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1,2-Bis(diphenylphosphino)ethane (dppe)-ligated palladium(II) complexes catalyze the annulation of internal alkynes with 2-(cyanomethyl)phenylboronates to provide 3,4-disubstituted-2-naphthalenamines in good yields. The annulation reaction proceeds under mild and neutral conditions and requires methanol as an essential solvent. In addition to symmetrical alkynes, unsymmetrical alkynes substituted by aryl, alkyl, and alkynyl groups participate in the annulation to afford the corresponding 2-naphthalenamines with electron-withdrawing sp2- and sp-carbons preferentially located at the C-3 position. Substituents including an alkyl or alkoxy group on the cyanomethyl moiety and a halogen atom on the benzene ring in the boronates are compatible with the reaction conditions. The annulation proceeds through the transmetalation of the palladium(II) complexes with the boronates and alkyne insertion followed by nucleophilic addition of the generated alkenylpalladium(II) species to the intramolecular cyano group. Stoichiometric reactions revealed that the methanol solvent was effective for both transmetalation and catalyst regeneration. [ABSTRACT FROM AUTHOR]

While B3LYP, M06-2X, and MP2 calculations predict the ΔG° values for exchange equilibria between enamines and ketones with similar acceptable accuracy, the M06-2X/6-311+G(d,p) and MP2/6-311+G(d,p) methods are required for enamine formation reactions (for example, for enamine 5a, arising from 3-methylbutanal and pyrrolidine). Stronger disagreement was observed when calculated energies of hemiaminals (N,O-acetals) and aminals (N,N-acetals) were compared with experimental equilibrium constants, which are reported here for the first time. Although it is known that the B3LYP method does not provide a good description of the London dispersion forces, while M06-2X and MP2 may overestimate them, it is shown here how large the gaps are and that at least single-point calculations at the CCSD(T)/6-31+G(d) level should be used for these reaction intermediates; CCSD(T)/6-31+G(d) and CCSD(T)/6-311+G(d,p) calculations afford ΔG° values in some cases quite close to MP2/6-311+G(d,p) while in others closer to M06-2X/6-311+G(d,p). The effect of solvents is similarly predicted by the SMD, CPCM, and IEFPCM approaches (with energy differences below 1 kcal/mol). [ABSTRACT FROM AUTHOR]

The direct chlorination and bromination of (E)-enamines and (Z)-enamides to the corresponding (Z)-configurated α-chloroenamines, α-bromoenamines, and α-chloroenamides have been realized using NiCl2·6H2O or tetrabutyl ammonium bromide as a halide source and (1,1-diacetoxyiodo)benzene as an oxidant. The high stereoselective reactions which produce products with only (Z)-configurations can be attributed to the structure of the intermediates, the conformations of which are controlled by the electrostatic attractions between the positively charged nitrogen atoms and the oxygen atoms of the carbonyl group. This type of electrostatic effect has never been reported in olefin halogenations. For this reason, the three-membered bromonium ion is only a minor intermediate in the enamine bromination pathway. These methods open pathways to prepare α-chloroenamines and α-chloroenamides, which are not accessible via the currently used methods. [ABSTRACT FROM AUTHOR]

HCV NS5B polymerase inhibitor GSK852A (1) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (3) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core 15 from the β-keto ester in one pot and the efficient conversion of ester 6 to amide 19 via enamine lactone 22. Serendipitous events led to identification of the isolable enamine lactone intermediate 22. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone 22. The hydrogen bond was considered an enabler in the proposed pathway from ester 6 to enamine lactone 22 and its rearrangement to amide 19. GSK852A (1) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of 1. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps. [ABSTRACT FROM AUTHOR]

Herein, we describe the synthesis and reactivity of enamines derived from ylidenemalononitriles and ylidenecyanoacetates. The enamine scope was expanded by (1) increasing yields of aldehyde-derived ylidenemalononitriles, (2) incorporating silyl functionalities, and (3) using other amide acetals to expand the substitution patterns of pyridines resulting from enamine cyclization. In addition, methods to produce α-pyrones and polysubstituted pyridines from both ylidenemalononitriles and ylidenecyanoacetates are described. [ABSTRACT FROM AUTHOR]

