Catalytic Asymmetric Construction of Quaternary α‐Amino Acid Containing Pyrrolidines through 1,3‐Dipolar Cycloaddition of Azomethine Ylides to α‐Aminoacrylates

The first catalytic enantioselective 1,3‐dipolar cycloaddition of azomethine ylides to α‐aminoacrylate catalyzed by a AgOAc/ferrocenyl oxazolinylphosphine (FOXAP) system was developed, which exhibits excellent exo‐ and enantioselectivity (92–99 % ee). This process provides efficient access to useful 4‐aminopyrrolidine‐2,4‐dicarboxylic acid (APDC)‐like compounds containing a unique quaternary α‐amino acid unit.     

2,3,4,6‐Tetra‐O‐acetyl‐α‐d‐glucopyranosyl azide

The Cu^I‐catalysed 1,3‐dipolar cycloaddition of an azide and a terminal alkyne is becoming an increasingly popular tool for synthetic chemists. This is the most representative of the so‐called `click reactions' and it is used to generate 1,4‐disubstituted triazoles in high yield. During studies on such cycloaddition reactions, a reduced reactivity of an α‐glucosyl azide with respect to the corresponding β‐anomer was observed. With the aim of understanding this phenomenon, the structure of the title compound, C₁₄H₁₉N₃O₉, has been determined at 140 K. The glucopyranosyl ring appears in a regular ⁴C₁ chair conformation with all the substituents in equatorial positions, except for the anomeric azide group, which adopts an axial orientation. The observed bond lengths are consistent with a strong anomeric effect, which is reflected in a change in dipolar character and hence reduced reactivity of the α‐glucosyl azide.     

Synthesis of new 3‐(4‐oxo‐4H‐chromen‐3‐yl)‐3a,6a‐dihydropyrrolo[3,4‐d]isoxazole‐4,6‐dione derivatives by 1,3‐dipolar cycloaddition reaction

A series of new 3‐(4‐oxo‐4H‐chromen‐3‐yl)‐3a,6a‐dihydropyrrolo[3,4‐d]isoxazole‐4,6‐dione have been synthesized by the reaction of N‐arylmaleimides with nitrile oxide, prepared from α‐chloro‐4‐oxo‐4H‐chromen‐carbaldehyde oximes in situ through 1,3‐dipolar cycloaddition reaction. The structures of all new compounds were confirmed by elemental analysis, ir,¹H nmr and mass spectral data.     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

Synthesis of (3‐N‐substituted‐piperidin‐4‐ylidene)acetic Acid Ethyl Esters

A convenient preparation of skeletons 2A and 2B (cyclic γ,δ‐diamino‐α,β‐unsaturated esters) is reported by a three‐step synthetic route based on a sequence of NBS‐mediated one‐pot α‐bromination/Wittig olefination of piperidin‐4‐one 3 , nucleophilic addition with NaN₃, and followed by PPh₃‐promoted Staudinger reduction/substitution or CuI‐catalyzed Huisgen 1,3‐dipolar cycloaddition.     

Asymmetric Construction of Pyrrolidines Bearing a Trifluoromethylated Quaternary Stereogenic Center via CuI‐Catalyzed 1,3‐Dipolar Cycloaddition of Azomethine Ylides with β‐CF3‐β,β‐Disubstituted Nitroalkenes

A direct and convenient method has been developed for the synthesis of optically active pyrrolidines bearing a quaternary stereogenic center containing a CF₃ group at the C‐3 position of the pyrrolidine ring. The synthesis system, Cu^I/Si‐FOXAP‐catalyzed exo‐selective 1,3‐dipolar cycloaddition of azomethine ylides with β‐CF₃‐β,β‐disubstituted nitroalkenes, provides pyrrolidines with high diastereoselectivities (up to >98:2 d.r.) and excellent enantioselectivities (up to >99.9 ee) and performs well for a broad scope of substrates under mild conditions.     

Synthesis of New Bis‐1,2,4‐Oxadiazoline Derivatives via 1,3‐Dipolar Cycloaddition Reaction

A series of novel bis‐oxadiazoline derivatives 4 was synthesized via 1,3‐dipolar cycloaddition reaction of bis‐aldimines 3 , and nitrile oxides generated in situ from various benzohydroximinoyl chlorides in the presence of Et₃N. The target products were confirmed by IR, ¹H‐NMR, and mass spectrometry.     

