Synthesis and Crystal Structure of 3,3,6,6‐Tetramethylmorpholine‐2,5‐dione,and Its 5‐Monothioxo and 2,5‐Dithioxo Derivatives

The synthesis of 3,3‐dimethylmorpholine‐2,5‐diones 4a was achieved conveniently via the ‘direct amide cyclization’ of the linear precursors of type 3 , which were prepared by coupling of 2,2‐dimethyl‐2H‐azirin‐3‐amines 2 with 2‐hydroxyalkanoic acids 1 . Thionation of 4a with Lawesson's reagent yielded the corresponding 5‐thioxomorpholin‐2‐ones 10 and morpholine‐2,5‐dithiones 11 , respectively, depending on the reaction conditions. The structures of 3aa, 4aa, 10a , and 11a were established by X‐ray crystallography. All attempts to prepare S‐containing morpholine‐2,5‐dione analogs or thiomorpholine‐2,5‐diones by cyclization of corresponding S‐containing precursors were unsuccessful and led to various other products. The structures of some of them have also been established by X‐ray crystallography.     

Reactions of Thioketones Possessing a Conjugated CC Bond with Diazo Compounds

The reactions of several thioketones containing a conjugated C?C bond with diazo compounds were investigated. All of the selected compounds reacted via a 1,3‐dipolar cycloaddition with the C?S group and subsequent N₂ elimination to yield thiocarbonyl ylides as intermediates, which underwent a 1,3‐dipolar electrocyclization to give the corresponding thiirane 25 , or, by a subsequent desulfurization, to give the olefins 33a and 33b . None of the intermediate thiocarbonyl ylides reacted via 1,5‐dipolar electrocyclization. If the α,β‐unsaturated thiocarbonyl compound bears an amino group in the β‐position, the reactions with diazo compounds led to the 2,5‐dihydrothiophenes 40a – 40d . In these cases, the proposed mechanism of the reactions led once more to the thiocarbonyl ylides 36 and thiiranes 38 , respectively. The thiiranes reacted via an S_Ni′‐like mechanism to give the corresponding thiolate/ammonium zwitterion 39 , which underwent a ring closure to yield the 2,5‐dihydrothiophenes 40 . Also in these cases, no 1,5‐dipolar electrocyclization could be observed. The structures of several key products were established by X‐ray crystallography.     

Synthesis of N‐Benzylated Anilines from the Reaction of Anilines and Benzyl Chloroformate

Abstract

Reactions of benzyl chloroformate with a series of substituted anilines produced N‐carbobenzyloxy “CBZ” products along with the unexpected N‐benzylated “Bn” compounds. Reaction of aniline, 1a, gave the CBZ, or 2a, and Bn, or 3a, products in 29% and 14% yield, respectively. For 2‐nitro‐, 2‐bromo‐, and 2‐bromo‐5‐nitroanilines, the N‐benzylated compounds were produced exclusively. However, 2‐methoxy‐, 4‐bromo, 4‐iodo, and 4‐ethylanilines gave mainly CBZ products. Other compounds reported in this study gave mixtures of the two products. For 4‐chloro‐3‐nitroaniline, in addition to the Bn and CBZ products (53% and 14% yield, respectively), a N,N‐dibenzylated product was isolated in 27% yield. Collectively, the results indicated that electron‐withdrawing groups, particularly at the ortho position, directed the formation of Bn compounds, whilst electron‐donating groups, especially at the ortho and para positions, favored the synthesis of CBZ products.     

New Optically Active Bis‐Heterocycles Derived from (S)‐Proline

Enantiomerically pure bis‐heterocycles containing a (S)‐proline moiety have been prepared starting from (S)‐N‐benzylprolinehydrazide ( 2b ). The reactions with isothiocyanates or butyl isocyanate in refluxing MeOH led to the corresponding thiosemicarbazide 5 and semicarbazide 9 with a N‐benzylprolinoyl residue. The structure of the tert‐butyl derivative 5d was established by X‐ray crystallography. Base‐catalyzed cyclization of 5 and 9 led to (S)‐3‐(pyrrolidin‐2‐yl)‐1H‐1,2,4‐triazole‐5(4H)‐thiones 6 and the corresponding 5(4H)‐one 8 , respectively, whereas, in concentrated H₂SO₄, compounds 5 undergo cyclization to give (S)‐5‐amino‐2‐(pyrrolidin‐2‐yl)‐1,3,4‐thiadiazoles 7 . Furthermore, 2b reacted with hexane‐2,5‐dione in boiling ⁱPrOH to yield the (S)‐N‐(2,5‐dimethylpyrrol‐1‐yl)prolinamide 10 . In the case of the bis‐heterocycle 8 , treatment with HCOONH₄ and Pd/C in MeOH gave the debenzylated product 12 .     