A synthetic route to a wide range of 2-alkoxyaryl-2-aryl enamines is developed from Rh-catalyzed alkoxyarylation of N-sulfonyl-4-aryl-1,2,3-triazoles with aryl ethers via the elimination of nitrogen molecule. In addition, 2-alkoxyaryl-2-aryl enamines are prepared via tandem Cu-catalyzed cycloaddition and Rh-catalyzed alkoxyarylation starting from alkynes, N-sulfonyl azides, and aryl ethers in one-pot. [ABSTRACT FROM AUTHOR]

Acetylenic enamines generated in situ from readily available enynones and primary amines undergo thermal cyclization in diphenyl ether providing easy access to 4-aryl-2-(trimethylsilylmethylene)-1,2-dihydro-3H-pyrrol-3-ones. This reaction is inherently versatile, allowing for variations of substituents in both enynone and amine. Full regioselectivity along with short reaction time (1-2 h) and simple workup afford single products in good to excellent isolated yields. Fluorescent properties of the obtained compounds were studied. [ABSTRACT FROM AUTHOR]

The reaction of 3-benzoylquinoxalin-2(1H)-ones with enamines (generated in situ from ammonium acetate and the corresponding methylaryl(hetaryl)ketones) proceeds smoothly to give the corresponding substituted 1-(pyrrolyl)benzimidazolone derivatives in moderate yields through the novel rearrangement of 3-benzoylquinoxalin-2(1H)-ones involving a dual cleavage of the C3=N4 and C2-C3 bonds under mild conditions. [ABSTRACT FROM AUTHOR]

α-Branched ketones remain a challenging type of substrates in aminocatalysis due to their congested structures as well as the associated difficulties in controlling chemo- and stereoselectivity. In this work, we have explored asymmetric aminocatalysis with α-substituted β-ketoesters. A simple chiral primary amine catalyst was identified to enable unprecedentedly effective catalysis of β-ketoesters in α-hydrazination and Robinson annulation reaction with good yields and high enantioselectivities. Stoichiometric experiments with preformed enamine ester intermediates revealed their enamine-catalytic nature as well as the critical roles of acidic additives in facilitating catalytic turnovers and in tuning the chemo- and stereoselectivity. With the identical catalytic system, the two reactions demonstrated opposite chiral inductions in terms of the absolute configurations of the newly formed stereogenic centers. Investigations into this intriguing issue by DFT have revealed divergent stereocontrol modes. For α-hydrazination, H-bonding-directed facial attack determines the stereoselectivity, whereas a steric model is applied to the Robinson annulation where dual activations of both β-ketoester and vinyl ketone/aldehyde are involved. [ABSTRACT FROM AUTHOR]

A synthetically useful protocol has been developed for the preparation of highly functionalized N-pyrrolylbenzimidazol-2-ones. The reaction of variously substituted 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with commercially available enamines in acetic acid results in a rapid rearrangement and formation of N-pyrrolylbenzimidazol-2-ones in modest to excellent yields. The key step of the rearrangement involves the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with enamines. In this case, the atom of carbon which is displaced from the pyrazine ring of quinoxalin-2(1H)-one becomes the fourth carbon atom of the newly formed pyrrole ring. The method is applicable for the aza analogues of quinoxalin-2(1H)-ones. [ABSTRACT FROM AUTHOR]

As demonstrated with the β-(2-furyl)-substituted analogue 1b, β-aryl-α-nitro-α,β-enals (1) behave as heterodienes against enamines and enol ethers using their enal unit (e.g., 1b → 12). α-Nitro-α,β-enals can act as well as highly reactive dienophiles to render adducts endowed with nitrogenated quaternary centers (e.g., 1b → 15a). A hetero-Diels-Alder (HDA)/Diels-Alder (DA) sequence from 1b also proved feasible on serial treatment with ethyl vinyl ether and Danishefsky's diene (1b → 14). [ABSTRACT FROM AUTHOR]