1,3‐Dipolar cycloadditions of 9‐diazofluorenes and diphenyldiazomethane to 2‐acyl‐2H‐1,2,3‐diazaphospholes

A series of 2‐acyl‐2H‐1,2,3‐diazaphospholes 3 underwent ready 1,3‐dipolar cycloaddition reactions with 9‐diazofluorenes as the 1,3‐dipole, yielding the respective bicyclic phosphiranes 5 or trimers 7 depending on the reaction conditions employed. The reaction is believed to proceed via the formation of the [3+2]‐cycloaddition adducts followed by elimination of nitrogen from the cyclic azo moiety. In the case of 3c , the phosphatetraazabicyclooctadiene compound 6 has been isolated with no loss of nitrogen. Likewise, the dipolar cycloaddition reaction of diphenyldiazomethane with the >C?P‐ moiety as the 1,3‐dipolarophile gave phosphadiazabicyclohexenes 8 in 32–68% yields.     

Highly Enantioselective Intramolecular 1,3‐Dipolar Cycloaddition: A Route to Piperidino‐Pyrrolizidines

Enantioselective catalytic intermolecular 1,3‐dipolar cycloadditions are powerful methods for the synthesis of heterocycles. In contrast, intramolecular enantioselective 1,3‐dipolar cycloadditions are virtually unexplored. A highly enantioselective synthesis of natural‐product‐inspired pyrrolidino‐piperidines by means of an intramolecular 1,3‐dipolar cycloaddition with azomethine ylides is now reported. The method has a wide scope and yields the desired cycloadducts with four tertiary stereogenic centers with up to 99 % ee. Combining the enantioselective catalytic intramolecular 1,3‐dipolar cycloaddition with a subsequent diastereoselective intermolecular 1,3‐dipolar cycloaddition yielded complex piperidino‐pyrrolizidines with very high stereoselectivity in a one‐pot tandem reaction.     

Metal‐Free Route for the Synthesis of 4‐Acyl‐1,2,3‐Triazoles from Readily Available Building Blocks

Functionalized 1,2,3‐triazole heterocycles have been known for a long time and hold an extraordinary potential in diverse research areas ranging from medicinal chemistry to material science. However, the scope of therapeutically important 1‐substituted 4‐acyl‐1H‐1,2,3‐triazoles is much less explored, probably due to the lack of synthetic methodologies of good scope and practicality. Here, we describe a practical and efficient one‐pot multicomponent reaction for the synthesis of α‐ketotriazoles from readily available building blocks such as methyl ketones, N,N‐dimethylformamide dimethyl acetal, and organic azides with 100 % regioselectivity. This reaction is enabled by the in situ formation of an enaminone intermediate followed by its 1,3‐dipolar cycloaddition reaction with an organic azide. We effectively utilized the developed strategy for the derivatization of various heterocycles and natural products, a protocol which is difficult or impossible to realize by other means.     

A Simple,Efficient One‐Pot Synthesis of 2‐Isoxazoline Derivatives and their Antimicrobial Activity

Synthesis of substituted 2‐isoxazolines derivatives with sulfone functional groups was accomplished by 1,3‐dipolar cycloaddition reaction. The 1,3‐dipolar nitrile oxides generated in situ by reacting α‐formaldoximes with N‐bromosuccinimide in the presence of triethylamine on reaction with activated alkenes in toluene at room temperature afford the corresponding 2‐isoxazolines in high yields. All the 2‐isoxazoline derivatives were assayed for their antibacterial activities against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and antifungal activities against Aspergillus niger and Candida albicans. Most of the compounds showed good antibacterial and antifungal activities.     

Solving the loss of orthogonality during the polyaddition of α‐azide‐ω‐alkyne monomers catalyzed by Cu(PPh3)3Br: Application to the synthesis of high‐molar mass polytriazoles

Polyaddition of an α‐azide‐ω‐alkyne monomer by Cu(PPh₃)₃Br catalyzed 1,3‐dipolar cycloaddition was thoroughly studied as a model system to investigate the orthogonality of this click chemistry process. Indeed, loss of chain‐end functionality and occurrence of side reactions have a tremendous impact on the molar mass of polymers obtained by step growth polymerization. Particularly, SEC, ¹H, and ³¹P NMR experiments have highlighted the occurrence of a Staudinger side‐reaction between azide chain‐ends and PPh₃ from the copper(I) catalyst that dramatically alters M_n of the resulting polytriazoles. A significant enhancement of M_n could be achieved by using an alternative catalyst and optimized experimental conditions, that is, dilution and reaction time. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2470–2476, 2010     

Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine – A Computational Study

It has been shown previously that the reaction of diazomethane with 5‐benzylidene‐3‐phenylrhodanine ( 1 ) in THF at ?20° occurs at the exocyclic C?C bond via cyclopropanation to give 3a and methylation to yield 4 , respectively, whereas the corresponding reaction with phenyldiazomethane in toluene at 0° leads to the cyclopropane derivative 3b exclusively. Surprisingly, under similar conditions, no reaction was observed between 1 and diphenyldiazomethane, but the 2‐diphenylmethylidene derivative 5 was formed in boiling toluene. In the present study, these results have been rationalized by calculations at the DFT B3LYP/6‐31G(d) level using PCM solvent model. In the case of diazomethane, the formation of 3a occurs via initial Michael addition, whereas 4 is formed via [3+2] cycloaddition followed by N₂ elimination and H‐migration. The preferred pathway of the reaction of 1 with phenyldiazomethane is a [3+2] cycloaddition, subsequent N₂ elimination and ring closure of an intermediate zwitterion to give 3b . Finally, the calculations show that the energetically most favorable reaction of 1 with diphenyldiazomethane is the initial formation of diphenylcarbene, which adds to the S‐atom to give a thiocarbonyl ylide, followed by 1,3‐dipolar electrocyclization and S‐elimination.     

Rhodium(II)‐Catalyzed Annulation of Azavinyl Carbenes Through Ring‐Expansion of 1,3,5‐Trioxane: Rapid Access to Nine‐Membered 1,3,5,7‐Trioxazonines

The rhodium(II)‐catalyzed denitrogenative coupling of N‐alkylsulfonyl 1,2,3‐triazoles with 1,3,5‐trioxane led to nine‐membered‐ringed trioxazonines in moderate‐to‐good yields. 1,3,5‐Trioxane, acting as an oxygen nucleophile, reacted with the α‐aza‐vinylcarbene intermediate, giving rise to ylide formation, which was probably the key step in the reaction. Triazoles that contained aryl substituents with various electronic and steric features on the C4 carbon atom were well‐tolerated. The synthesis of trioxazonine derivatives was achieved through a one‐pot, two‐step procedure from 1‐mesylazide and a terminal alkyne by combining Cu^I‐catalyzed 1,3‐dipolar cycloaddition and rhodium‐catalyzed transformations.     

Éthyl 5‐méthylthio‐3‐(4‐nitrophényl)‐3a‐phényl‐3a,4‐dihydro‐3H‐[1,2,4]­triazolo[4,3‐a][1,5]benzodiazépine‐1‐carboxylate

Condensation of N‐p‐nitrophenyl‐C‐ethoxycarbonylnitril­im­ine with 2‐methylthio‐4‐phenyl‐3H‐1,5‐benzodiazepine leads to the title compound, C₂₆H₂₃N₅O₄S. It has been established that 1,3‐dipolar cycloaddition occurs on the C4 =N5 double bond of the 1,5‐benzodiazepine.     

1,3‐Dipolar Cycloaddition Reactions of Organic Azides with Morpholinobuta‐1,3‐dienes and with an α‐Ethynyl‐enamine

The cycloaddition of organic azides with some conjugated enamines of the 2‐amino‐1,3‐diene, 1‐amino‐1,3‐diene, and 2‐aminobut‐1‐en‐3‐yne type is investigated. The 2‐morpholinobuta‐1,3‐diene 1 undergoes regioselective [3+2] cycloaddition with several electrophilic azides RN₃ 2 ( a , R=4‐nitrophenyl; b , R=ethoxycarbonyl; c , R=tosyl; d , R=phenyl) to form 5‐alkenyl‐4,5‐dihydro‐5‐morpholino‐1H‐1,2,3‐triazoles 3 which are transformed into 1,5‐disubstituted 1H‐triazoles 4a , d or α,β‐unsaturated carboximidamide 5 (Scheme 1). The cycloaddition reaction of 4‐[(1E,3Z)‐3‐morpholino‐4‐phenylbuta‐1,3‐dienyl]morpholine ( 7 ) with azide 2a occurs at the less‐substituted enamine function and yields the 4‐(1‐morpholino‐2‐phenylethenyl)‐1H‐1,2,3‐triazole 8 (Scheme 2). The 1,3‐dipolar cycloaddition reaction of azides 2a – d with 4‐(1‐methylene‐3‐phenylprop‐2‐ynyl)morpholine ( 9 ) is accelerated at high pressure (ca. 7–10 kbar) and gives 1,5‐disubstituted dihydro‐1H‐triazoles 10a , b and 1‐phenyl‐5‐(phenylethynyl)‐1H‐1,2,3‐triazole ( 11d ) in significantly improved yields (Schemes 3 and 4). The formation of 11d is also facilitated in the presence of an equimolar quantity of tBuOH. The three‐component reaction between enamine 9 , phenyl azide, and phenol affords the 5‐(2‐phenoxy‐2‐phenylethenyl)‐1H‐1,2,3‐triazole 14d .     