1,5‐Dipolar Electrocyclizations of Thiocarbonyl Ylides Bearing CN Groups: Reactions of N‐[(Dimethylamino)methylene]thiobenzamide and 2‐(Dimethylhydrazono)‐1‐phenylethane‐1‐thione with Diazo Compounds

The reactions of thiobenzamide 8 with diazo compounds proceeded via reactive thiocarbonyl ylides as intermediates, which underwent either a 1,5‐dipolar electrocyclization to give the corresponding five membered heterocycles, i.e., 4‐amino‐4,5‐dihydro‐1,3‐thiazole derivatives (i.e., 10a, 10b, 10c , cis‐ 10d , and trans‐ 10d ) or a 1,3‐dipolar electrocyclization to give the corresponding thiiranes as intermediates, which underwent a S_Ni′‐like ring opening and subsequent 5‐exo‐trig cyclization to yield the isomeric 2‐amino‐2,5‐dihydro‐1,3‐thiazole derivatives (i.e., 11a, 11b, 11c , cis‐ 11d , and trans‐ 11d ). In general, isomer 10 was formed in higher yield than isomer 11 . In the case of the reaction of 8 with diazo(phenyl)methane ( 3d ), a mixture of two pairs of diastereoisomers was formed, of which two, namely cis‐ 10d and trans‐ 10d , could be isolated as pure compounds. The isomers cis‐ 11d and trans‐ 11d remained as a mixture. In the reactions of the thioxohydrazone 9 with diazo compounds 3b and 3d , the main products were the alkenes 18 and 23 , respectively. Their formation was rationalized by a 1,3‐dipolar electrocyclization of the corresponding thiocarbonyl ylide and subsequent desulfurization of the intermediate thiiran. As minor products, 2,5‐dihydro‐1,3‐thiazol‐5‐amines 21 and 24 were obtained, which have been formed by 1,5‐dipolar electrocyclization of the thiocarbonyl ylide, followed by a 1,3‐shift of the dimethylamino group.     

Ultrasound‐Assisted Synthesis of 3‐(Arylamino)‐1‐ferrocenylpropan‐1‐ones

A successful aza‐Michael addition of arylamines to a conjugated enone, acryloylferrocene, has been achieved by ultrasonic irradiation of the mixture of these reactants and the catalyst, i.e., montmorillonite K‐10. This solvent‐free reaction, yielding ferrocene containing Mannich bases, 3‐(arylamino)‐1‐ferrocenylpropan‐1‐ones, considered as valuable precursors in organic synthesis, has been performed by using a simple ultrasonic cleaner. Among 17 synthesized β‐amino ketones, three were new ones, and these were fully characterized by spectroscopic means. X‐Ray crystallographic analysis of three of these crystalline products enabled the insight into the conformational details of these compounds. All compounds were evaluated for their antibacterial activities against six Gram‐positive and five Gram‐negative strains in a microdilution assay. The observed promising antibacterial activity (with a MIC value of 25 μg/ml (ca. 0.07 μmol/ml) as the best result for almost all tested compounds against Micrococcus flavus) seems not only to be compound but also bacterial species‐specific.     

