Rhodium‐Catalyzed Addition of Aryl Boronic Acids to 2,2‐Disubstituted Malononitriles

β‐Ketonitriles bearing a quaternary carbon at the 2‐position were prepared through Rh‐catalyzed addition of aryl boronic acids to 2,2‐disubstituted malononitriles. In contrast to the previously described transnitrilative cyanation of aryl boronic acids with dialkylmalononitriles, the present reaction avoids retro‐Thorpe collapse of the intermediate addition product through the use of a milder base. The reaction was amenable to a variety of aryl boronic acids and disubstituted malononitriles, providing a diverse array of β‐ketonitriles. The products could be further derivatized to valuable chiral α,α‐disubstituted‐β‐aminonitriles through addition reactions to the corresponding N ‐tert ‐butanesulfinyl imines.     

Chemoselective Synthesis of β‐Amino Ester or β‐Lactam via Sonochemical Reformatsky Reaction

A series of β‐amino esters were synthesized by the reaction of N‐tosyl aldimine or N‐hydroxy aldimine with bromoacetate by sonochemical Reformatsky reaction. The β‐N‐hydroxyamino ester was obtained and the formed sensitive hydroxylamino functionality was resistant under the reaction condition. The β‐lactam also was synthesized by the reaction of N‐p‐methoxy aldimine as reacting substrate under this sonochemical Reformatsky reaction condition.     

Transition‐Metal‐Catalyzed Cyanation by Using an Electrophilic Cyanating Agent,N‐Cyano‐N‐phenyl‐p‐toluenesulfonamide (NCTS)

The ability to introduce a nitrile group into a biologically active compound is very useful in organic synthesis, owing to the importance of nitrile groups in transformations and tuning molecular properties. To date, nucleophilic cyanation has been the most used strategy for this purpose, whilst electrophilic cyanation reactions are less developed. Recently, the electrophilic cyanation reagent N‐cyano‐N‐phenyl‐p‐toluenesulfonamide (NCTS) has received increasing attention, owing to its superior properties in terms of safety and practicality. This Focus Review summarizes recent progress in transition‐metal‐catalyzed cyanation reactions that use NCTS.     

Palladium‐Catalyzed Carbonylative α‐Arylation to β‐Ketonitriles

A carbonylative α‐arylation process employing unactivated nitriles for the first time is described. The reaction tolerates a range of (hetero)aryl iodides and several nitrile coupling partners. No prefunctionalization of the nitriles is necessary and the resulting β‐ketonitriles are obtained in good to excellent yields. The methodology also allows for a convenient ¹³C‐labelling of the generated carbonyl moiety.     

Glycopolymeric inhibitors of β‐glucuronidase I. Synthesis and polymerization of styrene derivatives having pendant D‐glucaric moieties

Two kinds of novel vinyl monomers having D ‐glucaric moieties leading to a new type of glycopolymeric inhibitors of β‐glucuronidase, N‐p‐vinylbenzyl‐6‐D ‐glucaramide (6 ) and potassium N‐p‐vinylbenzyl‐6‐D ‐glucaramid‐1‐ate (8 ), were synthesized by the reaction of D ‐glucaro‐6,3‐lactone (3 ) with p‐vinylbenzylamine (5 ) with no catalyst, and the subsequent treatment of the reaction mixture with acetic anhydride and potassium hydroxide aqueous solution, respectively. The radical copolymerization of 8 with acrylamide in various feed ratios at 60°C in 0.1 N potassium chloride aqueous solution gave water‐soluble copolymers (9 ) composed of a synthetic polymeric main chain and many pendant D ‐glucaric chains. The resulting glycopolymers (9 ) were found to inhibit the activity of β‐glucuronidase strongly through a model reaction with p‐nitrophenyl β‐D ‐glucuronide (10 ) in acetic buffer solution (pH 4.7). © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 303–312, 1999     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

Bimetallic Catalytic Asymmetric Tandem Reaction of β‐Alkynyl Ketones to Synthesize 6,6‐Spiroketals

