A convenient synthesis of N-vinyl enamides via the lithiation and ring-opening reaction of 2-phenyl-2-oxazolines

A simple and efficient synthesis of N-vinyl enamides via the lithiation and ring-opening reaction of 2-phenyl-2-oxazolines with lithium diisopropylamide at room temperature has been developed. This method is especially suitable for the synthesis of multifunctional enamides. Good yields have been obtained when the reactions were amplified to gram scale.     

Synthesis of 4-amino-1,2,3,4-tetrahydropyridine derivatives by intramolecular nucleophilic addition of tertiary enamides to in-situ generated imines

The reactivity of stable tertiary enamides in nucleophilic addition reaction with various in-situ generated imines was explored. Under very mild conditions, formyl-bearing tertiary enamides reacted with both aromatic and aliphatic amines to form imine intermediates. In the absence or presence of p-toluenesulfonic acid as a catalyst, intramolecular nucleophilic addition of enamide to imine functionality proceeded effectively to produce diverse 4-amino-1,2,3,4-tetrahydropyridine derivatives in good to excellent yields.     

A complementary method to obtain N-acyl enamides using the Heck reaction: extending the substrate scope for asymmetric hydrogenation

A method to prepare N-acyl enamides is reported that is complementary to the existing protocols. Heck reaction of a variety of aryl trifluoromethanesulfonates with commercially available N-vinylacetamide occurred in a highly regioselective fashion to provide these valuable synthetic intermediates. This method permits the formation of N-acyl enamides containing functionality that would not be tolerated by the existing methods. Asymmetric hydrogenation using [diphosphine RhCOD]BF₄ complexes provided optically active protected amines in up to 99% ee. De-acylation occurs without affecting the amine enantiopurity.     

Et_2Zn-promoted β-trans-selective hydroboration of ynamide

The trans-hydroboration of alkyne represents a challenging task in organic synthesis.Reported herein is an Et2 Zn promoted β-trans hydroboration of ynamides by using N-heterocyclic carbene(NHC)-ligated borane as boryl source.The reaction leads to a stereoselective construction of enamides bearing a valuable boryl substituent.Both aromatic and aliphatic ynamides were applicable to the reaction.Synthetic transformation of the C-B bond in the product via Suzuki-Miyaura coupling provides a simple and stereospecific route to multi-substituted enamides.Mechanistic studies were conducted and the possible mechanism was discussed     

Direct C?H Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Direct C? H functionalization of various enamides and enecarbamates was realized through visible‐light photoredox catalyzed reactions. Under the optimized conditions using [Ir(ppy)₂(dtbbpy)PF₆] as photocatalyst in combination with Na₂HPO₄, enamides such as N‐vinylpyrrolidinone could be easily functionalized by irradiation of the reaction mixture overnight in acetonitrile with visible light. The scope of the reaction with respect to enamide and enecarbamate substrates by using diethyl 2‐bromomalonate for the alkylation reaction was explored, followed by an investigation of the scope of alkylating reagents used to react with the enamides and enecarbamates. The results indicated that reaction takes place with quite broad substrate scope, however, tertiary enamides with an internal C?C double bond in the E configuration could not be alkylated. Alkylation of N‐vinyl tertiary enamides and enecarbamates gave monoalkylated products exclusively in the E configuration. Alkylation of N‐vinyl secondary enamides gave doubly alkylated products. Double bond migration was observed in the reaction of electron‐deficient bromides such as 3‐bromoacetyl acetate with N‐vinylpyrrolidinone. A mechanism is proposed for the reaction that is different from reported reactions of SOMOphiles with a nonfunctionalized C?C double bond. Further tests on the trifluoromethylation and arylation of enamides and enecarbamates under similar conditions showed that the reactions could serve as a mild, practical, and environmentally friendly approach to various functionalized enamides and enecarbamates.     

Highly enantioselective hydrogenation of N-phthaloyl enamides

Rh- or Ru-catalyzed highly enantioselective hydrogenation of N-phthaloyl enamides is presented. Electron-rich TangPhos and DuanPhos are found to be effective ligands for Rh-catalyzed hydrogenation of α-aryl enamides and up to 99% ee has been achieved. In contrast, for the hydrogenation of α-alkyl enamide, the Ru-C₃-TunePhos complex is more effective and up to 69% ee can be observed. This work is the first report of the hydrogenation of N-phthaloyl enamides.     

Access to multi-functionalized oxazolines via silver-catalyzed heteroannulation of enamides with sulfoxonium ylides

Disclosed herein is an efficient Ag-catalyzed 4+1 heteroannulation reaction of enamides with α-carbonyl sulfoxonium ylides.The diastereoselective transformation provides a practical access to a diverse range of multi-functionalized oxazoline derivatives.The synthetic utility of the resultant tetrasubstituted oxazolines is further demonstrated by a series of useful manipulations into valuable building blocks of pharmaceutical relevance.     