Photochemical Ring Enlargement of Macrocyclic N‐Phenyl Imides into Cyclophanes

Allylic N‐phenyl imides containing 12‐ and 14‐membered rings, such as compounds 3 and 12 , are easily synthesized by ring enlargement from cycloalkanones and phenyl isocyanates. Irradiation of 3 and 12 in EtOH and MeCN, with high‐ and low‐pressure Hg lamps, led, via the photo‐Fries rearrangement, to the same primary products: the orthocyclophane 8 and the paracyclophane 9 from 3 (Scheme 2), and the corresponding compounds 13 and 14 from 12 (Scheme 3). Besides the primary photorearrangement products, secondary products, the aminocyclophanes 10 and 11 , or 15 and 16 , respectively, were also formed. The total yields of the four products were very high when the N‐phenyl imides were irradiated in MeCN with a low‐pressure Hg lamp: 97 and 93%, respectively. If the para‐position in 3 or 12 is blocked by a Me group, the para‐photo‐Fries rearrangement is prevented. In this case, only one primary photoproduct is formed: the corresponding orthocyclophane ( 17 or 23 , resp.). The most remarkable result was observed on irradiation of the 12‐membered N‐(4‐tolyl) imide 5 in MeCN (low‐pressure lamp). It reacted nearly quantitatively to give only two products: 15‐methyl‐1‐aza[12]orthocyclophane‐2,12‐dione (=16‐methyl‐2‐azabicyclo[12.4.0]octadeca‐1(14),15,17‐triene‐3,13‐dione; 17 ) in 80% yield and 17‐amino‐14‐methyl[11]metacyclophane‐1,11‐dione (=17‐amino‐15‐methylbicyclo[11.3.1]heptadeca‐1(17),13,15‐triene‐2,12‐dione; 19 ) in 16% yield (Scheme 5).     

Synergistic Catalysis with Azomethine Ylides

Azomethine ylides are useful intermediates for the rapid construction of chiral N‐containing compounds. However, its synthetic potential has not been fully developed due to the limited reaction models. In combination with synergistic catalysis and azomethine ylide chemistry, we have developed several types of novel catalytic system including Cu/Pd, Cu/Ir and PTC/Ir catalysis, which can convert readily‐available azomethine ylides to various high‐valued molecules such as unnatural α‐amino acids, homoallylic amines and N‐heterocycles. Compared with the traditional mono‐catalysis, the synergistic catalyst system exhibits enhanced catalytic efficiency and chiral induction ability in many cases. In addition, we have demonstrated that these strategies could be applied in the construction of bioactive compounds and natural products.     

One‐Pot Synthesis of (1,2,3‐Triazolyl)methyl 3,4‐Dihydro‐2‐oxo‐1H‐pyrimidine‐5‐carboxylates as Potentially Active Antimicrobial Agents

A simple and efficient one‐pot four‐component procedure has been developed for the synthesis of a wide range of compounds containing the (triazolyl)methyl oxo‐pyrimidine‐carboxylate system from propargyl β‐keto esters, various azides, aldehydes, and urea in the presence of catalytic amounts of (AcO)₂Cu/sodium ascorbate in AcOH. The method worked well with different aryl and heteroaryl aldehydes, and for a variety of substituents in the triazolyl part of the molecule. The antimicrobial activities of the products were evaluated against two Gram‐positive and Gram‐negative bacteria, and one fungus. Compound 5j was active against Staphylococcus aureus and Candida albicans.     

Asymmetrical Fluorene[2,3‐b]benzo[d]thiophene Derivatives: Synthesis,Solid‐State Structures,and Application in Solution‐Processable Organic Light‐Emitting Diodes

A series of novel asymmetrical fused compounds containing the backbone of fluorene[2,3‐b]benzo[d]thiophene (FBT) were effectively synthesized and fully characterized. Single‐crystal X‐ray studies demonstrated that the length of the substituent side chains greatly affects the solid‐state packing of the obtained fused compounds. DFT, photophysical, and electrochemical studies all showed that the FBTs have large band gaps, low‐lying HOMO energy levels, and therefore good stability toward oxidation. Moreover, the substituents strongly influence the fluorescence properties of the resulting FBT derivatives. The di‐n‐hexyl compound exhibits intense fluorescence in solution with the highest quantum yield of up to 91 %. Solution‐processed green phosphorescent organic light‐emitting diodes with the di‐n‐butyl derivative as the host material exhibited a maximum brightness of 14 185 cd m^?2 and a luminescence efficiency of 12 cd A^?1.     

A New and Convenient Synthesis of Amino‐phthalimide (1H‐Isoindole‐1,3(2H)‐dione) Derivatives and Their Photoluminescent Properties

A new and convenient synthesis for amino‐phthalimide (1H‐isoindole‐1,3(2H)‐dione) derivatives has been developed starting from an α,β‐unsaturated ketone. The ketones were reacted with amines to give aromatic amine products. This is the first time that substituted amine groups have been incorporated in aromatic rings. The mechanism of the product formation is rationalized by the 1,2‐addition of amines to ketones. All aromatic compounds exhibited high fluorescence properties at the blue‐green region.     