Stereoselective palladium-catalyzed oxidative C--N bond coupling reactions between aromatic amines and alkenes involving a solvent-controlled regioselective bromination process under 1 atm of oxygen atmosphere are disclosed, providing easy access to two different brominated enamines. The addition of hydrogen peroxide (30% aq) as a co-oxidant in the system is crucial for the dehydrogenative aminohalogenation under molecular oxygen (1 atm), and in such a case, the C--N bond coupling/electrophilic bromination reaction cascade is proposed. Furthermore, the different reaction media leads to a switched regioselectivity of the process. [ABSTRACT FROM AUTHOR]

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one, 1) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of trans-isoquinolinone 2 (4-aH, 9-O-trans-9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound 12. Optical resolution was carried out on 2, and each of the enantiomers were used in efficient syntheses of the "unnatural" 4aR,7aS,12bR-(+)-1) and its "natural" enantiomer (-)-1. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (-)-2), gave (+)- and (-)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12bR)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo[2,3]oxocino[5,4-c]pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study. [ABSTRACT FROM AUTHOR]

The reaction of ortho-lithiated aryloxiranes with various enaminones straightforwardly affords new functionalized isochromanes as mixtures of two epimeric stereoisomers in reasonable to very good yields (50-90%). The two diastereomers, which show a high structural variability, can be easily separated by column chromatography. [ABSTRACT FROM AUTHOR]

The iridoid natural products iridomyrmecin, isoiridomyrmecin, teucriumlactone, and dolicholactone were prepared from citronellol using a divergent diastereoselective approach. Key steps include a highly diastereoselective enamine/enal cycloaddition and the selective reduction of masked aldehyde functionalities by ionic hydrogenation. [ABSTRACT FROM AUTHOR]

A ligand-free method for the Pd-catalyzed direct arylation of cyclic enaminones using aryl iodides was developed. This method can be applied to a wide range of cyclic enaminones and aryl iodides with excellent C5-regioselectivity. Using widely available aryl iodides, the generality of this transformation provides easy access to a variety of 3-arylpiperidine structural motifs. [ABSTRACT FROM AUTHOR]

A simple and effective method for the synthesis of 7-oxabicyclo[2.2.1]heptanes and 8-oxabicyclo[3.2.1]octanes from acetonyl C-glycoside substrates is described, which involves an intramolecular cyclization reaction through a nucleophilic substitution at C-5 or C-6 of C-glycosides by a 2'-enamine intermediate formed in the presence of pyrrolidine. Because anomeric epimerization occurs under these conditions, C-glycoside substrates with either anomeric configuration were converted to the same product(s) in same stereoselectivity and similar chemical yield. [ABSTRACT FROM AUTHOR]

An efficient and straightforward four-component synthetic protocol has been developed to synthesize imidazo[1,2-a]pyridines and imidazo[1,2,3-ij][1,8]naphthyridine derivatives incorporating medicinally privileged heterosystems from heterocyclic ketene aminals, aldehydes, diketene, and amines via cascade reactions, including diketene ring-opening, Knoevenagel condensation, aza--ene reaction, imine--enamine tautomerization, cyclocondensation, and intramolecular SNAr. This strategy can provide an alternative approach for easy access to the highly substituted imidazo[1,2-a]pyridine derivatives in moderate to good yields using four simple and readily available building blocks under mild conditions. Importantly, the unusual splitting peaks in the ¹H NMR spectra of the products derived from heterocyclic ketene aminals with an o-halogen atom on the aryl ring were explained reasonably by varying the temperature in NMR analysis. [ABSTRACT FROM AUTHOR]