Efficient construction of polycyclic chromans through 4-methylbenzenesulfonic acid mediated domino 1,6-addition/oxa-Mannich reaction of ortho-hydroxyphenyl substituted para-quinone methides and cyclic enamides

A practical TsOH promoted novel domino 1,6-addition/oxa-Mannich reaction of cyclic enamides and ortho-hydroxyphenyl substituted para-quinone methides was established smoothly under mild reaction conditions. With this developed protocol, sorts of polycyclic compounds with chroman motifs were obtained in high level of yields and moderate to excellent diastereoselectivities (up to >99% yield, >20:1 dr).     

A concise synthesis of indolic enamides: coscinamide A, coscinamide B, and igzamide

A concise synthesis of indolic enamides coscinamide A, coscinamide B, and the brominated tryptamine derivative igzamide is described. Both E- and Z-isomers of these natural compounds were obtained during the thermally assisted dehydration reaction and were tested for antitumor activity. Coscinamide B was found to possess antitumor activity against DU145 with an IC₅₀ of 7.6 μg/mL.     

Reversal of nucleophilicity of enamides in water: control of cyclization pathways by reaction media for the orthogonal synthesis of dihydropyridinone and pyrrolidinone Clausena alkaloids

A highly efficient, metal-free, and divergent method for the synthesis of 3,4-dihydropyridin-2-one and pyrrolidin-2-one Clausena alkaloids and their analogs is reported. While the oxirane-containing enamides underwent the TFA-mediated 6-endo-enamide-epoxide cyclization reaction in Bu(t)OH to produce homoclausenamides, an unprecedented nucleophilic reaction occurred at the alpha-carbon of enamides in water to yield 5-endo-enamide-epoxide cyclization products in excellent yields. The reversal of nucleophilicity of enamides in intramolecular cyclization is discussed in terms of steric and electronic effects of the oxirane-containing enamides.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

1-(N-Acylamino)alkyltriphenylphosphonium salts as synthetic equivalents of N-acylimines and new effective α-amidoalkylating agents

1-(N-Acylaminoalkyl)triphenylphosphonium salts 2a-f on reaction with DBU in MeCN are transformed into 1-(N-acylaminoalkyl)amidinium salts 3a-f. Amidinium salts 3d-f with a proton at the β-position undergo slow tautomerization into the corresponding enamides 6d-f. The same 1-(N-acylamino)alkyltriphenylphosphonium salts 2d-f in the presence of Hünig’s base are transformed directly into the corresponding enamides. Phosphonium salts 2, amidinium salts 3, and enamides 6 react with dialkyl malonates in the presence of DBU to give the corresponding amidoalkylation products. α-Amidoalkylation of dialkyl malonates is not observed in the presence of (i-Pr)₂EtN, yet proceeds well under these conditions with more acidic nucleophiles, for example, phthalimide or benzyl mercaptan.     

Ritter-type iodo(iii)amidation of unactivated alkynes for the stereoselective synthesis of multisubstituted enamides

The Ritter reaction, Brønsted- or Lewis acid-mediated amidation of alkene or alcohol with nitrile via a carbocation, represents a classical method for the synthesis of tertiary amides. Although analogous reactions through a vinyl cation or a species alike may offer a route to enamide, an important synthetic building block as well as a common functionality in bioactive compounds, such transformations remain largely elusive. Herein, we report a Ritter-type trans-difunctionalization of alkynes with a trivalent iodine electrophile and nitrile, which affords β-iodanyl enamides in moderate to good yields. Mediated by benziodoxole triflate (BXT), the reaction proves applicable to a variety of internal alkynes as well as to various alkyl- and arylnitriles. The benziodoxole group in the product serves as a versatile handle for further transformations, thus allowing for the preparation of various tri- and tetrasubstituted enamides that are not readily accessible by other means.

Ritter-type trans-selective iodo(iii)amidation of internal alkynes with benziodoxole triflate and various nitriles has been achieved for the stereocontrolled synthesis of multisubstituted enamides.     

FeCl3-promoted alkylation of indoles by enamides

An efficient iron-promoted alkylation of indoles with enamides has been accomplished under mild reaction conditions. The reaction proceeded with remarkable regioselectivity leading exclusively to substitution by indoles at α-position of enamides.     

