Experimental and Theoretical Conformational Analysis of 5‐Benzylimidazolidin‐4‐one Derivatives – a ‘Playground’ for Studying Dispersion Interactions and a ‘Windshield‐Wiper’ Effect in Organocatalysis

The PF₆ salts of 5‐benzyl‐1‐isopropylidene‐ and 5‐benzyl‐1‐cinnamylidene‐3‐methylimidazolidin‐4‐ones 1 (Scheme) with various substituents in the 2‐position have been prepared, and single crystals suitable for X‐ray structure determination have been obtained of 14 such compounds, i.e., 2 – 10 and 12 – 16 (Figs. 2–5). In nine of the structures, the Ph ring of the benzyl group resides above the heterocycle, in contact with the cis‐substituent at C(2) (staggered conformation A ; Figs. 1–3); in three structures, the Ph ring lies above the iminium π‐plane (staggered conformation B ; Figs. 1 and 4); in two structures, the benzylic C? C bond has an eclipsing conformation ( C ; Figs. 1 and 5) which places the Ph ring simultaneously at a maximum distance with its neighbors, the CO group, the N?C‐π‐system, and the cis‐substituent at C(2) of the heterocycle. It is suggested by a qualitative conformational analysis (Fig. 6) that the three staggered conformations of the benzylic C? C bond are all subject to unfavorable steric interactions, so that the eclipsing conformation may be a kind of ‘escape’. State‐of‐the‐art quantum‐chemical methods, with large AO basic sets (near the limit) for the single‐point calculations, were used to compute the structures of seven of the 14 iminium ions, i.e., 3, 4 / 12, 5 – 7, 13 , and 16 (Table) in the two staggered conformations, A and B , with the benzylic Ph group above the ring and above the iminium π‐system, respectively. In all cases, the more stable computed conformer (‘isolated‐molecule’ structure) corresponds to the one present in the crystal (overlay in Fig. 7). The energy differences are small (≤2 kcal/mol) which, together with the result of a potential‐curve calculation for the rotation around the benzylic C? C bond of one of the structures, 16 (Fig. 8), suggests that the benzyl group is more or less freely rotating at ambident temperatures. The importance of intramolecular London dispersion (benzene ring in ‘contact’ with the cis‐substituent in conformation A ) for DFT and other quantum‐chemical computations is demonstrated; the benzyl‐imidazolidinones 1 appear to be ideal systems for detecting dispersion contributions between a benzene ring and alkyl or aryl CH groups. Enylidene ions of the type studied herein are the reactive intermediates of enantioselective organocatalytic conjugate additions, Diels–Alder reactions, and many other transformations involving α,β‐unsaturated carbonyl compounds. Our experimental and theoretical results are discussed in view of the performance of 5‐benzyl‐imidazolidinones as enantioselective catalysts.     

Homopolymerization and copolymerization of a dilactone, 13,26‐dihexyl‐1,14‐dioxa‐cyclohexacosane‐2,15‐dione: Synthesis of bio‐based polyesters and copolyesters consisting of 12‐hydroxystearate sequences

A dilactone, 13,26‐dihexyl‐1,14‐dioxacyclohexacosane‐2,15‐dione (12‐HSAD), was synthesized by lipase‐catalyzed reaction of 12‐hydroxystearic acid (12‐HSA) in high yield. It was subjected to the ring‐opening polymerization with various catalysts to obtain poly(12‐hydroxystearate) (PHS). The polymerization system of 12‐HSAD showed an interesting polymerization behavior because of its large ring system. The polymers produced by this polymerization were directly reacted with L ‐lactide to obtain a diblock copolymer of poly(L ‐lactide)‐block‐poly‐(12‐hydroxystearate) (PLLA‐b‐PHS). Characterization of the resultant copolymers was also performed. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Polyaddition of bifunctional 1,3‐benzoxazine and 2‐methylresorcinol

