Enamine System Research Articles

Configurational and Constitutional Dynamics of Enamine Molecular Switches.

Dual configurational and constitutional dynamics in systems based on enamine molecular switches has been systematically studied. pH‐responsive moieties, such as 2‐pyridyl and 2‐quinolinyl units, were required on the „stator“ part, also providing enamine stability through intramolecular hydrogen‐bonding (IMHB) effects. Upon protonation or deprotonation, forward and backward switching could be rapidly achieved. Extension of the stator π‐system in the 2‐quinolinyl derivative provided a higher E‐isomeric equilibrium ratio under neutral conditions, pointing to a means to achieve quantitative forward/backward isomerization processes. The „rotor“ part of the enamine switches exhibited constitutional exchange ability with primary amines. Interestingly, considerably higher exchange rates were observed with amines containing ester groups, indicating potential stabilization of the transition state through IMHB. Acids, particularly BiIII, were found to efficiently catalyze the constitutional dynamic processes. In contrast, the enamine and the formed dynamic enamine system showed excellent stability under basic conditions. This coupled configurational and constitutional dynamics expands the scope of dynamic C−C and C−N bonds and potentiates further studies and applications in the fields of molecular machinery and systems chemistry.

Molecular mechanism of Hetero Diels-Alder reactions between (E)-1,1,1-trifluoro-3-nitrobut-2-enes and enamine systems in the light of Molecular Electron Density Theory

The molecular mechanism of the reaction of (E)-1,1,1-trifluoro-3-nitrobut-2-ene 1 with 3,3-dimethyl-2-morpholinobutene 2 has been studied within the Molecular Electron Density Theory (MEDT). This theoretical study confirm the possibility of the formation of zwitterionic structures in the first reaction stage. Interestingly, that localized zwitterions are however not common intermediates for identified in the postreaction mixture products. The further Bonding Evolution Theory (BET) study show, that the key, HDA reaction takes place in one-step but in a non-concerted manner since three stages are clearly identified. First the C5–C6 double bond breaks, then the C1–C2 bond breaks, and in the last phase we observed the formation of the C1–C6 single bond and V(C2) and V’ (C2) pseudoradical centers in Z1 molecule. In turn, the molecular mechanism of the conversion of zwitterion Z1 to product 3 can be divided also in three groups in which we observed the disappearance of the two pseudoradical centers and formation O4–C5 single and C3–N3 double bonds, respectively.

Facile Reduction of β-Enamino Oxopyrrolidine Carboxylates Mediated by Heterogeneous Palladium Catalyst

The synthesis of diastereoisomers via diastereoselective hydrogenation of unreactive endocyclic enamine system of ethyl 4-hydrazinyl- and 4-(2-hydroxyethylamino)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylates using palladium-based catalyst was developed. The steric and electronic properties of substituents, especially of the C2 substituent, influenced both the yield and diastereoselectivity. Despite the reaction generated three chiral centers, the reduced compounds had either cis–trans or all-trans configuration which was successfully determined by means of 1D and 2D NMR experiments.

β,β,β‐Trichloroethyl‐NH‐Enamine as Viable System for 5‐Endo‐trig Radical Cyclization via Multifaceted CuI−CuII Redox Catalysis: Single Step Synthesis of Multi‐Functionalized NH‐Pyrroles

AbstractHere we report a mild and regioselective copper‐catalyzed direct synthesis of multi‐substituted and functionalized NH‐pyrroles in high yields from diverse β,β,β‐trichloroethyl‐NH‐enamines via a novel 5‐endo‐trig radical cyclization mode, previously known to be unviable in the enamine system. An approach to transform a geometrically ‘disfavored to favored’ 5‐endo‐trig radical cyclization mode in NH‐enamine systems via multifaceted CuI−CuII redox catalysis generating radicals, preventing dehalogenative reduction of radical precursors and dehydrohalogenating the 5‐endo‐trig cyclized products have been demonstrated experimentally. With wider substrate scope, this method incorporates halo‐, NH‐ and carbonyl functionalities besides alkyl, aryl and heteroaryl substituents in the pyrrole unit easily. These difficult to prepare 3‐halo‐NH‐pyrroles are potential sources for natural products, agrochemicals, pharmaceuticals and organometallic chemistry.magnified image

Synthesis of external β-turn templates by reaction of protected dehydroamino acids with cyclic enaminoesters

Two external β-turn templates have been synthesised and one of them has been derivatised as a GLDV-tetrapeptide. In the course of the synthesis an interesting dichotomy was observed in the condensation of exocyclic enamines such as 4 and 19 with protected dehydroamino acids using phosphorus trichloride. When dehydroamido acids were condensed with the enamines 4 and 19 then 6/6 and 6/5 fused bicyclic compounds such as 5 and 20 , respectively, were obtained, whereas, when dehydroamino acid urethanes were used, the 5/6 and 5/5 fused products 7 and 23 were obtained. The bicyclic template 20 was converted to the GLDV-tetrapeptide derivative 31 but the sensitivity to base of the acyl–enamine system of the template reduced the yield in the synthesis of the external turn 35 .

