Cationic Gold‐ and Silver‐Catalyzed Cycloisomerizations of Propargylic Ureas: A Selective Entry to Oxazolidin‐2‐imines and Imidazolidin‐2‐ones

A comparative study on transition metal‐catalyzed cycloisomerizations of propargylic ureas derived in situ from secondary propargylic amines and tosyl isocyanate was performed. The influence of catalytic system on the reaction outcome was thoroughly studied on two model examples resulting in the establishment of two selective protocols for both O‐ and N‐cyclizations. The application of cationic gold(I) catalysis generally resulted in a formation of oxazolidin‐2‐imines as major products while the application of silver(I) triflate selectively provided the corresponding imidazolidin‐2‐ones. An attempt to rationalize the observed chemoselectivity is described. The scope of both processes was demonstrated through the use of variously substituted secondary propargylic amines.     

Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

C8‐N‐arylamine adducts of 2′‐deoxyguanosine (2′‐dG) play an important role in the induction of the chemical carcinogenesis caused by aromatic amines. C8‐N‐acetyl‐N‐arylamine dG adducts that differ in their substitution pattern in the aniline moiety were converted by cycloSal technology into the corresponding C8‐N‐acetyl‐N‐arylamine‐2′‐deoxyguanosine‐5′‐triphosphates and C8‐NH‐arylamine‐2′‐deoxyguanosine‐5′‐triphosphates. Their conformation preference has been investigated by NOE spectroscopy and DFT calculations. The substrate properties of the C8‐dG adducts were studied in primer‐extension assays by using Klenow fragment exo^? of Escherichia coli DNA polymerase I and human DNA polymerase β. It was shown that the incorporation was independent of the substitution pattern in the aryl moiety and the N‐acetyl group. Although the triphosphates were poor substrates for the human polymerases, they were incorporated twice before the termination of the elongation process occurred; this might demonstrate the importance of C8‐N‐arylamine‐2′‐deoxyguanosine‐5′‐triphosphates in chemical carcinogenesis.     

Synthesis of Spiro[piperidine‐3,3′‐oxindoles] via Gold(I)‐Catalyzed Dearomatization of N‐Propargyl‐ and N‐Homoallenyl‐2‐bromotryptamines

N‐Propargyl‐ and N‐homoallenyl‐2‐bromo‐β‐tryptamines undergo gold(I)‐catalyzed dearomatizing cyclizations to afford 2‐bromospiroindolenines that are in situ hydrolyzed to furnish spirooxindoles in a one‐pot process. Tryptophane derivatives (R²=CO₂Et) led upon cyclization to chiral spirooxindoles in excellent diastereoselectivities.

     

Synthese von Hetaryl‐pyridiniumsalzen und kondensierten 3‐Amino‐pyrid‐2‐onen

1‐(3‐Coumaryl)‐pyridinium salts 3 and 1‐(3‐coumaryl)‐tetrahydrothiophenium salts 5 were synthesized from 2‐acylphenyl chloro‐ or bromoacetates 2 . 2‐Chloro‐N¹‐(3,4‐dimethoxyphenyl)‐acetamide and substituted 2‐chloro‐N¹‐(2‐thienyl)‐acetamides 8 react with acetyl chloride and pyridine to yield the quinolinyl‐ and (thieno[2,3‐b]pyridin‐5‐yl)‐pyridinium salts 10 . Fused thieno[2,3‐b]pyridin‐ones 19 were formed from N‐chloroacetyl‐2‐aminothiophen‐3‐carbonitriles 16 with pyridine via Thorpe‐Ziegler cyclization and followed by cyclodehydrogenation. In presence of pyridine alkyl 2‐chloro‐acetylaminobenzoates 21 yield 3‐(1‐pyridinio)‐quinoline‐4‐olates 23 . Zincke‐cleavage of 10 and 23 with hydrazinium hydroxide leads to fused 3‐amino‐pyridine‐2‐ones 11 and 3‐amino‐4‐hydroxy‐quinoline‐2‐ones 24 , respectively. Oxazoloquinolines 25 were synthesized from 24 with acetic anhydride.     

Regioselective Synthesis of Naphtho‐fused Heterocycles via Palladium(0)‐Catalyzed Tandem Reaction of N‐Tosylhydrazones

We have developed a palladium(0)‐catalyzed tandem process which involves the cross‐coupling reaction of N‐tosylhydrazones with dibromide compounds followed by a sequence of intramolecular 5‐exo‐trig, 3‐exo‐trig cyclization, ring opening, and β‐hydride elimination to produce 6‐endo‐trig cyclized products. The strategy was successfully applied for the regioselective synthesis of substituted benzo[b]naphtho[2,1‐d]thiophenes, naphtho[1,2‐b]benzofurans, and benzo[a]carbazoles in moderate to excellent yields.