A polyaddition system consisted of a bifunctional N‐n‐propyl benzoxazine and 2‐methylresorcinol ( MR ) that proceeds at ambient temperature has been developed. In this system, the aromatic ring of MR acted as a bifunctional monomer, reacting with a two equivalent amount of benzoxazine moieties via their ring‐opening reaction. The polyaddition gave the corresponding linear polymer bearing phenolic moieties bridged by Mannich‐type linkage in the main chain. The linear polymer had a high glass transition temperature, which was comparable to that of the linear polybenzoxazine synthesized by the ring‐opening polymerization of a monofunctional N‐n‐propyl benzoxazine. The employment of a bifunctional N‐allyl benzoxazine in the polyaddition system resulted in the formation of the corresponding polymer with allyl pendants, which exhibited improved heat resistance due to its thermally induced crosslinking reaction. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3867–3872     

In vivo metabolite profiles of isoimperatorin and phellopterin in rats analyzed using HPLC coupled with diode array detector and electrospray ionization ion trap time‐of‐flight mass spectrometry technique

Isoimperatorin (IP) and phellopterin (PP) are two furocoumarins existing in Angelicae Dahuricae Radix. There is an isopentenyloxyl substituted at C‐5 in IP, and an isopentenyloxyl and a methoxyl substituted at C‐8 and C‐5, respectively, in PP. To elucidate the in vivo metabolic characteristics of PP and IP, HPLC coupled with diode array detector and electrospray ionization ion trap time‐of‐flight mass spectrometry technique was used. In total, 111 metabolites, including 53 new ones, were identified from the urine and plasma samples of rats after oral administration of IP and PP, respectively. The metabolites were formed through eight reactions on IP and PP: oxidation, hydroxylation–hydrogenation, carboxylation on the isopentenyloxyl, O‐dealkylation, hydroxylation on the furocoumarin nucleus, ring‐opening reaction on the furan ring and reduction or ring‐opening reaction on the lactone ring. Among these, hydroxylation on the furocoumarin nucleus was found for the first time for in vivo metabolites of PP and IP, and the ring‐opening reaction on the furan ring or lactone ring was found for the first time for in vivo metabolites of isopentenyloxyl furocoumarins. The research gave us a new insight into the in vivo metabolic profiles of IP and PP, which could help us better understand their important roles as two active constituents of Angelicae Dahuricae Radix.     

Two Sterically Encumbered 1,3,2‐Dioxaphospholanes – Reactions,Comparison of Crystal Structures and Computational Explanations

3,4,5,6‐Tetrachlorobenzo‐3‐(2,4,6‐tri‐tert‐butylphenyl)‐1,3,2‐dioxaphospholane ( 2 ) and benzo‐3‐(2,4,6‐tri‐tert‐butylphenyl)‐1,3,2‐dioxaphospholane ( 4 ), in which the reactive P^III‐center lies close to the sterically demanding Mes* group (Mes* = 2,4,6‐tri‐tert‐butylphenyl), were prepared from Mes*–Br and the corresponding P‐chloro‐phospholane. Compounds 2 and 4 reacted with various oxidants, azides, MeSO₃CF₃ or [(tht)AuCl] (tht = tetrahydrothiophene) to give the expected products. All crystal structures of the products display a strongly distorted Mes* system with a boat conformation of the phenyl ring and appreciable out‐of‐plane deviations of phosphorus and the ortho‐tert‐butyl groups to opposite sides of the ring. Quantum chemical calculations at the DFT (density functional theory) level of theory were used in order to discriminate between intra‐ and intermolecular forces, which are responsible for these distortions.     