Synthesis,Characterization, and thermoresponsive properties of Helical Polypeptides Derivatized from Poly(γ−4‐(3‐chloropropoxycarbonyl)benzyl‐L‐glutamate)

A series of side‐chain‐functionalized α‐helical polypeptides, i.e., poly(γ‐4‐(3‐chloropropoxycarbonyl)benzyl‐_L‐glutamate) (6) have been prepared from n‐butylamine initiated ring‐opening polymerization (ROP) of γ‐4‐(3‐chloropropoxycarbonyl)benzyl‐_L‐glutamic acid‐based N‐carboxyanhydride. Polypeptides bearing oligo‐ethylene‐glycol (OEG) groups or 1‐butylimidazolium salts were prepared from 6 via copper‐mediated [2+3] alkyne‐azide 1,3‐dipolar cycloaddition or nuleophilic substitution, respectively. CD and FTIR analysis revealed that the polymers adopt α‐helical conformations both in solution and the solid state. Polymers bearing OEG (m = 3) side‐chains showed reversible LCST‐type phase transition behaviors in water while polymers bearing 1‐butylimidazolium and I^? counter‐anions exhibited reversible UCST‐type transitions in water. Variable‐temperature UV‐vis analysis revealed that the phase transition temperatures (T_pts) were dependent on the main‐chain length and polymeric concentration. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2469–2480     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Highly Stereoselective β‐Mannopyranosylation via the 1‐α‐Glycosyloxy‐isochromenylium‐4‐gold(I) Intermediates

While the gold(I)‐catalyzed glycosylation reaction with 4,6‐O‐benzylidene tethered mannosyl ortho‐alkynylbenzoates as donors falls squarely into the category of the Crich‐type β‐selective mannosylation when Ph₃PAuOTf is used as the catalyst, in that the mannosyl α‐triflates are invoked, replacement of the ^?OTf in the gold(I) complex with less nucleophilic counter anions (i.e., ^?NTf₂, ^?SbF₆, ^?BF₄, and ^?BAr₄^F) leads to complete loss of β‐selectivity with the mannosyl ortho‐alkynylbenzoate β‐donors. Nevertheless, with the α‐donors, the mannosylation reactions under the catalysis of Ph₃PAuBAr₄^F (BAr₄^F=tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate) are especially highly β‐selective and accommodate a broad scope of substrates; these include glycosylation with mannosyl donors installed with a bulky TBS group at O3, donors bearing 4,6‐di‐O‐benzoyl groups, and acceptors known as sterically unmatched or hindered. For the ortho‐alkynylbenzoate β‐donors, an anomerization and glycosylation sequence can also ensure the highly β‐selective mannosylation. The 1‐α‐mannosyloxy‐isochromenylium‐4‐gold(I) complex ( Cα ), readily generated upon activation of the α‐mannosyl ortho‐alkynylbenzoate ( 1 α ) with Ph₃PAuBAr₄^F at ?35 °C, was well characterized by NMR spectroscopy; the occurrence of this species accounts for the high β‐selectivity in the present mannosylation.     

1,3‐Dipolar Cycloadditions of α‐Diazo Ketones Derived from N‐Protected (S)‐Proline with Aromatic and Cycloaliphatic Thioketones

Enantiomerically pure α‐oxo diazo compounds derived from (S)‐proline were used for 1,3‐dipolar cycloaddition with aryl and hetaryl thioketones, as well as with cycloalkanethiones. Whereas the reactions with hetaryl thioketones in boiling THF yield α,β‐unsaturated ketones via a cascade of cycloaddition, 1,3‐dipolar electrocyclization, and desulfurization, the analogous reactions with thiobenzophenone and cycloalkanethiones result in the formation of 1,3‐oxathiole derivatives. In the latter case, the 1,5‐dipolar electrocyclization of the intermediate thiocarbonyl ylide is the key step of the reaction sequence. In all cases, the isolated products are optically active, i.e., the multistep processes occur with retention of the stereogenic center incorporated via the use of (S)‐proline as the precursor of the diazo compounds.