Highly regioselective hydroformylation of enamides with phosphite ligands

The regioselective hydroformylation of enamides with a catalyst derived from monodentate phosphites and Rh(acac)(CO)₂ was studied. In the hydroformylation of N-vinylphthalimide, all the biphenol-based ligands led to the branched aldehyde; the fastest reaction was observed when using a sterically bulky phosphite. The olefins (E)-N-propenylphthalimide, vinylpyrrolidone, vinylcaprolactam and vinylcarbazole were also investigated.     

Ethanol as a Hydrogenating Agent: Palladium-Catalyzed Stereoselective Hydrogenation of Ynamides To Give Enamides

Ethanol is shown to act as a hydrogenating agent for ynamides under palladium catalysis. This behavior is different from the normally expected reaction of ethanol addition to alkynes. The reaction shows stereoselectivity for E enamides, which is in contrast to reports using other hydrogenating sources. The method was also extended to ynamines. Alternatively, the use of ethanol and ammonium formate as the hydrogenating source gives Z enamides. The role of ethanol in hydrogenation was demonstrated by means deuterium labeling experiment.     

Computational study of the mechanism and selectivity of ruthenium-catalyzed hydroamidations of terminal alkynes

Density functional theory calculations were performed to elucidate the mechanism of the ruthenium-catalyzed hydroamidation of terminal alkynes, a powerful and sustainable method for the stereoselective synthesis of enamides. The results provide an explanation for the puzzling experimental finding that with tri-n-butylphosphine (P(Bu)₃) as the ligand, the E-configured enamides are obtained, whereas the stereoselectivity is inverted in favor of the Z-configured enamides with (dicyclohexylphosphino)methane (dcypm) ligands. Using the addition of pyrrolidinone to 1-hexyne as a model reaction, various pathways were investigated, among which a catalytic cycle turned out to be most advantageous for both ligand systems that consists of: (a) oxidative addition, (b) alkyne coordination, (c) alkyne insertion (d) vinyl-vinylidene rearrangement, (e) nucleophilic transfer and finally (f) reductive elimination. The stereoselectivity of the reaction is decided in the nucleophilic transfer step. For the P(ⁿBu)₃ ligand, the butyl moiety is oriented anti to the incoming 2-pyrolidinyl unit during the nucleophilic transfer step, whereas for the dcypm ligand, steric repulsion between the butyl and cyclohexyl groups turns it into a syn orientation. Overall, the formation of E-configured product is favorable by 4.8 kcal mol^–1 (Δ^‡ GSDL) for the catalytic cycle computed with P(Bu)₃ as ancillary ligand, whereas for the catalytic cycle computed with dcypm ligands, the Z-product is favored by 7.0 kcal mol^–1 (Δ^‡ GSDL). These calculations are in excellent agreement with experimental findings.     

Ethanol as a Hydrogenating Agent: Palladium‐Catalyzed Stereoselective Hydrogenation of Ynamides To Give Enamides

Ethanol is shown to act as a hydrogenating agent for ynamides under palladium catalysis. This behavior is different from the normally expected reaction of ethanol addition to alkynes. The reaction shows stereoselectivity for E enamides, which is in contrast to reports using other hydrogenating sources. The method was also extended to ynamines. Alternatively, the use of ethanol and ammonium formate as the hydrogenating source gives Z enamides. The role of ethanol in hydrogenation was demonstrated by means deuterium labeling experiment.     

Direct alkenylation of non-aromatic enamides via palladium-catalyzed oxidative coupling: Synthetic developments and applications

Direct C(3) alkenylation of non-aromatic enamides through palladium(II)-catalyzed Fujiwara–Moritani cross-coupling was developed. The reaction scope includes a range of cyclic enamides as well as activated alkenes. The utility of this methodology is illustrated by the synthesis of octa- or tetrahydroquinoline cores obtained from conjugated enamides via Diels–Alder cycloaddition.     

A Giese reaction for electron-rich alkenes

A general method for the hydroalkylation of electron-rich terminal and non-terminal alkenes such as enol esters, alkenyl sulfides, enol ethers, silyl enol ethers, enamides and enecarbamates has been developed. The reactions are carried out at room temperature under air initiation in the presence of triethylborane acting as a chain transfer reagent and 4-tert-butylcatechol (TBC) as a source of hydrogen atom. The efficacy of the reaction is best explained by very favorable polar effects supporting the chain process and minimizing undesired polar reactions. The stereoselective hydroalkylation of chiral N-(alk-1-en-1-yl)oxazolidin-2-ones takes place with good to excellent diastereocontrol.

Giese reaction not anymore limited to electron poor alkenes! A general method for the radical mediated hydroalkylation of electron rich alkenes including enol ethers, silylenolethers, enamides, and enecarbamates has been developed.