Ring‐Opening Reactions of 3‐Aryl‐1‐benzylaziridine‐2‐carboxylates and Application to the Asymmetric Synthesis of an Amphetamine‐Type Compound

Nucleophilic ring‐opening reactions of 3‐aryl‐1‐benzylaziridine‐2‐carboxylates were examined by using O‐nucleophiles and aromatic C‐nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3) was observed with O‐nucleophiles as a major reaction path in the ring‐opening reactions of aziridines carrying an electron‐poor aromatic moiety, whereas mixtures containing preferentially the syn‐diastereoisomer were generally obtained when electron‐rich aziridines were used (Tables 1–3). In the reactions of electron‐rich aziridines with C‐nucleophiles, S_N2 reactions yielding anti‐type products were observed (Table 4). Reductive ring‐opening reaction by catalytic hydrogenation of (+)‐trans‐(2S,3R)‐3‐(1,3‐benzodioxol‐5‐yl)aziridine‐2‐carboxylate (+)‐trans‐ 3c afforded the corresponding α‐amino acid derivative, which was smoothly transformed into (+)‐tert‐butyl [(1R)‐2‐(1,3‐benzodioxol‐5‐yl)‐1‐methylethyl]carbamate((+)‐ 14 ) with high retention of optical purity (Scheme 6).     

Enantiospecific Synthesis of (R)‐3‐Amino‐4‐(2,4,5‐trifluorophenyl)butanoic Acid Using (S)‐Serine as a Chiral Pool

Starting from (S)‐serine, a new method was developed for the synthesis of the β‐amino acid part of sitagliptin in ten steps and with an overall yield of 30%. The crucial step of the synthesis was the ring opening of N‐ and O‐protected (R)‐aziridin‐2‐methanol with (2,4,5‐trifluorophenyl)magnesium bromide to give N‐ and O‐protected (R)‐2‐amino‐3‐(2,4,5‐trifluorophenyl)propan‐1‐ol.     

Ring Opening of 2‐(Benzylamino)‐2H‐1,4‐benzoxazin‐3(4H)‐ones and 2‐Bromo‐2H‐1,4‐benzoxazin‐3(4H)‐ones

Substituted 2‐(benzylamino)‐2H‐1,4‐benzoxazin‐3(4H)‐ones are unstable under alkaline and acidic conditions, undergoing opening of the benzoxazinone ring. 2‐Bromo‐2H‐1,4‐benzoxazin‐3(4H)‐ones show similar degradation under alkaline conditions, while replacement of Br at C(2) to give 2‐hydroxy‐2H‐1,4‐benzoxazin‐3(4H)‐ones was observed only under mild alkaline conditions. Mechanisms of ring opening and degradation to 2‐aminophenol derivatives are proposed.     

Model Construction for the A–B–C Ring System of Lysergic Acid via Vilsmeier–Haack‐Type Cyclization of 1H‐Indole‐4‐propanoic Acid Derivatives

Vilsmeier–Haack‐type cyclization of 1H‐indole‐4‐propanoic acid derivatives was examined as model construction for the A–B–C ring system of lysergic acid ( 1 ). Smooth cyclization from the 4 position of 1H‐indole to the 3 position was achieved by Vilsmeier–Haack reaction in the presence of K₂CO₃ in MeCN, and the best substrate was found to be the N,N‐dimethylcarboxamide 9 (Table 1). The modified method can be successfully applied to an α‐amino acid derivative protected with an N‐acetyl function, i.e., to 27 (Table 2); however, loss of optical purity was observed in the cyclization when a chiral substrate (S)‐ 27 was used (Scheme 5). On the other hand, the intramolecular Pummerer reaction of the corresponding sulfoxide 20 afforded an S‐containing tricyclic system 22 , which was formed by a cyclization to the 5 position (Scheme 3).     

Synthesis of a Benzannulated Pyrrolizidine by a Copper‐Catalyzed Intramolecular α‐Arylation Reaction

A synthetic route to the pyrrolo[1,2‐a]indole ring system (benzannulated pyrrolizidine) involving a base‐induced intramolecular aza‐Michael reaction as the key C? N bond‐forming penultimate step, followed by a Cu‐catalyzed intramolecular α‐arylation reaction, to provide the tricyclic framework over six steps is described.     

