New and Convergent Synthesis of Osimertinib

New and convergent synthetic route of osimertinib is described on a dozen of grams scale. A key cyclization of 1‐(4‐((2‐(dimethylamino)ethyl)(methyl)amino)‐2‐methoxy‐5‐nitrophenyl)guanidine and 3‐(dimethylamino)‐1‐(1‐methyl‐1H‐indol‐3‐yl)prop‐2‐en‐1‐one is adopted to give the 4‐(1H‐indol‐3‐yl)‐N‐phenylpyrimidin‐2‐amine structure. Osimertinib is prepared in 40.4% yield over six steps and 99.1% purity (HPLC). Purification methods of the intermediates involved in the route are also given.     

On the Influence of the Carbohydrate Moiety on Chromophore Formation during Food‐Related Maillard Reactions of Pentoses,Hexoses, and Disaccharides

The influence of the carbohydrate moiety on the formation of 2‐[4‐oxo‐3‐(pyrrolidin‐1‐yl)cyclopent‐2‐en‐1‐ylidene]furan‐3(2H)‐one chromophores during food‐related Maillard reactions from pentoses, hexoses, and disaccharides is reported. The orange compounds 1a , b and 2a , b , detected in a roasted xylose/ L ‐proline mixture, were identified as (2E)/(2Z)‐4‐hydroxy‐5‐methyl‐2‐[4‐oxo‐3‐(pyrrolidin‐1‐yl)cyclopent‐2‐ene‐1‐ylidene]furan‐3(2H)‐one and (2E)/(2Z)‐5‐methyl‐2‐[4‐oxo‐3‐(pyrrolidin‐1‐yl)cyclopent‐2‐en‐1‐ylidene]‐4‐(pyrrolidin‐1‐yl)furan‐3(2H)‐one, respectively, by 1D‐ and 2D‐NMR, LC/mass, and UV/VIS spectroscopy, as well as by synthetic experiments. Studies on their formation revealed that 1a , b and 2a , b are formed upon condensation of pentose‐derived 4‐hydroxy‐5‐methyl‐ ( 3 ) and 5‐methyl‐4‐(pyrrolidin‐1‐yl)furan‐3(2H)‐one ( 4 ), respectively, with 2‐hydroxycyclopenta‐2,4‐dien‐1‐one ( 5 ) and L ‐proline (Scheme 1). Further condensation reaction of 1a , b with furan‐2‐carbaldehyde yielded the red (2Z)‐2‐{(5Z)‐5‐[(2‐furyl)methylidene]‐4‐oxo‐3‐(pyrrolidin‐1‐yl)cyclopent‐2‐en‐1‐ylidene}‐4‐hydroxy‐5‐methylfuran‐3(2H)‐one ( 6 ) as an additional novel Maillard chromophore. Replacement of the pentose by glucose in the mixture with L ‐proline led, after dry‐heating, to the identification of the structurally related colored (2Z)/(2E)‐2‐[5‐hydroxy‐5‐methyl‐4‐oxo‐3‐(pyrrolidin‐1‐yl)cyclopent‐2‐en‐1‐ylidene]‐4‐hydroxy‐5‐methylfuran‐3(2H)‐one ( 7a / 7b ) and to the characterization of 2,4,5‐trihydroxy‐5‐methylcyclopent‐2‐en‐1‐one ( 10 ) and 5‐hydroxy‐5‐methylcyclopent‐3‐ene‐1,2‐dione ( 11 ) as key intermediates in chromophore formation from hexoses. Comparative studies on disaccharides revealed that not 7a / 7b , but the colorless 4‐(α‐D ‐glucopyranosyloxy)‐2‐hydroxy‐2‐methyl‐6H‐pyran‐3(2H)‐one ( 8 ) and 2‐(α‐D ‐glucopyranosyloxy)‐4,5‐dihydroxy‐5‐methylcyclopent‐2‐en‐1‐one ( 9 ) were formed amongst the major degradation products of maltose (Scheme 4). The aglycons of 8 and 9 could not be liberated under food‐related heating conditions, thus, inhibiting the formation of the color precursors 10 and 11 and, in consequence, of 7a / 7b (Scheme 6). These data strongly suggest that the 1,4‐glycosidic linkage of disaccharides is responsible for their lower efficiency in browning development compared to pentoses or hexoses.     