Whereas cascade reactions catalyzed by secondary amines combine iminium- and/or enamine-catalyzed reactions, we introduce the feasibility of combining these modes of catalysis with dienamine-catalysis as a new general mechanism for cascade reactions. Enantioenriched β-functionalized-γ-amino alcohols were produced from simple achiral enals in one flask by combining dienamine- and iminium-catalyzed intermolecular reactions. Reaction products are precursors of γ-amino acids, γ-lactams, and pyrrolidines; one was employed in a synthesis of γ-amino acid (S)-vigabatrin, the bioactive enantiomer of Sabril. [ABSTRACT FROM AUTHOR]

Novel enamine--metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved. [ABSTRACT FROM AUTHOR]

Regio- and stereoselective alkynylation of various N-heterocydes 1a-1 using potassium and cesium salts in DMSO is described. Terminal alkynes 2a-k and internal alkynes 4a-f provided the kinetically stable Z-enamines 3a-1 and 5a-i in good to excellent yields using KOH at 120 °C. Addition of heterocyclic amines to 1,3- and 1,4-diethynyIbenzene 6a-b provided the mixture of E/Z isomers with KOH; however, with Cs2CO3 selectively Z-isomers 7ab-db were obtained by the hydroamination at one triple bond. This developed methodology also provides an easy and novel access for the synthesis of enaminones 10a-c. The detailed work also supports the formation of cis-isomer by preferential addition of o-haloarylalkynes followed by intramolecular C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo[2,1-a]isoquinolines. [ABSTRACT FROM AUTHOR]

Treatment of β-monosubstituted enamines with phenyliodine bis(trifluoroacetate) (PIFA) was found to give a variety of 4,5-disubstituted 2-(trifluoromethyl)oxazoles. This approach allows the incorporation of the trifluoromethyl moiety in PIFA into the final products, which presumably takes place via the oxidative β-trifluoroacetoxylation of the enamine substrates followed by subsequent intramolecular cyclization. [ABSTRACT FROM AUTHOR]

A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed- The coupling procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol% of copper(l) iodide and 20 mol% of ethylenediamine as the catalyst in dioxane at 110°C in the presence of K3PO4 as the base. When treated with acid, these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracydic indole derivatives with a quaternary stereocenter attached to the C2-position of the indole ring. An alternative strategy for selective functionalizarion at the C2-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical cyclization of a santhate derivative. The work described provides an attractive route to the tetracyclic core of some vinca alkaloids, including the tetrahydroisoquinocarbazole RS-2135. [ABSTRACT FROM AUTHOR]

A set of coumarin-fused electron-deficient 1,3-dienes was synthesized, which differ in the nature of the electron-withdrawing group (EWG) at the terminus of the diene unit and (when EWG = CO2Me) the nature and position of substituents. These dienes reacted with the enamine derived from cyclopentanone and pyrrolidine to afford the corresponding cyclopenteno-fused 6H-dibenzo[b,d]pyran-6-ones, most likely via a domino inverse electron demand Diels--Alder (IEDDA)/elimination/transfer hydrogenation sequence. The parent diene (EWG = CO2Me, no substituents) was reacted with a range of electron-rich dienophiles (mostly enamines) to afford the corresponding 6H-dibenzo[b,d|pyran-6-ones or their nondehydrogenated precursors, which were aromatized upon treatment with a suitable oxidant. The enamines could either be synthesized prior to the reaction or generated in situ. The syntheses of 30 dibenzopyranones are reported. [ABSTRACT FROM AUTHOR]

We report herein a three-component reaction of propargylic alcohols with 2-butynedioates and secondary amines, which furnished functionalized dihydroazepines. In the cases where benzylmethylamine and benzyl-i-propylamine were used as the secondary amine, the reaction afforded 2,5-dihydro-lH-pyrroIes and 2,3-dihydro-1H-pyrroles, respectively, as the major product along with the desired dihydroazepines. The reaction mode depends on the electronic and steric effect of the substitutents on the secondary amines used. A tentative mechanism for this cascade process is postulated. The key intermediate is ascribed to 1,3,4-pentatrien-1-amine, which is formed by trapping the in situ generating allenic carbocation with enamine. Because of the reactivity of 1,3,4-pentatrien-1-amine formed, different products were thus formed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A new and efficient synthesis of polysubstituted pyrroles by a sequential one-pot three-component reaction between primary aliphatic amines, active methylene compounds, and 1,2-diaza-1,3-dienes (DDs) is reported. The reactions were performed without catalyst and under solvent-free conditions with complete control of pathway selectivity. Notably, the ready availability of the starting materials and the high level of practicability of the reaction and work up make this approach an attractive complementary method for access to unknown poly-substituted pyrroles. [ABSTRACT FROM AUTHOR]

