Enamine Fragment Research Articles

A Study on Sulfonylation of Cyanohydrins with α‐Functionalized Sulfonyl Chlorides

AbstractHerein we describe the reaction of cyanohydrins with α‐functionalized sulfonyl chlorides and discuss the reactivity of target α‐functionalized β‐enamino γ‐sultones. Depending on electron‐withdrawing activity of α‐functionality of given sulfonyl chlorides the reaction with cyanohydrins either accomplished in one‐pot manner (tandem sulfonylation–CSIC reaction) affording β‐enamino γ‐sultones (α‐functionality=CO2Me, CN, p‐C6H4‐CO2Me) or resulted in sulfonylated cyanohydrins, which can be converted into target β‐enamino γ‐sultones through the t‐BuOK‐mediated CSIC reaction (α‐functionality=Ph). The nature of α‐functionality drastically affects the reactivity of α‐functionalized β‐enamino γ‐sultones. Specifically, α‐CO2Me and α‐CN β‐enamino γ‐sultones are less reactive toward electrophiles and tolerate the nucleophiles. This is the consequence of high degree of conjugation between amino group and EWG within the sultone framework. At the same time, α‐aryl β‐enamino γ‐sultones possess significantly lower degree of conjugation (due to steric hindrance between aryl core and sultone framework) and therefore retain reactivity of the enamine fragment.

Synthesis of Dithiacrown Ethers and Evaluation of Their Cytotoxic Activity

AbstractNew derivatives of thiacrown ethers were synthesized based on the domino reaction of 1,5‐bis(2‐formylphenthio)‐3‐oxapentane with ketones containing active methylene group and ammonium acetate. After 24 hours at moderate temperature, the reaction afforded new substances containing both polyether chain S(CH2)2−O−(CH2)2−S and heterocyclic piperidone. Particularly when benzyl acetoacetate was used, the three ‐ component reaction provided a final tetrahydropyridine derivative product containing enamine fragment instead of piperidone as expected. Physico‐chemical methods of analyses including IR, 1H &13C‐NMR and HRMS were used to clarify these structures. Subsequently, the cytotoxicity of five novel derivatives were evaluated on four cancer cells including HeLa (HeLa cervical cancer), Hep‐G2 (human hepatocellular carcinoma), MCF7 (human breast adenocarcinoma), Lu‐1 (human lung adenocarcinoma) and Vero cell. The result showed the potential application of these compounds in terms of biological activity.

Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity

A series of novel 2-(5-aminomethylene-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl esters has been synthesized. Target compounds were evaluated for their trypanocidal activity towards Trypanosoma brucei brucei and Trypanosoma brucei gambiense. Several hit-compounds (8, 10, 12) inhibited growth of the parasites at sub-micromolar concentrations (IC50 0.027–1.936 µM) and showed significant selectivity indices (SI = 108–1396.2) being non-toxic towards the human primary fibroblasts. The screening of anticancer activity in vitro within NCI DTP protocol allowed to identify active 2-(5-{[5-(2,4-dichlorobenzyl)-thiazol-2-ylamino]-methylene}-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl ester 14 that demonstrated inhibition against all 59 human tumor cell lines with the average GI50 value of 2.57 μM. It was established that the activity type (antitrypanosomal or anticancer) as well as its level depends on the character of enamine fragment in the C5 position of thiazolidinone core.

Thiocyanation of Enamines of the 3,3-Dialkyl-1,2,3,4-tetrahydroisoquinoline Series

Thiocyanation of secondary enamines of the 3,3-dialkyl-1,2,3,4-tetrahydroisoquinoline series and their benzo[f]-fused analogs (esters, amides, ketones, and nitriles) with thiocyanogen generated in situ afforded thiazolo[4,3-a]isoquinoline derivatives. Analogous reaction with a tertiary enamino ketone gave product of hydrogen substitution at the β-carbon atom of the enamine fragment.

