Vinylic Substitution Reactions Research Articles

Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals.

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.

A formal vinylic substitution reaction for the synthesis of α,β-unsaturated enol esters and their anticancer potential.

Arylsulfonyl group-bearing α,β-unsaturated enol esters were readily assembled via the Cs2CO3-mediated union of 2-bromoallyl sulfones and cinnamic acids. The overall transformation is equivalent to an sp2 carbon-oxygen coupling reaction, and therefore constitutes a formal vinylic substitution. Several of the products display promising levels of antiproliferative activities higher than that of the anticancer drug carboplatin. Thiophenol reacted with 2-bromoallyl sulfones under identical conditions to afford α-thiophenyl-α'-tosyl acetone via an apparent aerial oxidation.

Photocatalyzed Perfluoroalkylation of Endoglycals.

The visible light-induced perfluoroalkyl (RF) radical reactions on peracetylglycals derived from hexoses and pentoses (galactal, glucal, arabinal, and xylal derivatives) were investigated. Various photocatalysts and perfluoroalkyl iodides (RF-I) were employed as sources of RF radicals with LEDs as the irradiation source. Particularly noteworthy was the use of an Iridium photocatalyst, Ir[dF(CF3)ppy]2(dtbpy))PF6, which yielded two distinct product types when applied to glucal. On the one hand, the 2-RF-substituted glucal was formed, a trend observed even when utilizing organic dyes as photocatalysts. On the other hand, the unexpected addition product, namely the 1-RF-2-iodo-α-manno-configured C-glycosyl derivative, was also obtained, as a result of a highly regioselective addition reaction of the RF moiety into the anomeric carbon, followed by attachment of the iodine atom on C-2 in axial disposition. This result contrasted with other radical reactions carried out on 2-unsubstituted glycals, where the incipient radical adds to C-2, generating a stabilized 1-glycosyl radical. The photocatalyzed radical perfluoroalkylations of peracetyl glycals derived from galactose, arabinose, and xylose all afforded the 2-RF-substituted glycals in good yields as a result of the expected vinylic substitution reaction. Mechanistic studies revealed that the 1-RF-2-iodo-α-manno-configured C-glycosyl derivatives arise from a radical chain reaction, whereas the 2-RF-substituted glycals proceed from inefficient chain processes.

β-chlorovinylaldehydes as intermediates in the synthesis of new substituted β–fluoroalkoxyvinyl aldehydes and corresponding alcohols

A convenient synthesis of a series of new β-fluoroalkoxyvinyl aldehydes and their corresponding alcohols from β-chloro-α,β-unsaturated aldehydes was developed. The etherification reaction and the carbonyl reduction were successfully achieved, affording the desired products in good yields. The mechanism of the nucleophilic vinylic substitution reaction of the 3-chloro-3-phenylacrylaldehyde has been studied using DFT methods. IRC analysis shows the presence of a hidden intermediate, in agreement with a one kinetic step two-stage process. The isomerization of hidden intermediate Z-3-chloro-3-phenylacrylaldehyde (IntZ) into hidden intermediate E-3-chloro-3-phenylacrylaldehyde (IntE) was explained in terms of the small energy gap difference between the two intermediates IntZ and IntE and the thermodynamic stability of stereoisomer E compared to Z.

Regioselective synthesis of arylsulfonyl heterocycles from bromoallyl sulfones via intramolecular Heck coupling reaction

Indoles, benzofurans and benzosultams endowed with arylsulfonyl groups were prepared in two steps from 2-bromoallyl sulfones. ortho-Halosulfonamides and ortho-iodophenol reacted with 2-bromoallyl sulfones in the presence of cesium carbonate to furnish products resulting from a formal vinylic substitution reaction. Palladium-catalyzed intramolecular Heck reaction of these adducts furnished sulfonylated indoles, benzosultams and benzofurans. Isomerization of the double bond participating in the Heck reaction under basic conditions led to the formation of two isomeric products in two cases. Conditions for selectively accessing each of the regioisomeric indoles were developed.