A complete reversal of diastereoselectivity was observed for reactions of the trifluoroacetaldehyde ethyl hemiacetal with enamines and imines, derived from propiophenones, that produce 4,4,4-trifluoro-1-aryl-3-hydroxy-2-methyl-1-butanones. This process serves as the first reliable, metal-free, complementary anti- and syn-selective method to prepare 4,4,4-trifluoro-1-aryl-3-hydroxy-2-methyl-1-butanones. [ABSTRACT FROM AUTHOR]

A Cu(II)-mediated synthesis of indolequinones from the corresponding bromoquinones and enamines is reported. The key oxidative cyclization proceeds in good yield for a broad range of substrates and can be performed on a multigram scale, allowing access to biologically interesting structures. [ABSTRACT FROM AUTHOR]

The addition of the N-H bond over alkene and alkyne н-systems, the hydroamination transformation, represents a powerful method for the introduction of the amine functionality.' Such transformations give access to a range of valuable nitrogen-containing building blocks such as amines, imines, and enamines. Within this group of reactions the intermolecular hydroamination of allenes has become increasingly important due to the regiochemical factors in such transformations. Allenes (1) can undergo either Markovnikov or anti-Markovnikov addition, giving rise to allylamines (2a) or imines (2b) (Scheme 1). This first group of substrates, allylamines, are vital synthetic building blocks since they are contained within a number of important biological systems and are key intermediates in organic synthesis.2 A number of transition metal approaches toward the hydroamination of allenes have been reported, including the use of Zr (anti-Markovikov), Hg (Markovnikov), Pt (Markovnikov), and Pd (Markovnikov) salts.3 Additional to these transition metals, Au salts have proved to be particularly attractive in hydroamination reactions due to their low toxicity and increased stability to moisture and air.4 Consequently, a number of groups have utilized Au salts in these transformations to great effect.1b5 Recently, we reported6 the first intermolecular hydroarylation of allenamides7 with electron-rich aromatics using an Au(l) caalyst to give the corresponding enamides. Enamides8 are a class substrates that have become particularly topical due to their use in the construction of heterocycles and chiral amines and their presence in a number of natural product frameworks.9 This transformation was high yielding for most substrates and gave exclusively the E-enamide. [ABSTRACT FROM AUTHOR]

A method for the fluorocyanation of enamines has been described. The reaction involves fluorination of the elec- tron rich double bond with N-F reagent (Selectfluor or NFSI) accompanied by trapping of β-fluoroiminium cationic intermediate with cyanide nucleophile. [ABSTRACT FROM AUTHOR]

The synthesis of 3H-indoles was achieved via the iodinemediated intramolecular cyclization of enarnines. A wide variety of 3 H-indole derivatives bearing multi functional groups were obtained in good to high yields under transition metal-free react ion conditions. [ABSTRACT FROM AUTHOR]

An alternative synthesis of 1,1'-bis-valienamine 5, which was demonstrated to be a potent trehalase inhibitor, has been achieved from u-glucose in 12 steps with 15% overall yield via enone 12 as the key intermediate, involving a direct aldol reaction of a glucose-derived diketone and a palladium-catalyzed allylic coupling reaction as the key steps. [ABSTRACT FROM AUTHOR]