The enantioselective tandem reaction of β,γ‐unsaturated α‐ketoesters with β‐alkynyl ketones was realized by a bimetallic catalytic system of achiral Au^ΙΙΙ salt and chiral N,N′‐dioxide‐Mg^ΙΙ complex. The cycloisomerization of β‐alkynyl ketone and asymmetric intermolecular [4+2] cycloaddition with β,γ‐unsaturated α‐ketoesters subsequently occurred, providing an efficient and straightforward access to chiral multifunctional 6,6‐spiroketals in up to 97 % yield, 94 % ee and >19/1 d.r. Besides, a catalytic cycle was proposed based on the results of control experiments.     

Synthesis of glycopolymers bearing mannaric pendants as inhibitors on the β‐glucuronidase activity: The inhibition mechanisms of mannaric‐ and glucaric‐compounds

A new styrene derivative having D ‐mannaric moiety, N‐p‐vinylbenzyl‐D ‐mannaramic acid (VB‐D ‐ManaH, 8 ) was synthesized though the ring‐opening reaction of D ‐mannaro‐1,4:6,3‐dilactone (D ‐MDL) with p‐vinylbenzylamine. VB‐D ‐ManaH was copolymerized with acrylamide (AAm) to give novel polymers having D ‐mannaric moiety in the pendants, P(VB‐D ‐ManaH‐co‐AAm), 10 . The resulting glycomonomer and polymer ( 8 and 10 ) bearing D ‐mannaric pendants were found to inhibit the β‐glucuronidase activity, although the inhibition ability of the corresponding saccharodilactone (D ‐MDL) was known to be low. Additionally, the inhibition ability of P(VB‐D ‐ManaH‐co‐AAm), 10 , was almost the same as that of the glycopolymer having D ‐glucaric pendants, P(VB‐6‐D ‐GlcaH‐co‐AAm), 1 , which was one of the most effective inhibitors for β‐glucuronidase, reported in our previous work. Thus, 10 and 8 may be the first D ‐mannaric strong inhibitors to the β‐glucuronidase activity. The Lineweaver–Burk plot suggested that the inhibition mechanisms of 10 and 8 were more complicated than in the case of the competitive and uncompetitive inhibition of N‐p‐(vinylbenzyl)‐6‐D ‐glucaramic ( 11 ) and N‐p‐(vinylbenzyl)‐1‐D ‐glucaramic acids ( 12 ), respectively. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2032–2042, 2009     

Ethyl 1,4‐Dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates by a Tandem SNAr‐Addition‐Elimination Reaction

A series of N‐substituted 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylate esters has been prepared in two steps from ethyl 2‐(2‐chloronicotinoyl)acetate. Treatment of the β‐ketoester with N,N‐dimethylformamide dimethyl acetal in N,N‐dimethylformamide (DMF) gave a 95% yield of the 2‐dimethylaminomethylene derivative. Subsequent reaction of this β‐enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47–82% yields by a tandem S_NAr‐addition‐elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.     

Benzenesulfonamidoquinolino‐β‐cyclodextrin as a Cell‐Impermeable Fluorescent Sensor for Zn2+

A water‐soluble benzenesulfonamidoquinolino‐β‐cyclodextrin has been successfully synthesized in 30 % yield by incorporating a N‐(8‐quinolyl)‐p‐aminobenzenesulfonamide (HQAS) group to β‐cyclodextrin through a flexible linker. This compound exhibits a good fluorescence response in the presence of Zn²⁺ in water but gives poor fluorescence responses with other metal ions commonly present in a physiological environment under similar conditions. Fluorescence microscopic and two‐dimensional NMR experiments showed that benzenesulfonamidoquinolino‐β‐cyclodextrin could bind to the loose bilayer membranes. As a result, benzenesulfonamidoquinolino‐β‐cyclodextrin was found to act as an efficient cell‐impermeable Zn²⁺ probe, showing a specific fluorescent sensing ability to Zn²⁺‐containing damaged cells whilst exhibiting no response in the presence of healthy cells.     