Piperidine‐Promoted Three‐Component Condensation: Synthesis of Chromene Heterocycles and Pyrazolotriazoles

Chromenes, the oxygen‐containing heterocyclic compounds, have a “special” place in biologically active natural products and in synthetic chemistry and in the fields of medicinal, agrochemical, cosmetic, and pigment industries. In this work, piperidine was used as a base catalyst for the convenient synthesis of 1,4‐dihydropyrano[2,3‐c ]pyrazole, 5,10‐dihydro‐4H‐benzo[g ]chromene, and pyrazolo[1,2‐a ] [1,2,4]triazole derivatives at ambient temperature. This methodology has several advantages including the use of easily accessible and inexpensive catalysts, short reaction times, high yields, convenient work‐up, and not needing column chromatography.     

Carbon–Carbon Bond Formation by Radical Cyclization: Regioselective Synthesis of Spiro Heterocyclic Compounds by n Bu3SnH‐Mediated Reaction

Several spiro heterocyclic compounds have been regioselectively synthesized in excellent yield by ⁿ Bu₃SnH‐AIBN‐mediated radical cyclization of 4‐(2′‐bromoaryloxymethyl)‐1‐methylquinolin‐2(1H)‐ones in refluxing benzene under nitrogen for 4 h.     

Synthesis of Dihydropyrans and Dihydrofurans via Radical Cyclization of Unsaturated Alcohols and 1,3‐Dicarbonyl Compounds

The oxidative cyclization reactions of 1,3‐dicarbonyl compounds 1a – 1c and α,β‐unsaturated alcohols 2a – 2f with Mn(OAc)₃ were performed, leading to dihydrofurans. Treatment of 1a and 1b with 2‐methylbut‐3‐en‐2‐ol ( 2a ) gave dihydrofurans 3aa and 3ba , and dihydropyrans 4aa and 4ba , as unexpected products. While the reaction of 2‐methylbut‐3‐yn‐2‐ol ( 2b ) with acetylacetone ( 1b ) yielded a bifuran, ethyl acetoacetate ( 1a ) led to a mixture of furan, bifuran, and salicylate derivatives. Besides, surprisingly, styryl‐substituted dihydrofurans were obtained from the reactions of 1,3‐dicarbonyl compounds and (3E)‐2,4‐diphenylbut‐3‐en‐2‐ol. The reaction mechanisms were proposed for the formation of the different products, considering intermediates in these reaction mixtures.     

Synthesis of Novel Thioglycoside Derivatives Containing Quinazolinone

A series of novel thioglycoside derivatives containing 4(3H)‐quinazolinone was designed and synthesized from 2‐chloromethyl‐quinazolin‐4(3H)‐ones and 1‐thioglycose. Several 2‐chloromethyl‐quinazolin‐4(3H)‐ones were synthesized on refluxing with 2‐(chloroacetylamino)‐benzoic acid and arylamines in acetonitrile. All of the novel compounds were characterized by IR, ¹H NMR spectra and elemental analysis. The structures of compounds 7b, 8b and 8c have been determined by X‐ray diffraction analysis.     

A Facile Synthesis of 1‐Substituted 3‐Alkoxy‐1H‐isoindoles Based on the Reaction of 2‐(Dialkoxymethyl)phenyllithiums with Nitriles,Followed by Acid‐Catalyzed Cyclization

A two‐step synthesis of 1‐substituted 3‐alkoxy‐1H‐isoindoles 4 has been developed. Thus, the reaction of 2‐(dialkoxymethyl)phenyllithium compounds, which are easily generated in situ by Br/Li exchange between 1‐bromo‐2‐(dialkoxymethyl)benzenes 1 and BuLi in THF at ?78°, with nitriles afforded [2‐(dialkoxymethyl)phenyl]methanimines 2 , which were treated with a catalytic amount of TsOH?H₂O in refluxing CHCl₃ to give the desired products in reasonable yields. Similarly, 3‐aryl‐1‐ethoxy‐1‐methyl‐1H‐isoindoles 7 have been prepared starting from 1‐bromo‐2‐(1,1‐diethoxyethyl)benzenes 5 .     