Photoswitchable “Turn‐on” Fluorescence Diarylethenes: Substituent Effects on Photochemical Properties and Electrochromism

A series of “turn‐on” fluorescence diarylethenes derived from 2,3‐bis(2‐methylbenzo[b]thiophen‐3‐yl)‐5,6‐dihydro‐4H‐thieno[2,3‐b]thiopyran‐4‐one ( 1 ) with alkyl and acetyl substituents were synthesized. The photochemical and photophysical properties of these derivatives, including the photoreaction of crystalline 1 , were thoroughly investigated to reveal substituent effects on their properties. The results indicated that alkyl substituents did not significantly affect the absorption and emission spectra of the diarylethenes. However, large absorption and emission wavelength shifts were observed for the diarylethene with an acetyl substituent due to extension of π–π conjugation. Significantly, all of the fluorescent ring‐closed forms of the compounds isomerized to their ring‐open forms in the presence of Cu²⁺ in the dark. EPR results provide clear evidence for the formation of the compound 1 radical cation intermediate that might be generated in the reaction between c‐ 1 and Cu²⁺. DFT calculations found that the ground‐state activation energy for ring‐opening of 1^.+ was approximately 9.2 kcal mol^?1 lower than that of 1 without Cu²⁺, such that a Cu²⁺‐catalyzed oxidative cycloreversion reaction at room temperature might be possible.     

The effects of heteroaryl ring on the photochromism of diarylethenes with a naphthalene moiety

Three new asymmetrical naphthalene-containing diarylethenes with different heteroaryl groups have been synthesized to investigate the heteroaryl effects on their properties. The three diarylethenes exhibited distinctive photochromism with good thermal stability, which may be attributed to the different heteroaryl effects. Their cycloreversion quantum yields increased in the order of 2-methylbenzofuran < 2-methylbenzothiophene < 1,2-dimethylindole, while the cyclization quantum yields exhibited a reverse trend. Compared to indole and benzothiophene, the benzofuran moiety could effectively shift the absorption maximum to a shorter wavelength and notably enhance the cyclization quantum yield and fluorescence quantum yield of the diarylethene. The results indicated that the category of heteroaryl groups played a vital role during the process of photoisomerization of naphthalene-containing diarylethene derivatives.     

New photochromic diarylethenes bearing a pyridine moiety

A new class of diarylethenes bearing a pyridine unit has been firstly developed and their properties such as photochromism, fatigue resistance, and fluorescence have been discussed. The pyridine unit was connected directly to the central cyclopentene ring as one aryl moiety and availably participated in the photoinduced cyclization reaction even in the crystalline phase. All of these diarylethenes exhibited excellent photochromism, remarkable fatigue resistance, and notable fluorescence photoswitches both in solution and in poly(methylmethacrylate) films. Moreover, the different substituents had a significant effect on their properties. The results indicated that the electron-donating substituent could significantly enhance the cyclization quantum yield and depress the cycloreversion quantum yield while the electron-withdrawing group had a notable contribution to the cycloreversion quantum yield and fluorescence quantum yield for these diarylethenes.     

A Novel Norlignan and a Novel Phenylpropanoid from Peperomia tetraphylla

A novel cyclobutane‐type norlignan, peperotetraphin (=methyl rel‐(1R,2S,3S)‐2,3‐bis(7‐methoxy‐1,3‐benzodioxol‐5‐yl)cyclobutanecarboxylate; 1 ), and a novel phenylpropanoid, i.e., methyl (2E)‐3‐(7‐methoxy‐1,3‐benzodioxol‐5‐yl)prop‐2‐enoate ( 2 ), along with three known compounds, α‐asarone (=1,2,4‐trimethoxy‐5‐[(1E)‐prop‐1‐en‐1‐yl]benzene), vanillic acid (=4‐hydroxy‐3‐methoxybenzoic acid), and veratric acid (=3,4‐dimethoxybenzoic acid), were isolated from the EtOH extract of the whole plant of Peperomia tetraphylla. Their structures were determined by spectroscopic methods, especially 1D‐ and 2D‐NMR techniques. This is the first report of naturally occurring cyclobutane‐type norlignans.     