Multicomponent Hantzsch cyclocondensation as a route to highly functionalized 2- and 4-dihydropyridylalanines, 2- and 4-pyridylalanines, and their N-oxides: preparation via a polymer-assisted solution-phase approach

An improved and efficient entry to highly functionalized β-(2-pyridyl)- and β-(4-pyridyl)alanines and the corresponding 1,4-dihydro and N-oxide derivatives has been developed by one-pot thermal Hantzsch-type cyclocondensation of aldehyde–ketoester–enamine systems in which one of the reagents (aldehyde or ketoester) was carrying the unmasked but protected chiral glycinyl moiety. Thus coupling N-Boc- O-benzyl aspartate β-aldehyde, acetoacetate and aminocrotonate esters afforded tetrasubstituted β-(4-dihydropyridyl)alanines (75% yield). One of these products was almost quantitatively transformed into the β-(4-pyridyl)alanine derivative which in turn was oxidized to the corresponding N-oxide. Each of these enantiomerically pure (Mosher's amide analysis) heterocyclic α-amino acids was incorporated into a tripeptide by coupling with ( S)-phenylalanine. In a similar way tetrasubstituted β-(2-dihydropyridyl)alanine, β-(2-pyridyl)alanine and β-(1-oxido-2-pyridyl)alanine were prepared via Hantzsch cyclocondensation reaction using benzaldehyde, aminocrotonate, and acetoacetate carrying the N-Boc- O-benzyl glycinate moiety. It was shown that the work up of the reaction mixtures derived from the cyclocondensation and oxidation reactions can be carried out by the use of polymer supported reagents and sequestrants thus allowing the isolation of the products in high purity without any chromatography.

Cyclic nitronic esters from highly diastereo-selective cycloaddition of 2-(4-morpholinyl)-norbornene to conjugated nitroolefins

The reactions of the morpholino enamine of 2-norbornanone towards a series of cyclic and acyclic conjugated nitroolefins resulted in the formation of the corresponding 1,2-oxazine N- oxides through an exo approach of the electrophiles. The stability of the heterocycles was strongly influenced by the nature of the substituents and in some cases it has been found to be unexpectedly high. Differently from analogous systems, opening of the heterocyclic ring to the corresponding enamine systems was not observed.

Protonation study of some enamine systems

The properties of enamines depend on slight changes in reaction conditions or structural factors. From the analysis of the data which is available in the literature, B3LYP/6-311+G(3df,3pd)//MP2/6-31+G∗∗ calculations and using the Taft and Topsom model of the intrinsic substituent effect in the basicity, we found a resonance effect that explains why vinylamine and N,N-dimethylvinylamine are both carbon and not nitrogen bases (the resonance factor for vinylamine increases carbon basicity by about 56kcal/mol).

13C NMR and crystallographic evidence of push-pull effects in furoindolic β-enamino esters

A series of cyclic enamine derivatives, stabilized through conjugation with an electron-attracting CO2Me group at the β-carbon of the enamine system, has been prepared. The influence of substituents at the vinylogous donor NH2 group on 13C chemical shifts has been investigated, and the results analyzed on the basis of resonance and steric effects on the dipolar charge distribution in the molecule. Intramolecular H-bonding was established for the N-methylated enamines 4a and 4b based on the high-frequency shift of the NH proton and its solvent immutability. Several deuterium-induced isotope effects on 13C chemical shift [nΔC(ND)] due to deuteration at the enamine nitrogen have been measured. The crystal structures of the enamine 1b and the N,N-diacetylated enamine 3a, determined by X-ray analyses, show that these compounds, in the solid state, adopt an s-trans disposition around the C-C=O bond, with the carbonyl ester group and the C=C double bond in an almost coplanar conformation. Comparison of bond lengths of 1b and 3a in the crystalline state provides information on changes in the extent of n-π delocalization arising from the nature of the N-substituent.Key words: β-enamino esters, furo[2,3-b]indoles, push-pull effects, 13C NMR, X-ray.