Regio‐, Diastereo‐, and Enantioselective Organocatalytic Addition of 4‐Substituted Pyrazolones to Isatin‐Derived Nitroalkenes

Hydroquinine 2,5‐diphenyl‐4,6‐pyrimidinediyl diether [(DHQ)2Pyr] catalyzed the regio‐, diastereo‐, and enantioselective addition of 4‐substituted pyrazolones to isatin‐derived nitroalkenes, providing a variety of chiral alkenylpyrazolone adducts containing a tetrasubstituted stereocenter bearing an oxindole moiety with excellent yields, regioselectivity, and diastereoselectivity, as well as a moderate enantioselectivity (up to 98 % yield, > 20:1 E/Z ratio dr and 78 % ee). The reaction harnesses a nitroalkene as an alkenylating agent through a Nucleophilic Vinylic Substitution (SNV) reaction.

Benzoxazoles as novel herbicidal agents.

Despite the need to develop new herbicides with different modes of action, due to weed resistance, many important classes of compounds have been studied poorly for this purpose. Benzoxazoles are considered privileged structures because of their biological activities, but their phytotoxic activities have not received a lot of attention until now. Double vinylic substitution reactions were carried out to furnish four 2-nitromethylbenzoxazoles and one oxazolidine. Benzoxazol-2-ylmethanamine was obtained by reduction of compound 3a. These compounds were evaluated for their phytotoxicity in Allium cepa (onion), Solanum lycopersicum (tomato), Cucumis sativus (cucumber) and Sorghum bicolor (sorghum). Comparison with oxazolidine analogue allowed us to understand that the benzoxazolic structure is very important for the herbicidal activity. All the synthesized compounds exhibited biological activity on seed germination. The four 2-nitromethylbenzoxazoles showed phytotoxic activity and the 5-chloro-2-(nitromethyl)benzo[d]oxazole (3b) exhibited higher inhibition than the commercial herbicide against all four plant species tested. © 2018 Society of Chemical Industry.

New Syntheses of Naphthostyryl Derivatives via Nucleophilic Vinylic Substitution

New substituted naphthostyryl derivatives have been synthesized by nucleophilic vinylic substitution reactions and converted to the corresponding N-alkyl derivatives by treatment with alkyl halides.

ChemInform Abstract: One‐Pot Syntheses of N‐(α‐Fluorovinyl)azole Derivatives from N‐(Diphenylmethylene)‐2,2,2‐trifluoroethanamine.

AbstractN‐(α‐fluorovinyl)azoles are prepared in moderate to good yield by the reaction of N‐(diphenylmethylene)‐2,2,2‐trifluoroethanamine with various N—H‐containing heterocycles in the absence of any metal catalyst under mild conditions via vinylic nucleophilic substitution reaction.

ChemInform Abstract: Carbonylmetallates — A Special Family of Nucleophiles in Aromatic and Vinylic Substitution Reactions

AbstractReview: [32 refs.

Cover Picture: Synthesis of Chiral Tertiary Alcohols by CuI‐Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones / Emergence of the First Catalytic Oligonucleotides in a Formamide‐Based Origin Scenario / Intermolecular Peptide Cross‐Linking by Using Diaminodicarboxylic Acids / Smart Polymeric Nanoparticles as Emerging Tools for Imaging—The Parallel Evolution of Materials / Transition Metal Nitrides for Electrocatalytic Energy Conversion: Opportunities and Challenges

Cover Picture: Synthesis of Chiral Tertiary Alcohols by Cu^I‐Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones / Emergence of the First Catalytic Oligonucleotides in a Formamide‐Based Origin Scenario / Intermolecular Peptide Cross‐Linking by Using Diaminodicarboxylic Acids / Smart Polymeric Nanoparticles as Emerging Tools for Imaging—The Parallel Evolution of Materials / Transition Metal Nitrides for Electrocatalytic Energy Conversion: Opportunities and Challenges

Carbonylmetallates--A Special Family of Nucleophiles in Aromatic and Vinylic Substitution Reactions.