Elucidating the Structure of Ranitidine Hydrochloride Form II: Insights from Solid-State Spectroscopy and Ab Initio Simulations

We present a complex, computationally supported solid-state spectroscopy study, elucidating the local order in a blockbuster anti-ulcer drug, ranitidine hydrochloride form II. To this end, dispersion-corrected periodic density functional theory calculations were combined with powder X-ray diffraction, solid-state nuclear magnetic resonance, and low-frequency vibrational spectroscopy, delivering a refined structural model. We found that a competition of nearly iso-energetic substructures, formed by enamine-type species, gives rise to the formation of several potential polymorphs. The considered models were critically examined in terms of both the stabilization energy and the spectral response. While previous studies left the crystal structure considered to be conformationally disordered at a molecular level, we found that the disorder is realized far beyond the local molecular arrangement, elucidating formation of infinite nets of hydrogen-bonded chains, linking both Z and E enamine fragments. Contrary to ...

Reaction of ninhydrin with enamino amides of the 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline series and drotaverine

“Push–pull” enamines of the 1,2,3,4-tetrahydroisoquinoline series, 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin- 1-ylidene)acetamides, reacted as 1,3-binucleophiles with ninhydrin to form tricyclic tetrahydroindeno[1,2-b]pyrrole system. The nucleophilic centers in the enamines were the amide NH2 group and s-carbon atom of the enamine fragment. The reaction of ninhydrin with 2-[2,2-dimethyl-2,3-dihydrobenzo[f]-isoquinolin-1(4H)-ylidene]-1-(pyrrolidin-1-yl)ethanone involved only addition to the s-carbon atom of the enamine fragment. The different reaction directions were rationalized by steric effect of two methyl groups in position 3 of the isoquinoline ring. The Knoevenagel condensation product was obtained by the reaction of ninhydrin with drotaverine (base). The structure of the 1,3-addition product, (3aS,8bS,Z)-{2,2-dimethyl-2,3- dihydrobenzo[f]isoquinolin-4(1H)-ylidene}-3a,8b-dihydroxy-1,3,3a,8b-tetrahydroindeno[1,2-b]pyrrole-2,4-dione, was confirmed by X-ray analysis.

Facile synthesis of functionalized 6-cyano-2-oxa-7-azabicyclo[4.1.0]hept-3-en-1-yl acetates: a catalyst free approach to access the pyran fused 2-acetoxy-NH-aziridines

Novel pyran fused 2-acetoxy-NH-aziridine scaffold was constructed by reacting the enamine fragment of 4-H-pyrans and spiropyrans using iodobenzene diacetate under catalyst free environment.

Ring-Chain Tautomerism of 3-Unsubstituted Trifluoromethyl-Containing n-Acyl-5-Hydroxy-2-Pyrazolines

Reaction of the hydrazides of aromatic and pyridine-3(4)-carboxylic acids with 4-ethoxy-1,1,1-tri-fluorobut-3-en-2-one leads to the formation of derivatives having a 5-hydroxy-2-pyrazoline structure. In solution in DMSO-d6 they are capable of exhibiting ring-chain equilibrium involving the 5-hydroxy-2-pyrazoline and enehydrazine tautomers. The latter form is represented by a mixture of Z- and E-isomers with a significant preponderance of the latter. The product from the reaction of 4-aminobenzohydrazide with 4-ethoxy-1,1,1-trifluorobut-3-en-2-one in a ratio of 1:2 has a structure containing 5-hydroxy-2-pyrazoline and enamine fragments.

RING-CHAIN TAUTOMERISM OF 3-UNSUBSTITUTED TRIFLUOROMETHYL-CONTAINING N -ACYL-5-HYDROXY-2-PYRAZOLINES

Reaction of the hydrazides of aromatic and pyridine-3(4)-carboxylic acids with 4‑ethoxy-1,1,1-tri-fluorobut-3-en-2-one leads to the formation of derivatives having a 5-hydroxy-2-pyrazoline structure. In solution in DMSO- d 6 they are capable of exhibiting ring-chain equilibrium involving the 5-hydroxy-2-pyrazoline and enehydrazine tautomers. The latter form is represented by a mixture of Z- and E‑isomers with a significant preponderance of the latter. The product from the reaction of 4‑aminobenzohydrazide with 4-ethoxy-1,1,1-trifluorobut-3-en-2-one in a ratio of 1:2 has a structure containing 5-hydroxy-2-pyrazoline and enamine fragments. How to Cite Pakal'nis, V. V.; Zerov, A. V.; Yakimovich, S. I.; Alekseev, V. V. Chem. Heterocycl. Compd. 2014 , 50 , 1107. [ Khim. Geterotsikl. Soedin. 2014 , 1201.] For this article in the English edition see DOI 10.1007/s10593-014-1570-8