Furopyridines. XXVI. Reactions of cyanopyridine derivatives of furo[2,3‐b]‐, ‐[3,2‐b]‐, ‐[2,3‐c]‐ and ‐[3,2‐c]pyridine

Bromination of α‐cyanopyridine derivatives of furopyridines 1a‐d gave the 2,3‐dibromo‐2,3‐dihydro compounds 2a‐d in excellent yields. Treatment of 2a‐d with sodium hydroxide in methanol yielded compounds formed through the dehydrobromination and solvolysis of the nitrile. N‐Oxidation of 1a and 1b gave N‐oxide in much poor yield, while 1c and 1d gave the N‐oxide 13c and 13d in good yields. The nucleophilic reactions (cyanation, chlorination and acetoxylatoin) of 13c through a Reissert‐Henze type reaction gave poor results, which would be caused by the strong electron withdrawing effect of the cyano group.     

Functionalization of Styrenes by Copper‐Catalyzed Borylation/ ortho‐Cyanation and Silver‐Catalyzed Annulation Processes

An efficient two‐step method for the assembly of indanone derivatives starting from a simple vinyl arene has been developed. The sequence first involves addition of bis(pinacolato)diboron (B₂pin₂) and N‐cyano‐N‐phenyl‐p‐methylbenzenesulfonamide (NCTS) to a broad range of styrenes by utilizing IMesCuCl as catalyst. This step simultaneously accomplishes hydroboration of the alkene and ortho cyanation of the benzene unit. The products thus obtained are further functionalized by a AgNO₃/Selectfluor‐mediated coupling of the BPin and cyano functionalities to annulate a new five‐membered ring. This combined two‐step sequence provides a versatile method for the site‐selective derivatization of a broad range of vinyl arene substrates.     

Glycopolymeric inhibitors of β‐glucuronidase. III. Configurational effects of hydroxy groups in pendant glyco‐units in polymers upon inhibition of β‐glucuronidase

Two kinds of new glycopolymers, (P(VB‐1‐GlcaH‐co‐AAm), 9 ) and (P(VB‐1‐Glco‐co‐AAm), 10 ), were synthesized through the radical copolymerization of styrene derivatives bearing pendant D ‐glucaric and D ‐gluconic moieties, N‐(p‐vinylbenzyl)‐1‐D ‐glucaramide (VB‐1‐GlcaH, 7 ), and N‐(p‐vinylbenzyl)‐D ‐gluconamide (VB‐1‐Glco, 8 ), with acrylamide (AAm). Glycopolymer 9 bearing the pendant glucaric moiety at the first position inhibited the hydrolysis of a model compound for xenobiotics‐β‐glucuronide conjugates, p‐nitrophenyl β‐D ‐glucuronide, uncompetitively, in contrast to the competitive inhibition in the presence of the corresponding isomeric glycopolymer bearing the pendant D ‐glucaric unit at the sixth position (P(VB‐6‐GlcaH‐co‐AAm), 3 ) reported in our previous article. On the other hand, another copolymer 10 bearing the gluconic moiety was found not to inhibit the hydrolysis as well as the corresponding copolymer bearing pendant gulonic unit (P(VB‐6‐Glco‐co‐AAm), 4 ). These results indicate that the hydrolysis is influenced not only by existence of pendant carboxyl units but also by the direction on the linkage of the glyco‐units to the polymer frame. Therefore the configurational position of hydroxy groups in pendant glyco‐units in macromolecular inhibitors may be essential for the interaction with β‐glucuronidase. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4895–4903, 2006     

An efficient preparation of β‐dimethylaminovinyl sulfone and sulfoximide,and investigation of their reactivity as dipolarophiles