Theoretical Study on Second‐order Nonlinear Optical Properties of Substituted Thiazole Derivatives

On the basis of ZINDO program, we have designed a program to calculate the nonlinear second‐order polarizability β_yk and β_μ according to the SOS expression. The second‐order nonlinear optical properties of 4‐nitro‐4′‐dimethylamino‐stilbene and a series of its thiazole derivatives were studied. The calculated results were that: When replacing a benzene ring in 4‐nitro‐4′‐dimethylamino‐stilbene by a thiazole ring, the influence on β values depends on the position of thiazole ring. When the thiazole ring connects with nitro group (acceptor), the β values increase significantly compared with corresponding stilbene derivatives. The β values of 2‐(p‐donor‐β‐styryl)‐5‐nitro‐thiazole derivatives (2–7) are larger than those of 2‐(p‐nitro‐β‐styryl)‐5‐donor‐thiazole derivatives (8–13) and 2‐(p‐donor‐phenyl)‐azo‐5‐nitro‐thiazole derivatives (14–19). The 2‐(p‐donor‐β‐styryl)‐5‐nitro‐thiazole derivatives (2–7) are good candidates as chromophores duo to their high nonlinearities and potential good thermal stability.     

Platinum‐Catalyzed Asymmetric Ring‐opening Reaction of Oxabenzonorbornadiene with Terminal Alkynes

A novel platinum‐catalyzed asymmetric ring‐opening reaction of oxabenzonorbornadiene with terminal alkynes is described. The reaction affords optically active cis‐2‐alkynyl‐1,2‐dihydronaphthalen‐1‐ols in moderate yields with good enantioselectivity in the presence of catalytic amounts of Pt(COD)Cl₂/(S)‐BINAP and an excess of zinc powder. The products were obtained exclusively with the relative cis‐configuration of the ring substituents and the prevalent (1R,2S)‐configuration of the stereocenters, as determined by single crystal X‐ray diffraction analysis.     

Asymmetric cyclopolymerization of N‐tert‐butyl‐N‐allylacrylamide in the presence of β‐cyclodextrin

The radical polymerization of N‐tert‐butyl‐N‐allylacrylamide (t‐BAA) was carried out in a dimethyl sulfoxide/H₂O mixture in the presence of β‐cyclodextrin (β‐CD). The polymerization proceeded with the complete cyclization of the t‐BAA unit and yielded optically active poly(t‐BAA). The IR spectrum of the obtained polymer showed that the cyclic structure in the polymer was a five‐membered ring. The optical activity of poly(t‐BAA) increased with an increasing molar ratio of β‐CD to the t‐BAA monomer. The interaction of β‐CD with t‐BAA was confirmed by ¹H NMR and ¹³C NMR analyses of the polymerization system. It is suggested that interaction of the t‐BAA monomer with the hydrophobic cavity of β‐CD plays an important role in the asymmetric cyclopolymerization of t‐BAA. The radical copolymerization of t‐BAA with styrene (St), methyl methacrylate, ethyl methacrylate, or benzyl methacrylate (BMA) also produced optically active copolymers with a cyclic structure from the t‐BAA unit. St and BMA carrying a phenyl group were predicted to compete with t‐BAA for interaction with β‐CD in the copolymerization system. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 2098–2105, 2000     

Base Mediated Aromatization of Carbonyl Condensation Products Derived from 2‐(2‐Bromoprop‐2‐enyl)cyclohexanone Derivatives via ‘Intramolecular Unsaturation Transfer’

Alkylbenzenes are synthesized for the first time from aliphatic hydrocarbons via an one pot, transition metal‐free coupling approach under basic conditions. The method consists of two steps: condensation of 2‐bromoprop‐2‐enyl‐ or 2‐propargylcyclohexanone with alcohols, amines, or amino alcohols, followed by base treatment (Scheme 1). Phenolic ethers and N‐phenylated polyalkyl aromatic compounds are shown to be in the scope of the demonstrated reaction (Table). The proposed mechanism suggests that the unsaturation in another part of the molecule (propargyl‐group equivalent) is transferred into the cyclohexane ring to yield a benzene ring through a series of prototropic shifts.     