Five-membered 2,3-dioxo heterocycles: XCVII. Reaction of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with Fischer’s base

Abstract —3-Aroylpyrrolo[1,2- a ]quinoxaline-1,2,4(5 H )-triones reacted with 1,3,3-trimethyl-2-methylidene-2,3-dihydro-1 H -indole (Fischer’s base) to give (2 Z )-1-aryl-2-[3-oxo-3,4-dihydroquinoxalin-2(1 H )-ylidene]-5-(1,3,3-trimethyl-2,3-dihydro-1 H -indol-2-ylidene)pentane-1,3,4-triones. * For communication XCVI, see [1]. Substituted 4-acyl-1 H -pyrrole-2,3-diones, including those fused by the [ e ] side to aza heterocycles, readily react with binucleophiles to produce a variety of fused heterocyclic and spiro-heterocyclic systems [2–4]. We previously studied reactions of 4-acyl-1 H -pyrrole-2,3-diones fused to quinoxalin-2-one fragment, 3-aroylpyr-rolo[1,2- a ]quinoxaline-1,2,4(5 H )-triones, with primary enamines. The reactions of pyrroloquinoxalinetriones with N -alkyl-substituted dimedone imines involved successive addition of the β-CH and NH groups in the enamine fragment of the latter (enamine tautomer) to the C 3a and C 2 atoms of pyrroloquinoxalinetrione, respectively, to give bridged 3,10,13-triazapentacyclo-[10.7.1.0

Acylation reaction of the 3,3-dimethylisoquinoline series enaminonitrile and properties of 5,5-dimethyl- 2,3-dioxo-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline- 1-carbonitrile

2-(3,3-Dimethyl-3,4-dihydro-2H-isoquinolin-1-ylidene)acetonitrile containing an enamine fragment has been acylated using acetyl or benzoyl chlorides to give the corresponding enamino ketones. The acylation using oxalyl chloride gives 5,5-dimethyl-2,3-dioxo-2,3,5,6-tetrahydropyrrolo[2,1-a]-isoquinoline-1-carbonitrile. Reaction of the latter with guanidine carbonate or o-phenylenediamine is accompanied by opening of the pyrrole ring and heterocyclization to give the corresponding 2-amino-4-imidazolone and 2-quinoxalone derivatives. Linear amines were formed in similar reactions with m-toluidine, 1-aminoadamantane, o-aminophenol, and 2-amino-3-hydroxypyridine.

ACYLATION REACTION OF THE 3,3-DIMETHYLISOQUINOLINE SERIES ENAMINONITRILE AND PROPERTIES OF 5,5-DIMETHYL-2,3-DIOXO-2,3,5,6-TETRAHYDROPYRROLO[2,1- a ]ISOQUINOLINE-1-CARBONITRILE

2-(3,3-Dimethyl-3,4-dihydro-2 H -isoquinolin-1-ylidene)acetonitrile containing an enamine fragment has been acylated using acetyl or benzoyl chlorides to give the corresponding enamino ketones. The acylation using oxalyl chloride gives 5,5-dimethyl-2,3-dioxo-2,3,5,6-tetrahydropyrrolo[2,1- a ]isoquinoline-1-carbonitrile. Reaction of the latter with guanidine carbonate or o -phenylenediamine is accompanied by opening of the pyrrole ring and heterocyclization to give the corresponding 2-amino-4-imidazolone and 2-quinoxalone derivatives. Linear amines were formed in similar reactions with m -toluidine, 1-aminoadamantane, o -aminophenol, and 2-amino-3-hydroxypyridine. Authors: A. G. Mikhailovskii, O. V. Surikova, P. A. Chugainov, and M. I. Vakhrin English Translation in Chemistry of Heterocyclic Compounds , 2013, 49 (7), pp 974-979 http://link.springer.com/article/10.1007/s10593-013-1334-x

