroscopy. The IR spectra of the obtained oximes contain bands of valence vibrations of the OH, NH, and CON groups. The 1H NMR spectra contain four NH-proton singlets of two amide groups, the proton singlet =N-OH group. The 13C NMR spectra of solutions of compounds contain signals of two carbon atoms of amide groups and a carbon atom of the C=N-OH group, which fully confirm the assumed structure.

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3',4',5'-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold.

Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 3′,4′,5′-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3′,4′,5′-trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC50 values ranging from 1.1 to 4.7 μM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site.

Single-Component Polycondensation of Bis(alkoxycarbonyldiazomethyl)aromatic Compounds To Afford Poly(arylene vinylene)s with an Alkoxycarbonyl Group on Each Vinylene Carbon Atom.

The original synthetic strategy for a new type of poly(arylene vinylene) (PAV) is presented, where the C=C-bond-forming coupling of bis(alkoxycarbonyldiazomethyl)aromatic compounds is utilized as propagation. The strategy is unique in that the resulting PAVs have an alkoxycarbonyl group as an electron-withdrawing substituent on each vinylene carbon atom in the polymer main chain. Among the transition-metal catalysts examined in this study, RuCl(cod)Cp* (cod = 1,5-cyclooctadiene, Cp* = pentamethylcyclopentadienyl) is the most efficient, affording PAVs from a series of bis(alkoxycarbonyldiazomethyl)aromatic compounds with a high trans-C=C-forming selectivity of up to 90%. A PAV sample with a fluorenylene framework as an arylene moiety prepared by the Ru catalyst exhibited a hole mobility of 4 × 10–6 cm2 V–1 s–1.

SYNTHESIS OF FLUORINE-CONTAINING ANALOGS OF ANESTHESINE AND NOVOKAINE

Methods for the synthesis of methyl, ethyl and butyl esters of meta- and para-pentafluoroethoxybenzoic acids starting with respective hydroxybenzoic acids have been developed. Firstly m- and p-hydroxybenzoic acids were esterificated with respective alcohol, and then obtained esters were treated with trifluoroacetic anhydride giving m- or p-alkyl trifluoroacetoxybenzoates that were treated with SF4 in anhydrous HF medium. Conditions for obtaining esters of meta- and para-pentafluoroethoxybenzoic acids with good yields have been discovered. It has been shown that the yields and ratios of the reaction products depend little on the size of the alkyl radical of the alkoxycarbonyl group, but substantially depend on the temperature, duration of the reaction, and the intensity of mixing. The lack of mixing of the reaction medium during treatment of m- and p-trifluoroacetoxybenzoates with SF4-HF leads to the cleavage of the trifluoroacetoxy group with the formation of the corresponding esters of m- and p-hydroxybenzoic acids. Increasing reaction temperature leads to formation of m- and p-pentafluoroethoxybenzotrifluorides in higher yields. Increasing duration of the reaction affects the same way. Anesthetic activity of obtained esters of meta- and para-pentafluoroethoxybenzoic acids was tested using white outbreed male mice. The esters have higher anesthetic activity compared to anesthesine. Ethyl para-pentafluoroethoxybenzoate exhibits the best anesthetic properties among the compounds obtained. meta-Pentafluoroethoxybenzoic acid has been obtained by means of hydrolysis of ethyl meta-pentafluoroethoxybenzoate. The acid has been treated with equimolar quantity of NaOH solution giving respective salt. The last one was then treated with 2-chloro-N,Ndiethylethanamine in DMF solution, giving analogue of novocaine with pentafluoroethoxy group in the meta-position of the benzene ring. Thus obtained novocaine analogue has also higher anesthetic activity compared to anesthesine.