Strategy for Molecular Design of Photochromic Diarylethenes Having Thermal Functionality

Thermal reactivities of photochromic diarylethene closed‐ring isomers can be controlled by the introduction of substituents at the reactive positions. Diarylethenes having bulky alkyl groups undergo thermal cycloreversion reactions. When bulky alkoxy groups are introduced, the diarylethenes have both thermal cycloreversion reactivities and low photocycloreversion quantum yields. Such photochromic compounds can be applied to thermally reusable photoresponsive‐image recordings. The thermal cycloreversion reactivity of the closed‐ring isomers can be evaluated using specific steric substituent constants and be correlated with the parameters. By introduction of trimethylsilyl or methoxymethyl groups at the reactive positions, the diarylethene closed‐ring isomers undergo thermal irreversible reactions to produce by‐products at high temperatures. These diarylethenes may be useful for secret‐image recordings. Furthermore, thiophene‐S,S‐dioxidized diarylethenes having secondary alkyl groups at the reactive positions undergo thermal by‐product formation reactions, in addition to the photostability of the colored closed‐ring isomers. Such materials may be used for light‐starting thermosensors. The thermal by‐product formation reactivity can be evaluated by the specific substituent constants and theoretical calculations of quantum chemistry. These results supply the strategy for the molecular design of the photochromic diarylethenes having thermal functionality.

     

Photochemical Transformations of Some 2‐(5‐Methylthiophen‐2‐yl)‐3‐[(naphthalen‐2‐yl)methoxy]‐4H‐chromen‐4‐ones Involving Type‐II Process

Photo‐irradiation of 2‐(5‐methylthiophen‐2‐yl)‐3‐[(naphthalen‐2‐yl)methoxy]‐4H‐chromen‐4‐ones yielded the fascinating angular tetracyclic products via cyclization involving both 2‐thienyl ring and naphthylmethoxy group via 1,4‐biradical generated in the Norrish type‐II process. The stereochemical dispositions of the products were determined by MM2 energy minimized programme and spectroscopic analysis.     

Novel π2s+π2a Electrocyclization of Triethylenic‐Malonic Acids Exemplified for a One‐Pot Synthesis of New γ‐Dilactones cis‐Fused with a Cyclopentene

A new, easy and rapid synthesis of γ‐dilactones is cis‐fused with a cyclopentenic ring via cyclization of 7‐chlorotriethylenic‐malonic acids. The key step implicates an intramolecular cyclization to a cyclopentenyl cation, according to an electrocyclic π_2s + π_2a conrotatory process. This cyclopentenyl cation led to unstable γ‐lactones intermediates that are rearrange to more stable isomers. δ‐lactones (6Z and 6E‐(3‐chlorobut‐2‐en‐2‐yl)‐5‐methyl‐3,6‐dihydro‐2H‐pyran‐2‐one) were obtained as secondary products. Mechanistic pathways were considered. The structures of the newly synthesized compounds were established by elemental and spectral data.     

A new approach to the synthesis of benzofuro[3,2‐b]quinolines,benzothieno[3,2‐b]quinolines and indolo[3,2‐b]quinolines

Treatment of 2‐hydroxy‐, 2‐mercapto‐, and 2‐ethoxycarbonylamino‐benzonitriles 12 with 2‐fluoro‐ or 2‐nitrophenacylbromides 13 under alkaline conditions provided the corresponding benzofuran, benzothiophene, and indole intermediates 10 , respectivelly. Nucleophilic cyclization of these compounds led to the corresponding tetracyclic quinolinones 7a, 7b , and 3. Denitrocyclization reaction of compounds 10 (R = NO₂) was found especially useful. Compounds 7a, 7b , and 3 were converted to their chloro derivatives 14a‐c , which were reduced with hydrogen and a catalyst to the corresponding compounds 8a, 8b , and 2. The presented pathway represents a new method of preparation of quindoline 2 and its O and S analogs 8. Chloro derivatives 14 are reactive enough to provide the corresponding methoxy derivatives 15 and dimethylamino derivatives 16. Methylation of compounds 7a and 7b with iodomethane providing mixtures of major N‐methyl derivatives 17 and minor O‐methyl derivatives 15 were also studied.     