     

Palladium‐Catalyzed Intramolecular Annulation of 3‐[2‐(2‐Iodobenzylamino)aryl]‐N‐arylpropiolamides: Synthesis of 3‐[5H‐Dibenzo[b,e]azepin‐11(6H)‐ylidene]indolin‐2‐ones

A novel palladium‐catalyzed intramolecular tandem annulation method is presented for the synthesis of 3‐[5H‐dibenzo[b,e]azepin‐11(6H)‐ylidene]indolin‐2‐ones. This method allows the conversion of various 3‐[2‐(2‐iodobenzylamino)aryl]‐N‐arylpropiolamides to the corresponding 3‐[5H‐dibenzo[b,e]azepin‐11(6H)‐ylidene]indolin‐2‐ones through the diarylation of an alkyne.     

Thermal degradation kinetics of poly(N‐adamantyl‐exo‐nadimide) synthesized by addition polymerization

The thermal decomposition behavior and degradation kinetics of poly(N‐adamantyl‐exo‐nadimide) were investigated with thermogravimetric analysis under dynamic conditions at five different heating rates: 10, 15, 20, 25, and 30°C/min. The derivative thermogravimetry curves of poly(N‐adamantyl‐exo‐nadimide) showed that its thermal degradation process had one weight‐loss step. The apparent activation energy of poly(N‐adamantyl‐exo‐nadimide) was estimated to be about 214.4 kJ/mol with the Ozawa–Flynn–Wall method. The most likely decomposition process was an F1 deceleration type in terms of the Coats–Redfern and Phadnis–Deshpande results. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3003–3009, 2007     

Highly Active and Diastereoselective N,O‐ and N,N‐Yttrium Complexes for Intramolecular Hydroamination

The intramolecular hydroamination of aminoalkynes and unactivated aminoalkenes catalyzed by yttrium N,O‐ and N,N‐complexes has been investigated. The N,N‐yttrium complexes are highly active, catalyzing the conversion of a wide range of terminal aminoalkenes at room temperature, and internal aminoalkenes at elevated temperature, to yield pyrrolidine and piperidine products in high yields. A high diastereoselectivity of up to 23:1 is observed at 0 °C with 1‐methyl‐4‐pentenylamine as substrate.     

Synthesis of Chiral N‐Sulfonyl and N‐Phosphinoyl α‐Halo Aldimine Precursors

α‐Halogenated aldimines have emerged as an important class of synthetic intermediates. The stability and reactivity of α‐halo aldimines can vary greatly depending on the nitrogen protecting group. A general synthesis of stable, chiral α‐halo‐N‐sulfonyl and N‐phosphinoyl aldimine precursors is presented (42–96% yield). The corresponding α‐halo aldimines can be isolated upon treatment with a mild base. Enantioenriched α‐chloro aldehydes can be employed to afford aldimine precursors with no erosion of optical purity. Both the enantioenriched aldimine precursor and the isolated aldimine can react with an alkynyllithium nucleophile to give trans‐β‐chloroamine products with excellent dr. Ring closure affords the enantioenriched trans‐aziridine, demonstrating the potential for this approach in complex molecule synthesis.     

Palladium‐Catalyzed Domino Cyclization (5‐exo/3‐exo), Ring‐ Expansion by Palladium Rearrangement,and Aromatization: An Expedient Synthesis of 4‐Arylnicotinates from Morita–Baylis–Hillman Adducts

Various 4‐arylnicotinate derivatives were synthesized via a palladium‐catalyzed cascade reaction of N‐(2‐bromoallyl)‐N‐cinnamyltosylamides in a one‐pot procedure in good yields. The reaction involves a domino 5‐exo/3‐exo carbopalladation, ring‐expansion by palladium rearrangement, and an aromatization process.     

A New Chiral P,N‐Ligand Derived from 1‐Phenylphospholane‐2‐carboxylic Acid (Phenyl‐P‐proline) for Palladium‐Catalyzed Asymmetric Allylic Substitution Reactions

New types of P,N‐ligands, cis‐ and trans‐ 3 , containing a tetrahydroisoquinoline skeleton as an N‐donor were synthesized from (1R,2S)‐1‐phenylphospholane‐2‐carboxylic acid (phenyl‐P‐proline, 1 ). The cis isomer, cis‐ 3 , was found to act as an excellent ligand in palladium‐catalyzed asymmetric allylic substitution reactions. The reactions of 1,3‐diphenyl‐2‐propenyl acetate ( 5 ) with several nucleophiles in the presence of [Pd(π‐allyl)Cl]₂, cis‐ 3 (Pd : ligand=1 : 2), and a base afforded the desired products in high yields with high enantioselectivity. It was suggested that these ligands did not serve as P,N‐bidentate ligands but as P‐monodentate ligands in these reactions.     