<sup>13</sup>C NMR and crystallographic evidence of push-pull effects in furoindolic β-enamino esters

A series of cyclic enamine derivatives, stabilized through conjugation with an electron-attracting CO2Me group at the β-carbon of the enamine system, has been prepared. The influence of substituents at the vinylogous donor NH2 group on 13C chemical shifts has been investigated, and the results analyzed on the basis of resonance and steric effects on the dipolar charge distribution in the molecule. Intramolecular H-bonding was established for the N-methylated enamines 4a and 4b based on the high-frequency shift of the NH proton and its solvent immutability. Several deuterium-induced isotope effects on 13C chemical shift [nΔC(ND)] due to deuteration at the enamine nitrogen have been measured. The crystal structures of the enamine 1b and the N,N-diacetylated enamine 3a, determined by X-ray analyses, show that these compounds, in the solid state, adopt an s-trans disposition around the C-C=O bond, with the carbonyl ester group and the C=C double bond in an almost coplanar conformation. Comparison of bond lengths of 1b and 3a in the crystalline state provides information on changes in the extent of n-π delocalization arising from the nature of the N-substituent.Key words: β-enamino esters, furo[2,3-b]indoles, push-pull effects, 13C NMR, X-ray.

A short synthesis of (2S,4S,5R)-4,5,6-trihydroxynorleucine

A direct synthesis of enantiomerically pure (2S,4S,5R)-4,5,6-trihydroxynorleucine ( 1) from a carbohydrate precursor (D-glucosamine), is described. D-glucosamine was oxidized to 2-amino-2-deoxy-D-gluconic acid ( 2), which was converted into the 2-acylamido-hex-2-enono-1,4-( 3, 4) and 1,5-lactone ( 5, 6, 11) derivatives. The hydrogenation of the enamine system of these compounds took place with excellent diastereofacial selectivity leading to the corresponding 3-deoxy-D- arabino-lactone derivatives ( 7–10, 12, 13). On N-deacetylation with HCl the hydrochloride derivative of 1, in its 1,4-lactone form, was obtained with 57% overall yield, from 2. The ammonium salt of 1 was also prepared.

Structure of neostrychnine. An enamine with a bridgehead nitrogen which undergoes efficient chemical reaction with singlet oxygen

Neostrychnine, 20,21-didehydro-21,22-dihydrostrychnidin-10-one, C 21 H 22 N 2 O 2 , contains an alicyclic enamine unit in which the N atom is located at a bridgehead, a fact of critical importance to an understanding of the manner in which it reacts with potential electrophiles, including singlet oxygen, O 2 ( 1 Δ g ). The X-ray structure shows that the steric constraints within the σ framework demand a high degree of pyramidalization of the N atom, which is independent of the fact that this atom is part of an enamine system. These data support the conclusion that the formation of an immonium species with a double bond at the N atom is likely to be highly unfavourable

Regioselective introduction of functional groups in α‐diimines by means of dialkylzinc compounds. Synthesis of functionalized 2‐ and 3‐pyrrolidinone derivatives

AbstractAlkylation of the 1,4‐diaza‐1,3‐butadiene t‐BuN=CH‐CH=N t‐Bu (t‐BuDAB) by functionally substituted diorganozinc compounds Zn[(CHR1XCH2)nXR2]2 (n = 1–3, R1 = H, Me, XR2 = OMe, OBn, SEt, NMe2, COOEt) occurs regioselectively. Alkylation occurs at the nitrogen atom of the N=C‐C=N skeleton of t‐BuDAB when primary diorganozinc compounds are used (R1 = H), but at the carbon atom when secondary and benzylic diorganozinc compounds are employed. The functional groups in the diorganozinc reagents proved to be important for the alkylation reaction only in the case of Zn[(CH2)3NMe2]2 (7) and Zn(C6H4CH2NMe2−2)2 (16), in which the strongly coordinating NMe2 groups give either a decrease of the alkylation rate (7), or no reactivity at all (16). When t‐BuDAB is reacted with Zn[(CH2)2COOEt]2 (10) alone, a 3‐pyrrolidinone (10c) is formed, whereas the same reaction with a mixture of 10 and ClZn(CH2)2COOEt affords a 2‐pyrrolidinone (10b). The reactions involve a two‐step process involving prior regioselective introduction of the alkyl group either at the N or C atom of an imine unit followed by an intramolecular nucleophilic substitution leading to 10b or 10c, respectively. The molecular structure of 10c shows the functionalized heterocycle to be part of a conjugated enamine system.

