Endocyclic Enamines Research Articles

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.

A catalyst-free one-step synthesis of N-pyrimidinyl amidines from endocyclic enamines and 4-azidopyrimidines

Novel N-pyrimidyl amidines of alycyclic acids were obtained in one step from of 4-azidopyrimidines and endocyclic enamines. The reaction mechanism involves [3 + 2]-addition of azide at the double bond followed by cleavage of thus formed 1,2,3-triazoline ring, and a contraction of alicycle.

NEW TRANSFORMATIONS OF N -HETARYLCYCLOPENTANO[ d ][1,2,3]TRIAZOLINE RING INTO 5-ALKOXYVALERAMIDINES

It was found that brief refluxing of N -hetarylcyclopentano[ d ][1,2,3]triazolines in methanol resulted in the elimination of nitrogen, accompanied by cyclopentane ring opening with the formation of N -hetarylvaleramidines. Amidines containing pyrimidine-2,4-dione ring were synthesized by a one-step procedure – the reaction of 5-azidopyrimidine-2,4-diones with endocyclic enamines containing a cyclopentene ring proceeded through an N-pyrimidyl-1,2,3-triazoline intermediate. Triazolines containing a 1,3,5-triazine ring at position 1 did not form valeramidines upon refluxing in methanol. N -(1,3,5-triazin-2-yl)cyclopenta[ d ][1,2,3]triazoline containing a morpholine ring at position 6a underwent a different type of transformation upon dissolving in acetic acid, resulting in the formation of N -(1,3,5-triazin-2-yl)diaminoalkene. Mechanisms for these transformations are proposed. Authors: Nikolay A. Belyaev, Tetyana V. Beryozkina, Gert Lubec, Wim Dehaen, Vasiliy A. Bakulev

DIASTEREOSELECTIVE SYNTHESIS OF 1,2,3-TRIAZOLINES FUSED WITH PENTANE AND DIHYDROPYRAN RINGS

As a result of studying the reactions of 5-azido-1-methyl-4-nitroimidazole and 2,4,5-trimethoxy-1,3,5-triazine with endocyclic enamines, a diastereoselective method was developed for the synthesis of 1-hetarylcycloalkano[1,2,3]triazolines with cis configuration of substituents at the bridgehead carbon atoms. The structures of the obtained reaction products were studied by methods of NMR spectroscopy, high-resolution mass spectrometry, and X-ray structural analysis. Authors: Nikolay A. Belyaev, Tetyana V. Beryozkina, Vasiliy A. Bakulev*, Oleg S. Eltsov, Gert Lubec

New transformations of N-hetarylcyclopentano[d][1,2,3]triazoline ring into 5-alkoxyvaleramidines

It was found that brief refluxing of N-hetarylcyclopentano[d][1,2,3]triazolines in methanol resulted in the elimination of nitrogen, accompanied by cyclopentane ring opening with the formation of N-hetarylvaleramidines. Amidines containing pyrimidine-2,4-dione ring were synthesized by a one-step procedure – the reaction of 5-azidopyrimidine-2,4-diones with endocyclic enamines containing a cyclopentene ring proceeded through an N-pyrimidyl-1,2,3-triazoline intermediate. Triazolines containing a 1,3,5-triazine ring at position 1 did not form valeramidines upon refluxing in methanol. N-(1,3,5-triazin-2-yl)cyclopenta[d][1,2,3]triazoline containing a morpholine ring at position 6a underwent a different type of transformation upon dissolving in acetic acid, resulting in the formation of N-(1,3,5-triazin-2-yl)diaminoalkene. Mechanisms for these transformations are proposed.

Diastereoselective synthesis of 1,2,3-triazolines fused with pentane and dihydropyran rings

As a result of studying the reactions of 5-azido-1-methyl-4-nitroimidazole and 2,4,5-trimethoxy-1,3,5-triazine with endocyclic enamines, a diastereoselective method was developed for the synthesis of 1-hetarylcycloalkano[1,2,3]triazolines with cis configuration of substituents at the bridgehead carbon atoms. The structures of the obtained reaction products were studied by methods of NMR spectroscopy, high-resolution mass spectrometry, and X-ray structural analysis.