A simple reaction affording (E)‐1‐dimethylamino‐2‐phenylsulfonylethylene, and S‐((E)‐2‐(N',N'‐dimethylamino)ethenyl)‐S‐phenyl‐N‐(p‐tolylsulfonyl) sulfoximide in high yields is described. A reversal in regioselectivity was observed when the β‐dimethylaminovinyl sulfone was employed as a dipolarophile in cycloadditions with nitrile oxides. The sulfone gives rise mainly to 4‐substituted isoxazoles, after elimination of dimethyl amine. In comparison, phenyl vinyl sulfone cycloadds to give 5‐substituted isoxazolines. Although not showing comparable dipolarophilic activity in reactions with nitrile oxides and nitrile imides, the β‐dimethylaminovinyl sulfoximide was easily converted to S‐((E)‐(3‐ethoxycarbonyl)prop‐2‐enyl)‐S‐phenyl‐N‐(p‐tolylsulfonyl) sulfoximide. This allylic sulfoximide cycloadds in good yield to both benzonitrile oxide and diphenylnitrile imide, but no stereoselectivity was observed in the process; and only modest regioselectivity was detected in the case of benzonitrile oxide.     

N‐Heterocyclic Carbene‐Catalysed Direct Synthesis of Cyano Esters via Cyanation‐Esterification Reaction of α‐Keto Esters

The cyanation‐esterification reaction of α‐keto esters catalysed by N‐heterocyclic carbenes (NHCs) is developed. Under the catalysis of 10 mol% 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene, aromatic and aliphatic α‐keto esters reacted with ethyl cyanoformate or acetyl cyanide to produce the corresponding cyano esters with a tetrasubstituted carbon center in high yields.     

Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐SNAr reaction

The ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2‐(2‐fluorobenzoyl)acetate. Treatment of this β‐ketoester with N,N‐dimethylformamide dimethyl acetal gives a 97% yield of the 2‐dimethylaminomethylene derivative. Reaction of this β‐enaminone with primary amines in N,N‐dimethylformamide at 140°C for 48 h then affords the 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters in 60–74% yields by a tandem addition‐elimination‐S_NAr reaction. The synthesis of the starting material as well as procedural details and a mechanistic scenario are presented. J. Heterocyclic Chem., (2011).     

β‐cyclodextrin‐capped palladium nanoparticle‐catalyzed ligand‐free Suzuki and Heck couplings in low‐melting β‐cyclodextrin/NMU mixtures

Low‐melting β‐cyclodextrin/N‐methylurea (NMU) mixture, an efficient catalytic system for ligand‐free Suzuki and Heck couplings in the presence of fresh native β‐CD‐capped Pd⁰ nanoparticles, has been successfully reported. This natural and convenient system can be performed in air and could afford the corresponding cross‐coupled products in good to excellent isolated yields after a simple workup under every low Pd loading (0.05 mol%). Remarkably, the catalytic system can be recycled and reused without loss of catalytic activity. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis of well‐defined 7‐arm and 21‐arm poly(N‐isopropylacrylamide) star polymers with β‐cyclodextrin cores via click chemistry and their thermal phase transition behavior in aqueous solution

The syntheses of well‐defined 7‐arm and 21‐arm poly(N‐isopropylacrylamide) (PNIPAM) star polymers possessing β‐cyclodextrin (β‐CD) cores were achieved via the combination of atom transfer radical polymerization (ATRP) and click reactions. Heptakis(6‐deoxy‐6‐azido)‐β‐cyclodextrin and heptakis[2,3,6‐tri‐O‐(2‐azidopropionyl)]‐β‐cyclodextrin, β‐CD‐(N₃)₇ and β‐CD‐(N₃)₂₁, precursors were prepared and thoroughly characterized by nuclear magnetic resonance and matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry. A series of alkynyl terminally functionalized PNIPAM (alkyne‐PNIPAM) linear precursors with varying degrees of polymerization (DP) were synthesized via atom transfer radical polymerization (ATRP) of N‐isopropylacrylamide using propargyl 2‐chloropropionate as the initiator. The subsequent click reactions of alkyne‐PNIPAM with β‐CD‐(N₃)₇ and β‐CD‐(N₃)₂₁ led to the facile preparation of well‐defined 7‐arm and 21‐arm star polymers, namely β‐CD‐(PNIPAM)₇ and β‐CD‐(PNIPAM)₂₁. The thermal phase transition behavior of 7‐arm and 21‐arm star polymers with varying molecular weights were examined by temperature‐dependent turbidity and micro‐differential scanning calorimetry, and the results were compared to those of linear PNIPAM precursors. The anchoring of PNIPAM chain terminal to β‐CD cores and high local chain density for star polymers contributed to their considerably lower critical phase separation temperatures (T_c) and enthalpy changes during phase transition as compared with that of linear precursors. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 404–419, 2009     