1H and 13C NMR spectral assignments of novel chromenylchalcones

Several types of chalcones containing 2H‐chromen group were synthesized. Claisen–Schmidt condensation of 2H‐chromen‐3‐carbaldehydes (I) with methoxy substituted acetophenones afforded (E)‐3‐(2H‐chromen‐3‐yl)‐1‐(methoxyphenyl)prop‐2‐en‐1‐ones (chromenylchalcones, 1–7). Other types of chromenylchalcone, (E)‐1‐(6‐methoxy‐2H‐chromen‐3‐yl)‐3‐(methoxyphenyl)prop‐2‐en‐1‐ones (8–13) were also obtained between reaction of methoxy substituted benzaldehydes and 1‐(6‐methoxy‐2H‐chromen‐3‐yl)ethanone (II). Dichromenylchalcones (14–16) were also synthesized through the same reaction between aldehydes (I) and ketone (II). Their complete ¹H‐NMR and ¹³C‐NMR assignments are reported here and more polysubstituted chromenylchalcones synthesized or isolated from the natural sources in the future can be identified on the basis of the NMR data reported here. Copyright © 2012 John Wiley & Sons, Ltd.     

Study of the Reaction of 5‐Aryl‐7‐hydrazino‐2‐phenylpyra‐zolo[1,5‐c]pyrimidines with 1,3‐Dicarbonyl Compounds

A novel synthetic method for the preparation of 5‐aryl‐7‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐2‐phenylpyrazolo[1,5‐c]‐pyrimidines and 1‐(5‐aryl‐2‐phenylpyrazolo[1,5‐c]pyrimidin‐7‐yl)‐3‐methyl‐1H‐pyrazol‐5‐ols is provided by condensative cyclization of 5‐aryl‐7‐hydrazino‐2‐phenylpyrazolo[1,5‐c]pyrimidines with 1,3‐dicarbonyl compounds. The study of the more reactive position for electrophilic substitusion reactions on such ring system was also achieved.     

Syntheses and properties of new photochromic diarylethene derivatives having a pyrazole unit

New photochromic diarylethenes 1a, 2a and 3a bearing a pyrazole unit have been synthesized. Their properties, including photochromic reactivity, fluorescence and electrochemical properties were investigated. These compounds showed good photochromic properties, high cycloreversion quantum yield and relatively strong fluorescence. The cycloreversion quantum yields of 1a, 2a and 3a are 0.46, 0.53 and 0.57, respectively, which are larger than those of their cyclization quantum yields (0.43, 0.45 and 0.47, respectively). The oxidations of diarylethenes 1a, 2a and 3a were initiated at 0.73, 1.11 and 0.79 V, respectively. Moreover, the position of the methoxyl substituent had remarkable impacts on the above optical and electrochemical properties.     

Synthesis of Some Novel 1,3,4‐Oxadiazol‐2‐yl‐4(3H)‐quinazolinones

N‐1‐Aroyl‐2‐{[(3‐methyl‐4(3H)‐quinazolinone‐2‐yl)methyl]anilino} ethano hydrazides (4), prepared from 2‐phenylaminomethyl‐3‐methyl‐4(3H)‐quinazolinone (1), underwent PPA‐catalyzed cyclization the to title compounds 5 in 51–67% yield.     

Synthesis and Antifungal Activities of ω‐[4‐Aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thio]‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenones

New 4‐aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thiones 3 have been synthesized by the intramolecular cyclization of 4‐aryl‐1‐(1‐phenyl‐5‐methyl‐1,2,4‐triazol‐4‐formyl)thiosemicarbazides 2 with an 8% NaOH solution, and then 3 reacted with ω‐bromo‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenone to afford ω‐[4‐aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thio]‐ω‐(1H‐1,2,4‐triazol‐1‐yl)‐acetophenones 4 . The preliminary biological test showed that the representative compounds possess some anti fungal activities.     

Synthesis and electrophilic cyclization reactions of diphenyl 3‐methylhexa‐ 1,3,4‐trien‐3‐yl phosphine oxide

Diphenyl 3‐methylhexa‐1,3,4‐trien‐3‐yl phosphine oxide can be readily prepared via an atom‐economical 2,3‐sigmatropic rearrangement of the mediated alkenynyl phosphinite formed in situ by a reaction of 2‐methylhex‐5‐en‐3‐yn‐2‐ol with diphenylchlorophosphine. Electrophilic cyclization reactions of prepared 1‐vinylallenyl phosphine oxide were investigated as it was established that the reactions proceeded with formation of heterocyclic compounds with participation of the allenic and/or 1,3‐dienic part of the vinylallenic system with neighboring group participation of the phosphoryl and/or vinylic group. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:345–351, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21023     

Synthesis of some new 1‐acyl‐5‐aryl‐3‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐4,5‐dihydro‐1H‐pyrazole

Some new compounds (E)‐3‐aryl‐1‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐prop‐2‐en‐1‐ones 5a–e were prepared by 1‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐ethanone and various aromatic aldehydes. Then one pot reaction was happened by compounds 5a–e with hydrazine hydrate in acetic acid or propionic acid, respectively, to give the title compounds 1acyl‐5‐aryl‐3‐(5‐methyl‐1‐p‐tolyl‐1H‐1,2,3‐triazol‐4‐yl)‐4,5‐dihydro‐1H‐pyrazoles 6a–i . All structures were established by MS, IR, CHN, ¹H‐NMR and ¹³C‐NMR spectral data. J. Heterocyclic Chem., (2012).     