Asymmetric Ring‐Opening of Cyclopropyl Ketones with Thiol,Alcohol, and Carboxylic Acid Nucleophiles Catalyzed by a Chiral N,N′‐Dioxide–Scandium(III) Complex

A highly efficient asymmetric ring‐opening reaction of cyclopropyl ketones with a broad range of thiols, alcohols and carboxylic acids has been first realized by using a chiral N,N′‐dioxide–scandium(III) complex as catalyst. The corresponding sulfides, ethers, and esters were obtained in up to 99 % yield and 95 % ee. This is also the first example of one catalytic system working for the ring‐opening reaction of donor–acceptor cyclopropanes with three different nucleophiles, let alone in an asymmetric version.     

Reaction of Optically Active Oxiranes with Thiofenchone and 1‐Methylpyrrolidine‐2‐thione: Formation of 1,3‐Oxathiolanes and Thiiranes

The SnCl₄‐catalyzed reaction of (?)‐thiofenchone (=1,3,3‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 10 ) with (R)‐2‐phenyloxirane ((R)‐ 11 ) in anhydrous CH₂Cl₂ at ?60° led to two spirocyclic, stereoisomeric 4‐phenyl‐1,3‐oxathiolanes 12 and 13 via a regioselective ring enlargement, in accordance with previously reported reactions of oxiranes with thioketones (Scheme 3). The structure and configuration of the major isomer 12 were determined by X‐ray crystallography. On the other hand, the reaction of 1‐methylpyrrolidine‐2‐thione ( 14a ) with (R)‐ 11 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 15 ) in 56% yield and 87–93% ee, together with 1‐methylpyrrolidin‐2‐one ( 14b ). This transformation occurs via an S_N2‐type attack of the S‐atom at C(2) of the aryl‐substituted oxirane and, therefore, with inversion of the configuration (Scheme 4). The analogous reaction of 14a with (R)‐2‐{[(triphenylmethyl)oxy]methyl}oxirane ((R)‐ 16b ) led to the corresponding (R)‐configured thiirane (R)‐ 17b (Scheme 5); its structure and configuration were also determined by X‐ray crystallography. A mechanism via initial ring opening by attack at C(3) of the alkyl‐substituted oxirane, with retention of the configuration, and subsequent decomposition of the formed 1,3‐oxathiolane with inversion of the configuration is proposed (Scheme 5).     

Rigid diol bearing 6‐6‐6 fused ring system derived from naturally occurring myo‐inositol and its polyaddition with diisocyanates

Naturally occurring myo‐inositol was developed into a highly rigid diol by converting its 3,4‐ and 1,6‐vicinal diols in trans configuration into the corresponding butane‐2,3‐diacetals. The resulting diol bearing 6‐6‐6 fused ring system, in which conformational change is strictly suppressed, was combined with diisocyanates to perform polyadditions. The resulting polyurethanes were analyzed by differential scanning calorimetry, and it was found that their glass transition temperatures were much higher than those of the previously reported myo‐inositol‐derived polyurethanes, which were synthesized from a myo‐inositol‐derived diol bearing 5‐6‐5 fused ring system. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 3798–3803     

Selenophen‐2‐yl‐Substituted Thiocarbonyl Ylides – at the Borderline of Dipolar and Biradical Reactivity

The reactions of aryl (selenophen‐2‐yl) thioketones with CH₂N₂ occur with spontaneous elimination of N₂, even at low temperature (?65°), to give regioselectively sterically crowded 4,4,5,5‐tetrasubstituted 1,3‐dithiolanes and/or a novel type of twelve‐membered dithia‐diselena heterocycles as dimers of the transient thiocarbonyl S‐methanides. The ratio of these products depends on the type of substituent located at C(4) of the phenyl ring. Whereas the formation of the 1,3‐dithiolanes corresponds to a [3+2] cycloaddition of an intermediate thiocarbonyl ylide with the starting thioketone, the twelve‐memberd ring has to be formed via dimerization of the ‘thiocarbonyl ylide’ with an extended biradical structure.     