The diastereo- and enantioselectivity obtained experimentally by List on the proline-catalized intramolecular aldol reaction of substituted 1,7-dicarbonylic compounds was accurately predicted using density functional theory methods at the B3LYP/6-31 ++G** level. A polarizable continuum model was used to describe solvent effects. The theoretical data agree in good extension with List's experimental results, both in enantioselectivity and diastereoselectivity, and allow for the confirmation of our previous rationalization of the main factors contributing to the reaction selectivity. While the enantioselectivity results from an important electrostatic contact between the forming alkoxyde group and the proline moiety, the calculated diasteroselectivity results from several steric contacts that can be established between the different substituents and from their relative orientation in respect to the ring conformation. However, for dialdehydes that can originate two diastereomeric enamine intermediates, the proline attack and the immonium formation steps can also be of major importance in the rationalization of the final reaction selectivity, as is the case in two of the six studied systems. The obtained data allows for a full rationalization of the known experimental systems as well as for the extrapolation to new ones with variable substitution at the carbonylic chain. [ABSTRACT FROM AUTHOR]

L-Prohne-catalyzed three-component reactions of ethyl 2- [(2-oxo-2-arylethyl)sulfonyllacetate or ethyl 2-[(2-ethoxy- 2-oxoethyl)sulfonyl]acetate, aromatic aldehydes, and 5- aryltetrahydro-3-thiophenone furnished a variety of highly substituted thieno[3,2-c]thiopyran derivatives. This facile transformation presumably occurs via a one-pot domino sequence of enamine formation/aldol condensation/Michael addition/6-exo-trig cyclization/elimination and involves the creation in a single operation of three C-C bonds and the generation of three new stereocenters with complete diastereoselectivity in all cases and a fourth one in ca. 7:3 diastereomeric ratio when starting from a 5-substituted tetrahydro-3-thiophenone derivative. [ABSTRACT FROM AUTHOR]

An α hydroxy pyrrolidine tricyclic nucleoside 3 and its spontaneous reaction with acetone is described. In this transformation highly functionalized polycyclic nucleosides with rather unusual molecular skeletons are formed in a complete regio- and stereoselective way. The reaction involves the formation of three new bonds, two of them novel carbon-carbon bonds, in a one-pot way. An enamine-iminium mechanism with participation of carbinolamine, iminium ion, and enamine intermediates is proposed as a plausible explanation for this transformation. The scope of the reaction is briefly studied concluding that the nature of the ketone (R¹COR²) is critical for the initial attack of the NH to the carbonyl group. [ABSTRACT FROM AUTHOR]

Rhodium-catalyzed carbozincation of ynamides using diorganozinc reagents or functionalized organozinc halides is described. Using a tri(2-furyl)phosphine-modified rhodium catalyst, the reaction course is altered to hydrozincation when diethylzinc is employed as the organozinc reagent. Trapping of the alkenylzinc intertnediates produced in these reactions in further functionalization reactions is possible. Collectively, these processes enable access to a range of multisubstituted enamides in stereo- and regiocontrolled fashion. [ABSTRACT FROM AUTHOR]

Cyclic enamine derivatives (enesulfonamides and enamides) tethered to an l-arylalkynyl fragment undergo a platinum(II)-catalyzed tandem alkyne addition/Friedel-Crafts ring closure to form nitrogen-containing polycydic structures. Regioselectivity in the initial addition of the eneaulfonamide or enamide nucleophile to the platinum(II)-alkyne complex is important. Electron-rich arenes and heterocycles led to the formation of products resulting from an initial 6-endo cyclization. Twenty-three examples of this process are presented. [ABSTRACT FROM AUTHOR]

The oxidation of 2-methyithiazoles to 2-formylthiazoles simplifies the implementation of the Bagley variant of the Bohlmann-Rahtz reaction as a key step in a concise new route to pyridine cores of thiopeptide antibiotics. [ABSTRACT FROM AUTHOR]