Solid‐Phase Synthesis of 3,4‐Dihydroquinoxalin‐2(1H)‐ones via the Cyclative Cleavage of N‐Arylated Carboxamides

We describe a practical (time‐efficient, with commercially available building blocks, user friendly reaction conditions, high purity of products) synthesis of pharmacologically relevant quinoxalinones with three points of diversification that takes advantage of solid‐phase synthesis and cyclative cleavage. Resin‐bound (S)‐2‐(N‐alkyl‐2‐nitrophenyl)sulfonamide‐3‐alkyl‐N‐(2‐hydroxyethyl)propanamides, which are accessible from Fmoc‐protected α‐amino acids, 2‐nitrobenzenesulfonyl chloride and alcohols, underwent base‐mediated N‐arylation. The reduction of the nitro group produced acyclic intermediates that were subjected to acid‐mediated cyclative cleavage to yield 3,4‐dihydroquinoxalin‐2(1H)‐ones.

     

Highly Efficient Synthesis of New α‐Arylamino‐α′‐chloropropan‐2‐ones via Oxidative Hydrolysis of Vinyl Chlorides Promoted by Calcium Hypochlorite

The oxidative hydrolysis of different trifluoroacetyl‐protected N‐(2‐chloroallyl)anilines, promoted by calcium hypochlorite, is able to yield several not previously described α‐arylamino‐α′‐chloropropan‐2‐ones, very valuable building blocks that are useful as precursors of several drugs, in excellent yields and short reaction times. The main requirement of the reaction for avoiding the undesired aromatic chlorination (N‐protection) is effectively solved by the use of the easily formed and removed N‐trifluoroacetyl group. Thus, it is possible to perform the oxidative hydrolysis‐deprotection step using a one‐pot strategy, obtaining quantitative yields in very short reaction times.     

α‐ and β‐Stannyl Trifluoromethylbutenoates: Regioselective Preparation and Use in Copper(I)‐Catalyzed Allylation and Propargylation Reactions

The palladium‐free hydrostannylation of ethyl 4,4,4‐trifluorobutynoate 1 with tributyltin hydride at room temperature is highly regio‐ and stereoselective, providing good yields of β‐trifluoromethyl (Z)‐α‐ or (Z)‐β‐stannylacrylates 2 . Vinylstannanes 2 undergo a copper(I)‐catalyzed coupling reactions with allylic or propargylic bromides leading selectively to good yields of the corresponding allylated or propargylated products without allylic or allenic transposition.     

N,N′‐Dioxide‐Magnesium Ditriflate Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters and β‐Keto Amides

The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)₂] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time.     

Solubilization of phthalocyanines into methanol with fluoroalkyl end‐capped N‐(1,1‐dimethyl‐3‐oxobutyl)‐ and N,N‐dimethyl‐acrylamide oligomers

Self‐assembled molecular aggregates of fluoroalkyl end‐capped N‐(1,1‐dimethyl‐3‐oxobutyl)‐ and N,N‐dimethyl‐acrylamide oligomers in methanol were found to interact with phthalocyanines as guest molecules to exhibit good solubility. On the other hand, the corresponding nonfluorinated oligomers were not effective in solubilizing phthalocyanines under similar conditions. In these oligomers, fluorinated N‐(1,1‐dimethyl‐3‐oxobutyl)acrylamide oligomers were more effective in solubilizing phthalocyanines in methanol. Self‐assemblies formed by fluorinated oligomer‐phthalocyanine complexes are applied to the surface modifications of polystyrene (PS), and the modified PS surface exhibited not only a strong oleophobicity imparted by fluorine but also good hydrophilicity. Thus, these fluorinated molecular aggregate‐phthalocyanine systems are suggested to have high potential for new fluorinated functional materials through their excellent properties imparted by fluorine and phthalocyanines. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 521–525, 2004     

Gold versus Silver‐Catalyzed Intermolecular Hydroaminations of Alkenes and Dienes