Anilinic N‐Oxides Support Cytochrome P450‐Mediated N‐Dealkylation through Hydrogen‐Atom Transfer

The mechanism of N‐dealkylation mediated by cytochrome P450 (P450) has long been studied and argued as either a single electron transfer (SET) or a hydrogen atom transfer (HAT) from the amine to the oxidant of the P450, the reputed iron–oxene. In our study, tertiary anilinic N‐oxides were used as oxygen surrogates to directly generate a P450‐mediated oxidant that is capable of N‐dealkylating the dimethylaniline derived from oxygen donation. These surrogates were employed to probe the generated reactive oxygen species and the subsequent mechanism of N‐dealkylation to distinguish between the HAT and SET mechanisms. In addition to the expected N‐demethylation of the product aniline, 2,3,4,5,6‐pentafluoro‐N,N‐dimethylaniline N‐oxide (PFDMAO) was found to be capable of N‐dealkylating both N,N‐dimethylaniline (DMA) and N‐cyclopropyl‐N‐methylaniline (CPMA). Rate comparisons of the N‐demethylation of DMA supported by PFDMAO show a 27‐fold faster rate than when supported by N,N‐dimethylaniline N‐oxide (DMAO). Whereas intermolecular kinetic isotope effects were masked, intramolecular measurements showed values reflective of those seen previously in DMAO‐ and the native NADPH/O₂‐supported systems (2.33 and 2.8 for the N‐demethylation of PFDMA and DMA from the PFDMAO system, respectively). PFDMAO‐supported N‐dealkylation of CPMA led to the ring‐intact product N‐cyclopropylaniline (CPA), similar to that seen with the native system. The formation of CPA argues against a SET mechanism in favor of a P450‐like HAT mechanism. We suggest that the similarity of KIEs, in addition to the formation of the ring‐intact CPA, argues for a similar mechanism of Compound I (Cpd I) formation followed by HAT for N‐dealkylation by the native and N‐oxide‐supported systems and demonstrate the ability of the N‐oxide‐generated oxidant to act as an accurate mimic of the native P450 oxidant.     

Regioselective,Unconventional Pictet–Spengler Cyclization Strategy Toward the Synthesis of Benzimidazole‐Linked Imidazoquinoxalines on a Soluble Polymer Support

A novel strategy for an unconventional Pictet–Spengler reaction has been developed for the regioselective cyclization of the imidazole ring system at the C2 position. The developed strategy was utilized to develop a diversity‐oriented parallel synthesis for bis(heterocyclic) skeletal novel analogs of benzimidazole‐linked imidazoquinoxalines on a soluble polymer support under microwave conditions. Condensation of polymer‐immobilized o‐phenylenediamines with 4‐fluoro‐3‐nitrobenzoic acid followed by nucleophilic aromatic substitution with an imidazole motif affords bis(heterocyclic) skeletal precursors for the Pictet–Spengler reaction. The unconventional Pictet–Spengler cyclization with various aldehydes was achieved regioselectively at the C2 position of the imidazole ring to furnish rare imidazole‐fused quinoxaline skeletons. During the Pictet–Spengler cyclization, aldehydes bearing electron‐donating groups afford 4,5‐dihydro‐imidazoquinoxalines, which then auto‐aromatize into benzimidazole‐linked imidazo[1,2‐a]quinoxalines. However, interestingly, aldehydes bearing electron‐withdrawing groups directly provide aromatized imidazo[1,2‐a]quinoxalines, which unexpectedly afford novel benzimidazole‐linked 4‐methoxy‐4,5‐dihydro‐imidazo[1,2‐a]quinoxalines after polymer cleavage.