A Cinchona Alkaloid‐Functionalized Mesostructured Silica for Construction of Enriched Chiral β‐Trifluoromethyl‐β‐Hydroxy Ketones over An Epoxidation‐Relay Reduction Process

A cinchona alkaloid‐functionalized heterogeneous catalyst is prepared through a thiol‐ene click reaction of chiral N‐(3,5‐ditrifluoromethylbenzyl)quininium bromide and a mesostructured silica, which is obtained by co‐condensation of 1,2‐bis(triethoxysilyl)ethane and 3‐(triethoxysilyl)propane‐1‐thiol. Structural analyses and characterizations disclose its well‐defined chiral single‐site active center, and electron microscopy images reveal its monodisperse property. As a heterogenous catalyst, it enables an efficient asymmetric epoxidation of achiral β‐trifluoromethyl‐β,β‐disubstituted enones, the obtained chiral products can then be converted easily into enriched chiral β‐trifluoromethyl‐β‐hydroxy ketones through a sequential epoxidation‐relay reduction process. Furthermore, such a heterogeneous catalyst can be recovered conveniently and reused in asymmetric epoxidation of 4,4,4‐trifluoro‐1,3‐diphenylbut‐2‐enone, showing an attractive feature in a practical construction of enriched chiral β‐CF₃‐substituted molecules.     

Supramolecular inclusion complexes of a star polymer containing cholesterol end‐capped poly(ε‐caprolactone) arms with β‐cyclodextrin

A novel hexa‐armed and star‐shaped polymer containing cholesterol end‐capped poly(ε‐caprolactone) arms emanating from a phosphazene core (N₃P₃‐(PCL‐Chol)₆) was synthesized by a combination of ring‐opening polymerization and “click” chemistry techniques. For this purpose, the terminal ? OH groups of the synthesized precursor (N₃P₃‐(PCL‐OH)₆) were converted into –Chol through a series of reaction. Both N₃P₃‐(PCL‐OH)₆ and N₃P₃‐(PCL‐Chol)₆ were then employed in the preparation of supramolecular inclusion complexes (ICs) with β‐cyclodextrin (β‐CD). The latter formed ICs with β‐CD in higher yield. The host–guest stoichiometry (ε‐CL:β‐CD, mol:mol) in the ICs of N₃P₃‐(PCL‐Chol)₆ was found to be 1.2. The formation of supramolecular ICs of N₃P₃‐(PCL‐Chol)₆ with β‐CD was confirmed by using Fourier transform infrared (FTIR) and ¹H nuclear magnetic resonance (NMR) spectroscopic methods, wide‐angle X‐ray diffraction (WAXD), and thermal analysis techniques. WAXD data showed that the obtained ICs with N₃P₃‐(PCL‐Chol)₆ had a channel‐type crystalline structure, indicating the suppression of the original crystallization of N₃P₃‐(PCL‐Chol)₆ in β‐CD cavities. Moreover, the thermal stabilities of ICs were found to be higher than those of the free star polymer and β‐CD. Furthermore, the surface properties of N₃P₃‐(PCL‐Chol)₆ and its ICs with β‐CD were investigated by static contact angle measurements. The obtained results proved that the wettability of N₃P₃‐(PCL‐Chol)₆ successfully increased with the formation of its ICs with β‐CD. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3406–3420