Stereoselective syntheses of the valuable fluorinated amino acids (2S,3S)-4,4,4-trifluorovaline and (2S,4S)-5,5,5-trifluoroleucine have been achieved starting from 4,4,4-trifluoro-3-methylbutanoic acid by using a conceptually simple transformation: conversion to a chiral oxazoline, SeO2-promoted oxidative rearrangement to the dihydro-2H-oxazinone, and face-selective hydrogenation of the CN bond, followed by hydrogenolysis-hydrolysis. The transformation is limited by the tendency of the intermediate β-trifluoromethyldihydrooxazinone to undergo imine-enamine isomerization. Both amino acids were obtained as configurationally pure hydrochloride salts identical in all respects with those in literature reports. [ABSTRACT FROM AUTHOR]

A practical and efficient synthesis of bradykinin B1 antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10. The key to the success of the synthesis was the development of a fluorodenitration step to install the fluorine in pyridine 7 and a catalytic enantioselective hydrogenation of N-acyl enamide 9 to set the stereochemistry. [ABSTRACT FROM AUTHOR]

A series of highly efficient organocatalysts have been derived from naturally available amino acids for carrying out enantioselective direct aldol reaction in both organic and aqueous medium. The aldol products were obtained in high diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) for a broader range of substrates using 1 mol % of a catalyst. The results demonstrate that the structural features of organocatalysts play a crucial role in obtaining high optical purity of aldol adducts in an aqueous medium. Further, the role of water in increasing the rate and enantioselectivity of the reaction has been illustrated. Moreover, the aldol products have been employed in the synthesis of chiral amino alcohols which act as useful intermediates for building up complex natural products. [ABSTRACT FROM AUTHOR]

The synthesis of highly functionalized N-hydroxypyrrole derivatives by the formal [3+2] cycloaddition reaction of enamines and nitroso alkenes derived from phosphine oxides and phosphonates is reported. Intermediate phosphorylated nitrones, whose formation can be explained by a conjugate addition of enamines to phosphorylated nitroso alkenes and formation of the five-membered heterocycles, are isolated. [ABSTRACT FROM AUTHOR]

A new class of discotics derived from tris(N-salicylidene-aniline)s have been synthesized and their thermal and photophysical properties are investigated. These systems with outer 1,3,4-oxadiazole wings exist in an inseparable mixture of two keto-enamine tautomeric forms with C3h and Cs rotational symmetries, and self-assemble into fluid columnar phase over a wide thermal range as evidenced by several complementary studies. They possess emissive characteristics in both solution and columnar states; the blue light (χ = 474 nm) emission has been evidenced for the former state. [ABSTRACT FROM AUTHOR]

A new reactivity mode of hindered lithium amides with terminal epoxides is described whereby aldehyde enamines are produced via a previously unrecognized reaction pathway. Some of these aldehyde enamines display unprecedented C-alkylation reactivity toward unactivated primary and secondary alkyl halides. For comparison, the reactivity of aldehyde enamines synthesized via a traditional condensation method was examined. C- rather than N-alkylation was the dominant reaction pathway found with a range of electrophiles, making this route to α-alkylated aldehydes more synthetically useful than previously reported. [ABSTRACT FROM AUTHOR]

Addition of guanidine to a 6-methyihexahydroindenone in MeOH at 85 °C afforded 7-epineoptilocaulin. A similar reaction with a 6-propyihexahydroindenone afforded netamine E. Mn02 oxidation of 7-epin- eoptilocaulin and netamine E afforded mirabilin B and netamine G, respectively. The netamines have the side chains trans, not cis as was initially proposed. A unified biosynthetic scheme for the batzelladines and ptilocaulin family is proposed. Conjugate addition of guanidine to a bis enone followed by an intramolecular Michael reaction of the enolate to the other enone, aldol reaction, dehydration, and enamine formation will lead to a tricyclic intermediate at the dehydroptilocaulin oxidation state. 1,4-Hydride addition will lead to ptilocaulin or 7-epineoptilocaulin depending on which face the hydride adds to. 1,2-Hydride addition will lead to isoptilocaulin. The key tricyclic intermediate was prepared from a tetrahydroindenone and guanidine and reduced with NaBH4 to give a mixture rich in ptilocaulin and isoptilocaulin. [ABSTRACT FROM AUTHOR]