Carbonylmetallates, [M(CO)(n)L](-), anionic transition-metal carbonyl complexes, represent a large family of metal-centered nucleophiles, and studying carbonylmetallates allows us to understand the differences in the behavior of the metal-centered complexes versus heteroatom-based nucleophiles. The mechanisms of carbonylmetallate reactions with aryl- and alkenyl halides have been examined by employing radical and, especially, carbanion trapping techniques. Carbonylmetallates show a marked preference for halogenophilic attack, and nucleophilic substitution with carbonylmetallates is often not a direct process, but proceeds through the initial attack at halogen with subsequent coupling of carbanion and HalM(CO)(n)L intermediates. Factors governing the competition between the halogenophilic and more common "carbophilic" reaction pathways, as well as the means of predicting the actual course of reaction are discussed. The review also considers other aspects of carbonylmetallate reactivity, including ion-pairing effects, radical-mediated nucleophilic substitution pathways, and the carbonylmetallate nucleophilicity scale in the reactions with π-electrophiles.

ChemInform Abstract: Base‐Mediated Direct Fluoroalkenylation of 2‐Phenyl‐1,3,4‐oxadiazole, Benzothiazole and Benzoxazole with gem‐Difluoroalkenes.

Direct α-fluorovinylation of 2-phenyl-1,3,4-oxadiazole, benzothiazole and benzoxazole with gem-difluoroalkenes via nucleophilic vinylic substitution reaction (SNV) under the assistance of KHMDS or NaH at room temperature is described.

Ring expansion and vinylic nucleophilic substitution competing for (tert-alkyl)2C[dbnd]C(Li)–Cl in carbenoid chain processes

Vinylic nucleophilic substitution (SNV) reactions of unactivated, cyclic α,α-dichloroalkenes [(tert-alkyl)2CCCl2] with aryllithiums (RLi) to give (tert-alkyl)2CC(Cl)–R are presented to be carbenoid chain reactions, which involve the unsaturated Cl,Li-carbenoids (tert-alkyl)2CC(Li)–Cl as transient intermediates. The chains are longer and the overall reactions much slower in tert-butyl methyl ether (t-BuOMe) than in THF as the solvent. In competition with the fast SNV step of these Cl,Li-carbenoids, the Fritsch–Buttenberg–Wiechell (FBW) ring expansion in t-BuOMe (but less so in THF) generates short-lived cyclohexyne species, which are trapped by the accompanying RLi species to yield chlorocyclohexene derivatives [(tert-alkyl)–(Cl)CC(R)–(tert-alkyl)] as the FBW chain products.

Reactivity in Nucleophilic Vinylic Substitution (SNV):SNVπ versus SNVσ Mechanistic Dichotomy

The intrinsic electronic factors that determine reactivity in prototypical identity nucleophilic vinylic substitution reactions, X(-) + ViX → XVi + X(-) (Vi = vinyl), have been studied by performing quantum chemical calculations (OPBE/6-311++G(d,p)). Of the two limiting reaction types envisaged--the S(N)Vπ and S(N)Vσ mechanisms--the former is preferred for most combinations of nucleophiles and substrates, except for the combination of unactivated substrates and poor nucleophiles, as seen for the much studied reactions Cl(-) + CH2CHCl and Br(-) + CH2CHBr. It was found that periodic trends for S(N)Vπ are essentially the same as those previously reported for nucleophilic aromatic substitution, S(N)Ar, while intrinsic S(N)Vσ nucleophilicity parallels aliphatic S(N)2. It is therefore concluded that S(N)V reactivity in general can be understood in terms of this mechanistic dichotomy. Furthermore, a few representative reactions were analyzed applying two complementary schemes for energy decomposition analysis.

Preparation and spectral properties of products of the reaction of N,N-dimethylhydrazine with selected enolethers/alkoxymethylene systems

There were studied series of activated enolethers (alkoxymethylene derivatives of malonic or 3-oxob- utanoic acids derivatives of general formula R—O—CH=C(R = CO2CH3, CO2CH2CH3, COCH3, CN) with N,N-dimethylhydrazine. They smoothly provided products of nucleophilic vinylic substitution reaction — dimethyl hydrazinyl methylene derivatives of malonic or 3-oxobutanoic acids (enhydrazines), respectively from 20 minutes to 2 hours at room temperature.