Architecture‐controlled synthesis of redox‐degradable hyperbranched polyglycerol block copolymers and the structural implications of their degradation

We have successfully synthesized a series of redox‐degradable hyperbranched polyglycerols using a disulfide containing monomer, 2‐((2‐(oxiran‐2‐ylmethoxy)ethyl)disulfanyl) ethan‐1‐ol (SSG), to yield PSSG homopolymers and hyperbranched block copolymers, P(G‐b‐SSG) and P(SSG‐b‐G), containing nondegradable glycerol (G) monomers. Using these polymers, we have explored the structures of the hyperbranched block copolymers and their related degradation products. Furthermore, side reaction such as reduction of disulfide bond during the polymerization was investigated by employing the free thiol titration experiments. We elucidated the structures of the degradation products with respect to the architecture of the hyperbranched block copolymer under redox conditions using ¹H NMR and GPC measurements. For example, the degradation products of P(G‐b‐SSG) and P(SSG‐b‐G) are clearly different, demonstrating the clear distinction between linear and hyperbranched block copolymers. We anticipate that this study will extend the structural diversity of PG based polymers and aid the understanding of the structures of degradable hyperbranched PG systems. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1752–1761     

Report on an Unusual Cascade Reaction between Azulenes and 2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone (=4,5‐Dichloro‐3,6‐dioxocyclohexa‐1,4‐diene‐1,2‐dicarbonitrile; DDQ)

The oxidation of 1‐(3,8‐dimethylazulen‐1‐yl)alkan‐1‐ones 1 with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (=4,5‐dichloro‐3,6‐dioxocyclohexa‐1,4‐diene‐1,2‐dicarbonitrile; DDQ) in acetone/H₂O mixtures at room temperature does not only lead to the corresponding azulene‐1‐carboxaldehydes 2 but also, in small amounts, to three further products (Tables 1 and 2). The structures of the additional products 3 – 5 were solved spectroscopically, and that of 3a also by an X‐ray crystal‐structure analysis (Fig. 1). It is demonstrated that the bis(azulenylmethyl)‐substituted DDQ derivatives 5 yield on methanolysis or hydrolysis precursors, which in a cascade of reactions rearrange under loss of HCl into the pentacyclic compounds 3 (Schemes 4 and 7). The found 1,1′‐[carbonylbis(8‐methylazulene‐3,1‐diyl)]bis[ethanones] 4 are the result of further oxidation of the azulene‐1‐carboxaldehydes 2 to the corresponding azulene‐1‐carboxylic acids (Schemes 9 and 10).     

The Structure and Configuration of Novel Polycyclic Products Derived from an Alicyclic 1,5,9‐Trione and Binucleophiles

As a continuation of our research of reactions with alicyclic 1,5,9‐trione 1 and its polycyclic form 2 , we have studied their reactions with binucleophiles, e.g., phenylene‐1,2‐diamine and 2‐aminophenol, leading to novel N,O‐containing polycyclic compounds. Trione 1 formed double cyclization products 11 and 12 with 2‐aminophenol and triple cyclization product 15 with phenylene‐1,2‐diamine. Hemiacetal 2 and its dehydration product 5 reacted with binucleophiles through initial isomerization into the intermediate cyclic form 4 of trione 1 . Thus, ketone 5 reacted with 2‐aminophenol stereoselectively unlike the hemiacetal 2 . The structure and configuration of the reaction products were studied by using advanced spectroscopic techniques including 1D‐ and 2D‐NMR experiments.     

Unexpected Reaction Course of 3‐Amino‐5‐aryl‐1H‐pyrazoles with Dialkyl Dicyanofumarates

On treatment of 3‐amino‐5‐aryl‐1H‐pyrazoles 1 with dialkyl dicyanofumarates (=(E)‐but‐2‐enedioates) 4 in boiling 1,2‐dichloroethane, two competitive reactions occurred leading to 3‐aryl‐5‐cyano‐6,7‐dihydro‐6‐oxo‐1H‐pyrazolo[3,4‐b]pyridine‐4‐carboxylates 10 and 7‐amino‐2‐arylpyrazolo[1,5‐a]pyrimidine‐5,6‐dicarboxylates 11 . In DMF at room temperature, as well as at 100°, only compounds 10 were isolated. The formation of the major products of type 10 was rationalized via Michael addition of 1 as a C(4)‐nucleophile onto 4 , followed by HCN elimination and lactamization. On the other hand, the minor products 11 result from a Michael addition of 1 onto 4 via the NH₂ group, and subsequent HCN elimination and cyclization. The structures of the products have been established by X‐ray crystallography.