Synthesis of dispiro hetero analogs of pyrrolizidine alkaloids

Reactions of spiro heterocyclic enamines with 1H-pyrrole-2,3-diones, including those fused at the N–C bond to nitrogen-containing heterocycles, were not studied. We have found that 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones Ia and Ib react with an equimolar amount of 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one (II) (which may be regarded as potential 1,3-C,N-binucleophile) in boiling anhydrous benzene (reaction time 2–5 min, until bright violet color typical of the initial pyrrolobenzoxazinetriones disappeared) to give 3′′-aroyl-4′′-hydroxy-1′′-(2-hydroxyphenyl)-3′,3′-dimethyl-2′,3′-dihydrodispiro[naphthalene-1,1′-pyrrolizine-6′,2′′-pyrrole]-4,5′,5′′(1′′H)-triones IIIa and IIIb in almost quantitative yield. The spectral parameters of compounds IIIa and IIIb are very similar to those found for model ethyl 4-benzoyl-3-hydroxy-1-(2-hydroxyphenyl)-8-methyl-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-9-carboxylate whose structure was proved by X-ray analysis [1]. Presumably, the first step is addition of the activated β-CH group in the enamino tautomer of II at the C atom in Ia or Ib, followed by closure of pyrrole ring via intramolecular attack by the amino group of the enamine fragment on the lactone carbonyl carbon atom in the oxazine ring and opening of the latter at the C–O bond, as was reported by us previously for the reaction of pyrrolobenzoxazinetriones with 1-methyl3,4-dihydroisoquinolines [2]. The described reaction is an example of regioselective synthesis of previously inaccessible dispiro heterocyclic system with various substituents in several positions of both heterocyclic fragments. The products may be regarded as dispiro heterocyclic analogs of pyrrolizidine alkaloids [3]. 4′′-Hydroxy-1′′-(2-hydroxyphenyl)-3′,3′-dimethyl-3′′-(4-methylbenzoyl)-2′,3′-dihydrodispiro[naph-

Kinetics and mechanism of organocatalytic aza-Michael additions: direct observation of enamine intermediates

The imidazoles 1a-g add to the CC-double bond of the iminium ion 2 with rate constants as predicted by the equation log k = s(N)(N + E). Unfavourable proton shifts from the imidazolium unit to the enamine fragment in the adduct 3 account for the failure of imidazoles to take part in iminium-activated aza-Michael additions to enals.

Ethyl 6-methyl-3-(2-methylprop-1-enyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

In the mol­ecule of the title compound, C18H22N2O3, the dihydro­pyrimidinone ring adopts an envelope conformation. The dihedral angle between the phenyl ring and the mean plane through the enamine fragment is 86.04 (7)°. The mol­ecular conformation is stabilized by an intra­molecular C—H⋯O hydrogen bond. In the crystal, inter­molecular N—H⋯O hydrogen bonds link pairs of mol­ecules into centrosymmetric dimers.

Synthesis of 2-(3,3-dimethyl-3,4-dihydroisoquinol-1-yl)propanoic acid amides and their influence on blood coagulation

A series of new 2-(3,3-dimethyl-3,4-dihydroisoquinol-1-yl)propanoic acid amides have been synthesized using the reaction of methyliodide with 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-idene)ethanamides that proceeds on the β-atom of the enamine fragment to form iodides of 2-(isoquinol-1-yl)propanoic acid derivatives. Investigation of the influence of the synthesized compounds on blood coagulation showed that all of them are hemostatics. The most active compounds possess radicals such as morpholine and 2-(3,4-dimethoxyphenyl)ethylamine, are not substituted at the amide fragment, and decrease the blood coagulation time by 14-16%.