Oxidative Damage of Pyrimidine Nucleosides by the Environmental Free Radical Oxidant NO3• in the Absence and Presence of NO2• and Other Radical and Non-Radical Oxidants

Analysis of the products formed in the reaction of the environmental free radical oxidant NO3• with permethylated uridine 1 and thymidine 2 in solution revealed highly complex reaction pathways following initial NO3• induced oxidative electron transfer at the pyrimidine ring. Product formation was found to depend not only on the nature of the nucleobase, but also on the presence of other free radical oxidants, namely NO2•. In the reaction of 1 with NO3•, which was generated through CAN photolysis, apart from formation of the highly oxidized nucleoside derivative 4 as the major product, cleavage of the C–N glycosidic bond did also occur, resulting in formation of ribolactone 5 and the free nucleobase 6. The suggested mechanism involves in situ generation of NO2• during the course of the reaction, which promotes conversion of the initially formed radical cation 7 to 4 in an autocatalytic fashion.When the reaction of NO2• with O3 was used to generate NO3•, the initially formed radical cation 7 in the reaction with permethylated uridine 1 is rapidly trapped by NO2• to give 5-nitrouridine 18 in a radical mediated vinylic substitution reaction. In contrast to this, under similar conditions in the reaction involving thymidine 2 the highly oxidized products 20 and 21 are obtained as major compounds, which result from addition to the C5–C6 double bond. No direct reaction between NO3• and the carbohydrate moiety in 1 and 2 was found. Also, no reaction occurred between the nucleosides and mixtures of NO2•/N2O4 and O3/O2, respectively.

Synthetic Exploitation of Halogenated Alkenes Containing EWG: Polysubstituted Sulfanyl Dinitro Butadienes from Sequential Nucleophilic Substitutions

Our novel approach starts from a 1,1,3,4-tetrachloro-2,4-dinitrobuta-1,3-diene (5) being one of the most prominent members of this relatively new class of synthetic building blocks. Because of its multifunctional chemical behavior, polyhalogenated nitrobuta-1,3- dienes proved to be versatile reagents in the synthesis of a large variety of sulfurated, (hetero)cyclic, and acyclic derivatives. We describe our studies concerning successive nucleophilic vinylic substitution reactions of dinitrobuta-1,3-diene in order to establish the reactivity profile of this precursor and determine whether this precursor could be used for the synthesis of many dinitrodiene analogues offering new methodology for the synthesis of polyfunctional precursors that are difficult to access. Some of the resulting perfunctionalized 2,4- dinitrobuta-1,3-dienes are subjected to further transformations to give promising candidates with respect to biological activity. Keywords: Click chemistry, Dienes, Nitro compounds, Nitroalkenes, Persulfurated Alkenes, Polyhalogenated Compounds, Polysulfanyl Buta-1,3-dienes, Sulfides

Synthesis of Pyridin-2(1H)-one Derivatives via Enamine Cyclization

The nucleophilic vinylic substitution reaction of the aliphatic enaminone 3-dimethylamino-2-formyl acrylonitrile 1 with the nucleophiles malononitrile and ethyl cyanoacetate produced the two unusual reaction adducts 3a and 3b in good to moderate yield under milder reaction conditions. Upon reaction with aromatic amines, these adducts yielded enamines 4 and 5, which eventually cyclized in the presence of base to produce the novel pyridin-2(1H)-one derivatives 8 and 9.

Halogenophilic and classical Ad N E mechanisms in nucleophilic vinylic substitution reactions involving the anions of transition metal carbonyls

The mechanism of the reaction of carbonylate anions ([M(CO) n L]–) with highly activated vinyl halides (Hal = Cl, Br, I) was investigated by the method of “anion traps” – the effect of proton donors on the composition of the reaction products. It was demonstrated that the reactions with PhCHal=C(Z)2 (Hal = Br, I;Z=CN, CO2Et) and PhCN=CClI take place through initial attack by the carbonylate at the halogen atom, the reactions with PhCCl=C(CO2Et)2 and PhCOCH=CHHal (Hal = Cl, I) take place through attack by the carbonylate at the π bond (AdNE mechanism), and in the case of E-and Z-PhCN=CHI the two mechanisms operate concurrently. The main laws determining the reaction mechanisms are analyzed.