A catalyst and additive-free three-component reaction of highly electrophilic azides with cyclic ketones and cycloaliphatic amines. Synthesis of novel N-heteroaryl amidines

Highly electrophilic 5-azido-1-methyl-4-nitro-1H-imidazole and sulfonyl azides were demonstrated to react with alicyclic amines and cyclic ketones in the absence of any catalyst or additive to afford novel N-(4-nitroimidazol-5-yl)- or N-sulfonylamidines respectively. Based on single crystal X-ray analysis, a revision of the previously reported data of Gao and co-workers on the direction of the reaction of sulfonyl azides with endocyclic enamines was made. The reaction of 2,6-diazidopyridine with an enamine, 4-(cyclohex-1-en-1-yl)morpholine, proceeded with cyclization of the azide moiety onto the pyridine CN bond to form an amidine bearing the tetrazolo[1,5-a]pyridine fragment.

Preparation of fluorine-containing exo- and endocyclic enamine derivatives of 2-acylcyclopentane-1,3-diones

The interaction of aromatic amines (4-fluorinebenzylamine, 3-trifluoromethylbenzylamine, 4-fluoroaniline, or 3,4-difluoroaniline) with either 2-acylcyclopentane-1,3-diones (fluorine-substituted or fluorine-free) or their enol derivatives (chlorovinyldiketones) has led to fluorine-containing exo- or endocyclic enamine derivatives of 2-acylcyclopentane-1,3-diones.

ChemInform Abstract: Chiral Nonracemic Synthesis and Reactivity of Two New Endocyclic Enamines in the Phenyloxazolopiperidine Series.

ChemInform Abstract: Chiral Nonracemic Synthesis and Reactivity of Two New Endocyclic Enamines in the Phenyloxazolopiperidine Series.

Synthesis and conformational study of 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines

A new class of endocyclic enamines, 1,6-disubstituted 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines, was synthesized from 4-piperidone imines by successive subjecting the latter to lithiation with lithium diethylamide, to alkylation with 1-bromo-3-chloropropane, and to intramolecular cyclization. All stages were carried out as a unique process without isolation of the intermediate compounds. A thorough optimization of the process conditions, workup, and product storage was carried out. The conformational study of 1,6-disubstituted 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines was performed.

Synthesis of Substituted Pyrrolidines and Piperidines from Endocyclic Enamine Derivatives. Synthesis of (.+-.)-Laburnamine.

For Abstract see ChemInform Abstract in Full Text.

Synthesis of Substituted Pyrrolidines and Piperidines from Endocyclic Enamine Derivatives. Synthesis of (.+-.)-Laburnamine.

For Abstract see ChemInform Abstract in Full Text.

Synthesis of Substituted Pyrrolidines and Piperidines from Endocyclic Enamine Derivatives. Synthesis of (.+‐.)‐Laburnamine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Generation of Quaternary Stereocenters by Asymmetric Michael Reactions: Enamine Regiochemistry as Configuration Switch

Regioselective enamine formation from cyclic beta-diketones 1 is obtained by the appropriate choice of activating agent: Brønsted acid catalyzed condensation gives endocyclic enamines 3 as the thermodynamically favored products. Activation with Lewis acid BF(3).OEt(2) affords betaines 8 as intermediate products, which can be reacted with L-valine diethylamide (2) to preferentially furnish exocyclic enamines 4 as kinetic products. Derivatives with quaternary stereocenters were accessible from both isomeric enamines by using asymmetric, copper(II)-catalyzed Michael reactions at ambient temperature. Both regioisomers afford the triketones 7 with the same constitution but bearing the opposite absolute configuration at the quaternary stereocenter. Thus, both enantiomers of the product are prepared by using the same chiral auxiliary derived from L-valine.