Acetals of amides and lactams in the synthesis of heterocyclic compounds

The review collects the results of investigations on the synthesis of heterocyclic compounds, mainly azaheterocycles, from amide and lactam acetals. The reasons for the high reactivity of these compounds with respect to nucleophilic and electrophilic reagents are considered, as are the principal pathways of heterocyclization of amidine and enamine systems synthesized via amide and lactam acetals.

Spectral properties and isomerism of nitro enamines. Part 2. 3-Amino-2-nitrocrotonic esters

The IR Raman, 1H and 13C NMR spectra of a series of 3-amino-2-nitrocrotonic esters (3), with both primary and secondary amino groups, have been studied. The spectral data show that these compounds exist in solution as equilibrium mixtures of the two enantiomeric quasi-s-cis-(Z) isomers (3A′)+(3A″) and the planar, and less polar s-cis(E)-(3C) isomer, the ratio [(3A′)+(3A″)]: (3B) being strongly dependent on the polarity of the medium. The E- and Z-forms can be easily distinguished by their vibrational and NMR spectra, and are separated by very low energy barriers (ΔG‡50–70 kJ mol–1), the magnitude of which decreases on increasing the electron-donor capacity of the substituent at the amino function. The spectral data and AM1 calculations indicate a strong polarization of the nitro enamine system with a large negative charge accumulation at C-2 and, to a lesser extent, at the NO2 group. This group acts as a weak π- and a strong σ-acceptor, and the ester group acts as a weak π-acceptor group and a σ-donor.

ChemInform Abstract: Reaction of (E)‐β‐Enamino Amides with Dimethyl Acetylenedicarboxylate (DMAD): Formation of Benzene Derivatives, Enamino Esters, and 2‐Pyridones.

AbstractThe addition reaction of the (E)‐enamino amides (I) with the diester (II) is shown to be influenced by the stereochemistry of the intermediates and the amine component of the enamine system.

Reaction of (E)-β-enamino amides with dimethyl acetylenedicarboxylate (DMAD): formation of benzene derivatives, enamino esters, and 2-pyridones

An investigation of the additions of (E)-enamino amides (1a–d) with DMAD has shown that they are influenced by the stereochemistry of the intermediates and the amine component of the enamine system. In dryacetonitrile (E)-benzyl(methyl)amino-(1b), (E)-pyrrolidin-1-ylamino-(1c), and (E)-piperidin-1-ylamino-(1d) acrylamides, following a known mechanism, yielded tetramethyl benzene-1,2,3,4-tetracarboxylate (5), the (E)-aminobutenedioates (6b–d), and the 3,4-bismethoxycarbonylpyridin-2-(1H)-one (8). Dimethylamino-(1a) and morpholin-1-ylamino-(1e)-acrylamides, owing to the different nucleophilicity of the β-carbon, formed a zwitterion (11) which eliminated propiolamide to give only the (E)-aminobutenedioates (6a, e).

Correlation between hydride transfer and one-electron oxidation of dihydropyridines and heterocycles

The 1,4-dihydrotrigonelline amides and esters are extensively used for brain-specific drug delivery. Oxidation of the dihydropyridine to a quaternary salt is the key step in this process. Water addition across the 5,6-double bond in these dihydropyridines is an unwanted, irreversible reaction. All these processes were studied theoretically, using MNDO/2. It was found that the oxidation process is very sensitive to substituents, like 6-methyl. An excellent correlation between the hydride removal vs. one-electron oxidation (both adiabatic and vertical I p- s) was found. The water addition is not affected sterically by the 6-substituent, as the protonation of the enamine system on C 5 is the rate determining step. The calculations were extended to pyridazines and 1-benzyldihydroisonicotinamide. All results are in very good agreement with experimental evidence and suggest that calculations of this kind can effectively predict the various rate processes involved in this chemical drug delivery system.

3-Amino-5,6-dihydro-4H-thiopyran 1,1-dioxides. Reactivity with diethyl azodicarboxylate and some α,β-unsaturated ketones

The secondary enamines derived from 5,6-dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide are in tautomeric equilibrium with their imine forms. With the title electrophiles, either they react at nitrogen or show the usual reactivity at the β-carbon atom of the enamine system. With electrophilic olefins carbocyclization compounds are also formed.

ChemInform Abstract: CYCLIC ALLYLAMINE‐ENAMINE SYSTEMS. PART 7. A THEORETICAL STUDY OF THE RELATIVE ENERGIES OF ISOMERIC CYCLIC ALLYLAMINE‐ENAMINE SYSTEMS

AbstractEnamine Systems.