Synthesis,Pharmacological, and Biological Screening of Novel Derivatives of Benzodiazepines

A series of novel 4‐(substituted phenyl)‐2‐(thiophen‐2‐yl)‐2,3‐dihydro‐1H‐benzo[b][1,4]diazepine have been synthesized from 3‐(substituted phenyl)‐1‐(thiophen‐2‐yl)prop‐2‐en‐1‐one. 3‐(Substituted phenyl)‐1‐(thiophen‐2‐yl)prop‐2‐en‐1‐one was prepared by condensing 2‐acetyl thiophene with various aromatic aldehydes in the presence of 20% NaOH as base. Different 3‐(substituted phenyl)‐1‐(thiophen‐2‐yl)prop‐2‐en‐1‐one on cyclization with o‐phenylenediamine in the presence of NaOH as base resulted in 4‐(substituted phenyl)‐2‐(thiophen‐2‐yl)‐2,3‐dihydro‐1H‐benzo[b][1,4]diazepine derivatives. The structures of synthesized compounds are confirmed by IR, ¹H NMR, mass spectra, and elemental analysis. All the compounds have been screened for their antimicrobial, analgesic, and anti‐inflammatory activities.     

Phenolic Derivatives from the Root Bark of Oplopanax horridus

Four new phenolic derivatives, including two phenylpropanoid glycosides, one benzoate glycoside, and one lignan glycoside, together with one known glyceride, were isolated from the root bark of Oplopanax horridus. The structures of the new compounds were elucidated as 3‐{4‐[(6‐O‐acetyl‐β‐D ‐glucopyranosyl)oxy]‐3,5‐dimethoxyphenyl}propanoic acid ( 1 ), (+)‐[5,6,7,8‐tetrahydro‐7‐(hydroxymethyl)‐10,11‐dimehoxydibenzo[a,c][8]annulen‐6‐yl]methyl β‐D ‐glucopyranoside ( 2 ), (+)‐methyl 4‐[6‐O‐{3‐hydroxy‐3‐methyl‐5‐(1‐methylpropyl)oxy]‐5‐oxopentanoyl}‐4‐O‐(β‐D ‐glucopyranosyl)‐β‐D ‐glucopyranosyl)oxy]‐3‐methoxybenzoate ( 3 ), and 2‐methoxy‐4‐[(1E)‐3‐methoxy‐3‐oxoprop‐1‐en‐1‐yl]phenyl 6‐O‐{3‐hydroxy‐3‐methyl‐5‐[(1‐methylpropyl)oxy]‐5‐oxopentanoyl‐4‐O‐β‐d‐ glucopyranosyl‐β‐d‐ glucopyranoside ( 4 ) on the basis of spectroscopic techniques including NMR and MS analyses. The known compound was identified as glycer‐2‐yl ferulate ( 5 ) by comparing its physical and spectral data with those reported in the literature.     

New Chemical Constituents from Borreria verticillata (Rubiaceae)

A phytochemical study on Borreria verticillata has led to the isolation of two novel simple indole alkaloids, 6‐methoxy‐4‐(3‐methylbut‐2‐en‐1‐yl)‐1H‐indole, named verticillatine A ( 1 ), and 1‐(1H‐indol‐6‐yl)‐3‐methylbutan‐1‐one, named verticillatine B ( 2 ), one new iridoid, 6′‐O‐(2‐glyceryl)scandoside methyl ester ( 3 ), with the glycerol unit linked to a glucose unit, and two known ones, asperuloside ( 4 ) and scandoside methyl ester ( 5 ). The structures of these compounds were elucidated on the basis of spectroscopic‐data analyses, mainly ¹H‐ and ¹³C‐NMR, including 2D experiments (¹H,¹H‐COSY, NOESY, HMBC, and HMQC), and HR‐ESI‐MS.