Synthesis of substituted pyrrolidines and piperidines from endocyclic enamine derivatives. Synthesis of (±)-laburnamine

Functionalization of the α- and β-positions of readily available endocyclic enamine derivatives provides a convenient method for the formation of substituted pyrrolidines and piperidines. α-Alkoxy-β-iodopyrrolidines are formed by the electrophilic addition of iodine to the endocyclic enamine double bond of an N-substituted 2-pyrroline, and nucleophillic attack by an alcohol on the intermediate iodonium ion. The resultant α-alkoxy-β-iodopyrrolidines can be used in radical cyclization reactions to give bicyclic hemiaminal compounds, which can be further elaborated using N-acyliminium chemistry to form α,β- cis-dialkylsubstituted pyrrolidines. A strategy for the incorporation of amino functionality at the β-position was also established by using iodoamination of the enamine double bond, followed by migration of the amine functionality through an aziridination/methanolysis protocol. An alternative method uses an azidomethoxylation protocol using ceric ammonium nitrate (CAN) in the presence of NaN 3 and methanol. Formation and trapping of the N-acyliminium ions derived from these substrates, afforded the 3-carbamate and 3-azido-2-substituted products with good diastereoselectivity, with the preferential formation of the trans and cis stereoisomers, respectively. Using the sequential iodoamination, aziridination in methanol and N-acyliminium transformation, trans-3-NHCO 2Me-2-allyl-pyrrolidine was prepared, which was used as the key precursor in a synthesis of the natural 1-amidopyrrolizidine alkaloid, (±)-laburnamine.

Organolanthanide Catalyzed Intramolecular 5-endo-dig Hydroamination: An Unusual Anti-Markovnikov Cyclization

Intramolecular 5-endo-dig hydroaminations of homopropargylamine derivatives were efficiently catalyzed by the organolanthanide precatalyst, Cp* 2 YbCH(TMS) 2 (Cp* = C 5 Me 5 ), to give the endocyclic enamine products. The 5-endo-dig hydroamination was also preferred in the presence of another olefin that would afford a 6-exo cyclization.

Regioselective Enamine Formation from Oxonia‐Boranuida‐Betaines and Their Application in Asymmetric Michael Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regioselective Enamine Formation from Oxonia‐Boranuida‐Betaines and Their Application in Asymmetric Michael Reactions

Abstractβ‐Diketonato borate betaines 2 are readily accessible by the reaction of β‐dicarbonyl compounds 1 with BF3·OEt2. Reaction of borates 2 with L‐valine diethylamide (3a) gives almost exclusively the exocyclic enamines 4 as the kinetic products. In contrast, direct, acid catalyzed conversion of β‐diketones 1 with the chiral auxiliary 3a yield the endocyclic enamines 5 as the thermodynamic products. Both enamines 4 and 5 give products with quaternary stereocenters in high selectivity in copper‐catalyzed asymmetric Michael reactions with methyl vinyl ketone (8). But interestingly, exo‐ and endocyclic enamines are complementary with respect to stereochemistry of the subsequent Michael reactions since they give stereocenters with opposite configurations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

A novel and efficient total synthesis of cephalotaxine.

[reaction: see text] Total synthesis of cephalotaxine (CET), the parent member of a class of structurally unique antileukemia Cephalotaxus alkaloids, was accomplished on the basis of a conceptually novel strategy featuring transannular reductive skeletal rearrangements as the key transformations for the construction of the pentacyclic ring skeleton of CET. The synthetic potential of the designated Clemmensen-Clemo-Prelog-Leonard reductive rearrangement was demonstrated for the first time in a facile synthesis of the benzazepine subunit of CET. A novel endocyclic enamine (cyclopentenone) annulation was discovered and rationalized as an unusual azo-Nazarov-type cyclization.

Regioselective Formation ofendo- andexo-Cyclic Enamines: Both Enantio­meric Products Accessible by the Same Chiral Auxiliary

The copper-catalyzed conversion of exo-cyclic enamines 4a-c with methyl vinyl ketone (2) yields spirocyclic products 6a-c in a sequence of Michael and aldol reaction. The application of the chiral auxiliary L-valine diethylamide results in the formation of quaternary stereocenters with high enantiomeric excess. The configuration of intermediate imine 5a is determined to be S. Thus, exo-cyclic enamines 4 yield S-configured spiroketones 6, whereas, as shown for spiroketone ent-6c, reaction of endo-cyclic enamines such as 1 generates the opposite configuration in the products applying the same auxiliary L-valine diethylamide 9.