A series of enyne-allenes, with and without benzannulation at the ene moiety and equipped with aromatic and carbonyl groups as internal triplet sensitizer units at the allene terminus, was synthesized. Both sets, the cyclohexenyne-allenes and benzenyne-allenes, underwent thermal C2-C6 cyclization exclusively to formal ene products. In contrast, the photochemical C2-C6 cyclization of enyne-allenes provided formal Diels-Alder and/or ene products, with higher yields for the benzannulated systems. A raise of the temperature in the photochemical cyclization of enyne-allene ib' led to increasing amounts of the ene product in relation to that of the formal Diels-Alder product. Laser flash photolysis at 266 and 355 nm as well as triplet quenching studies for lb,b' indicated that the C2-C6 cyclization proceeds via the triplet manifold. On the basis of a density functional theory (DFT) study, a short-lived transient (i = 30 ns) was assigned as a triplet allene, while a long-lived transient (r = 33 his) insensitive to oxygen was assigned as fulvene triplet diradical. An elucidation of the reaction mechanism using extensive DFT computations allowed rationalization of the experimental product ratio and its temperature dependence. [ABSTRACT FROM AUTHOR]

With the catalysis of CuI/N,N′-dimethylethylenediamine, intramolecular C-N coupling between sulfonamides and vinyl halides was successfully implemented, leading to the efficient synthesis of 5-, 6-, 7-, and even 8-membered heterocyclic enamines in both exo and endo modes. The bicyclic enamines thus formed provided a convenient entry to the corresponding 9- to 12-membered lactams by oxidative CC bond cleavage. [ABSTRACT FROM AUTHOR]

Recoverable (Sa)-binam-L-prolinamide in combination with benzoic acid is used as catalysts in the direct aldol reaction between cycloalkyl, alkyl, and α-functionalized ketones and aldehydes under solvent-free reaction conditions. Three different methods are assayed: simple conventional magnetic stirring, magnetic stirring after previous dissolution in THF and evaporation, and ball mill technique. These procedures allow one to reduce not only the amount of required ketone to 2 equiv but also the reaction time to give the aldol products with regio-, diastereo-, and enantioselectivities comparable to those in organic or aqueous solvents. Generally anti-isomers are mainly obtained with enantioselectivities up to 97%. The reaction can be carried out under these conditions also using aldehydes as nucleophiles, yielding after in situ reduction of the aldol products the corresponding chiral 1,3-diols with moderate to high enantioselectivities mainly as anti-isomers. The aldol reaction has been studied by the use of positive ESI-MS technique, providing the evidence of the formation of the corresponding enamine-iminium intermediates. [ABSTRACT FROM AUTHOR]

A combined experimental and. theoretical study is presented on 2-azetines, a class of azaheterocyclic compounds, which are difficult to access but have shown a unique reactivity as strained cyclic enamines. New highly substituted 2-azetines bearing aryl substituents at the 2- and 4-position were synthesized from 3,3-dichloroazetidines. Whereas 2-aryl-3,3-dichloroazetidines gave stable 2-aryl-3-chloro-2-azetines upon treatment with sodium hydride in DMSO, 2,4-diaryl-3,3-dichloroazetidjnes showed a remarkably different reactivity in that they afforded benzimidoyl-substituted alkynes under similar mild treatment with base. The formation of the alkynes involves electrocyclic ring opening of intermediate 2,4-diaryl- 3-chloro-2-azetines and elimination of hydrogen chloride. Ab initio theoretical calculations confirmed the experimental findings and demonstrated that the 4-aryl substituent is responsible for this remarkably enhanced reactivity of 2-azetines toward electrocyclic conrotatory ring opening by a significant decrease in reaction barrier of about 30 kJ/mol. This activation effect by an aryl group in the allylic position toward electrocyclic ring opening of unsaturated four-membered rings is of general importance since a similar increased reactivity of 4-aryloxetes, 4-arylthiete-1,1-dioxides, and 3-arylcyclobutenes has been reported in literature as well. [ABSTRACT FROM AUTHOR]