Synthesis of isoquinoline derivatives of quinoxalin-2-one from pyrrolo[2,1-a]isoquinoline-2,3-diones and o-phenylenediamine

Reactions of 5,5-dialkyl-2,3,4,5-tetrahydropyrrolo[2,1-a]isoquinoline-2,3-diones with o-phenylenediamine in the presence of a catalytic amount of hydrogen chloride or p-toluenesulfonic acid involved opening of the pyrrole ring with formation of 3-(3,3-dialkyl-1,2,3,4-tetrahydroisoquinolin-1-ylidenemethyl)quinoxalin-2(1H)-ones. The presence of an enamine fragment in the products was confirmed by reaction with oxalyl chloride.

Chemical modification of usnic acid 2. Reactions of (+)-usnic acid with amino acids

The condensation of amino acids with (+)-usnic acid involves the 2-positioned acetyl group of the latter and gives derivatives containing an enamine fragment.

Effect of the Inhibitor-Resistant M69V Substitution on the Structures and Populations of trans-Enamine β-Lactamase Intermediates

The objective of this study was to determine the molecular factors that lead to beta-lactamase inhibitor resistance for the M69V variant in SHV-1 beta-lactamase. With mechanism-based inhibitors, the beta-lactamase forms an acyl-enzyme intermediate that consists of a trans-enamine derivative in the active site. This study focuses on these intermediates by introducing the E166A mutation that greatly retards deacylation. Thus, by comparing the properties of the E166A and M69V/E166A forms, we can explore the consequences of the resistance mutation at the level of the enamine acyl-enzyme forms. The reactions between the beta-lactamase and the inhibitors tazobactam, sulbactam, and clavulanic acid are followed in single crystals of the enzymes by using a Raman microscope. The resulting Raman difference spectroscopic data provide detailed information about conformational events involving the enamine species as well as an estimate of their populations. The Raman difference spectra for each of the inhibitors in the E166A and M69V/E166A variants are very similar. In particular, detailed analysis of the main enamine Raman vibration near 1595 cm(-1) reveals that the structure and flexibility of the enamine fragments are essentially identical for each of the three inhibitors in E166A and in the M69V/E166A double mutant. This finding is in accord with the X-ray-derived structures, presented herein at 1.6-1.75 A resolution, of the trans-enamine intermediates formed by the three inhibitors in M69V/E166A. However, a comparison of Raman results for M69V/E166A and E166A shows that the M69V mutation results in a 40%, 25%, and negligible reductions in the enamine population when the beta-lactamase crystals are soaked in 5 mM tazobactam, clavulanic acid, and sulbactam solutions, respectively. The levels of enamine from tazobactam and clavulanic acid can be increased by increasing the concentrations of inhibitor in the mother liquor. Thus, the sensitivity of population levels to the inhibitor concentration in the mother liquor focuses attention on the properties of the encounter complex preceding acylation. It is proposed that for small ligands, such as tazobactam, sulbactam, and clavulanic acid, the positioning of the lactam ring in the active site in the correct orientation for acylation is only one of a number of poorly defined conformations. For tazobactam and clavulanic acid, the correctly oriented encounter complex is even less likely in the M69V variant, leading to a reduction in the level of inhibition of the enzyme via formation of the acyl-enzyme intermediate and the onset of resistance. Analysis of the X-ray structures of the three intermediates in M69V/E166A demonstrates that, compared to the structures for the E166A form, the oxyanion hole becomes smaller, providing one explanation for why acylation may be less efficient following the M69V substitution.

Substituted 4(5H)-Oxazolones and Their Salts. 10. Synthesis of 2-[β-(Phenylamino)vinyl]-4(5H)-oxazolones from Their Salts and Z,E-Isomerization at the Double Bond

2-[β-(Phenylamino)vinyl]-5-(1,1-dimethyl-2-acetoxyethyl)-4(5H)-oxazolonium perchlorate was synthesized. The deprotonation ability of this compound in chloroform by the action of sodium carbonate to give 4(5H)-oxazolone, containing enamine fragment at C(2) in the ring was studied. Z,E-Isomerization at the double bond was found at room temperature by the action of the solvents.