Comparative studies about the hydroamination of unactivated alkenes and dienes catalyzed by either cationic gold(I) triphenyl phosphite complexes or silver salts were performed using sulfonamides, anilines and carbamates as nucleophiles. Gold‐catalyzed reactions generally, need lower loadings than those carried out with silver salts. Simple alkenes react only with sulfonamides and weak aromatic amines such as p‐nitroaniline, whereas for conjugated dienes carbamates can also be used. Carbon‐carbon double bond isomerization is observed only with gold similarly to when triflic acid was used, affording mixtures of regioisomeric products in the same cases. Silver‐catalyzed hydroaminations failed with terminal alkenes, except with styrenes. Conjugate dienes can be hydroaminated either at 85 °C in toluene or at room temperature in dichloromethane. Non‐conjugated 1,4‐ and 1,5‐dienes suffer double hydroamination leading to saturated N‐tosylated heterocyclic amines The catalytic cycle for the silver(I)‐catalyzed hydroamination process has been computationally analyzed, resembling gold(I)‐catalyzed processes, although with some significant differences.     

Gold(I)‐Catalyzed Reactions of 1‐(ortho‐Alkynylaryl)ureas: Highly Selective Heterocyclization and Synthesis of Mixed N,O‐Acetals

Readily available 1‐(ortho‐ethynylaryl)urea derivatives undergo a selective gold/silver {[AuCl(IPr)]/AgSbF₆} catalyzed N‐6‐exo‐dig or N‐5‐endo‐dig heterocyclization process in dimethylformamide (DMF) at 60 °C. Benzoxazine derivatives, i.e., the products of O‐6‐exo‐dig ring closure through the urea oxygen, could be observed under catalytic conditions only when the N‐3 basicity was substantially diminished, but were readily isolable in stoichiometric processes carried out at low temperature. The open chain amino O,O‐acetals and a series of new cyclic mixed N,O‐acetals containing the trifluoroethyl group were synthesized when the reactions were performed in ethanol or trifluoroethanol, respectively, as solvent. The procedure allows for an easy access to this versatile class of key intermediates in organic synthesis from simple starting materials. The effect of using either DMF or protic solvents on the course of the reactions is reported.

     

Syntheses and biological activities of polymers containing methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid or 5‐fluorouracil

A series of novel copolymers, poly(methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid‐co‐exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalic acid) [poly(MTCA‐co‐ETAc)], poly(methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid‐co‐hydrogenethyl‐exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalate) [poly(MTCA‐co‐HEET)], and poly(methacryloyl‐2‐oxy‐1,2,3‐propanetricarboxylic acid‐co‐α‐ethoxy‐exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthaloyl‐5‐fluorouracil) [poly(MTCA‐co‐EETFU)], were prepared from corresponding monomers by photopolymerizations at 25°C for 48 h. The polymers were identified by FTIR, ¹H‐NMR, and ¹³C‐NMR spectroscopies. The number‐average molecular weights of the fractionated polymers determined by GPC were in the range from 9400 to 14,900 and polydispersity indices were 1.2–1.4. The in vitro IC₅₀ values of polymers against mouse mammary carcinoma (FM3A), mouse leukemia (P388), and human histiocytic lymphoma (U937) as cancer cell lines and mouse liver cells (AC2F) as a normal cell line were much higher compared to that of 5‐fluorouracil (5‐FU). The in vivo antitumor activities of monomers and polymers against mice bearing sarcoma 180 tumor cell line were better than those of 5‐FU. The inhibition of DNA replication and antiangiogenesis activities of MTCA and copolymers were better compared to those of 5‐FU. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 57–64, 2004     

tert‐Butyl Hydroperoxide and Tetrabutylammonium Iodide‐Promoted Free Radical Cyclization of α‐Imino‐N‐arylamides and α‐Azido‐N‐arylamides

The oxidizing system of tert‐butyl hydroperoxide (TBHP) and tetrabutylammonium iodide (TBAI) is capable of generating α‐(arylaminocarbonyl)iminyl radicals from ethyl 2‐(N‐arylcarbamoyl)‐2‐iminoacetates. These iminyl radicals preferably undergo intramolecular ipso attack on the benzene ring to give azaspirocyclohexadienyl radicals, which are readily captured by molecular oxygen under an oxygen atmosphere to yield azaspirocyclohexadienones. In the absence of oxygen, the reaction affords quinoxalin‐2‐one products. This oxidizing system is also effective to convert α‐aryl‐α‐azido‐N‐arylamides to the corresponding iminyl radicals under basic conditions (sodium tert‐butoxide, t‐BuONa), and the subsequent cyclization of these iminyl radicals results in the formation of azaspirocyclohexadienone products in high yields under an oxygen atmosphere. Plausible mechanisms are proposed to rationalize the experimental results, and factors influencing the reactions are discussed.