Synthesis and Antitumor Activity Evaluation of γ-Monofluorinated and γ,γ-Difluorinated Goniothalamin Analogues

A series of novel γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and 6a – 6i were synthesized. The key steps included the construction of C‐5 stereocenter adjacent to gem‐difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduction of aryl group via Stille coupling, and lactonization by 1,5‐oxidative cyclization. These γ,γ‐difluorinated Goniothalamin analogues 4a – 4i and their enantiomers 6a – 6i , together with several corresponding γ‐monofluorinated Goniothalamin analogues were biologically evaluated against four different cancer cell lines. Compound 7h showed a nearly equivalent potency as the parent (R)‐Goniothalamin in the micromolar range. The different fluorine effects between fluoromethylene and gem‐difluoromethylene on antitumor activity were discussed through the analysis of bioassay data.     

Unexpected Ritter Reaction During Acid‐Promoted 1,3‐Dithiol‐2‐one Formation

A series of aryl‐substituted 1,3‐dithiol‐2‐ones was prepared by the Bhattacharya? Hortmann cyclization method. Unexpectedly, a Ritter reaction occurred during the acid‐catalyzed cyclization at the cyano group of the aryl substituents and 1,3‐dithiol‐2‐ones bearing a carboxy or a carboxamide group could be selectively obtained (see 1 and 2a in Scheme 1). The formation of the acid or the amide functionality was temperature‐dependent so that the one or the other group could be introduced selectively by modifying the reaction temperature.     

gem‐Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2‐Pyridyl Sulfone: New Insights into the Julia–Kocienski Reaction

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem‐difluoroalkenes has been a long‐standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2‐pyridyl sulfone as a general gem‐difluoroolefination reagent. The gem‐difluoroolefination of diaryl ketones proceeds by acid‐promoted Smiles rearrangement of the carbinol intermediate; the gem‐difluoroolefination is otherwise difficult to achieve through a conventional Julia–Kocienski olefination protocol under basic conditions due to the retro‐aldol type decomposition of the key intermediate. Efficient gem‐difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem‐difluoroolefination of multi‐carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia–Kocienski reaction.     

New Approaches to the Synthesis of 4‐(2‐Aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones and 3‐Ureidoindoles and a Study of Their Interconversion

3‐Alkyl/aryl‐3‐ureido‐1H,3H‐quinoline‐2,4‐diones ( 2 ) and 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) react in boiling concentrated HCl to give 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ). The same compounds were prepared by the same procedure from 2‐alkyl/aryl‐3‐ureido‐1H‐indoles ( 4 ), which were obtained from the reaction of 3‐alkyl/aryl‐3‐aminoquinoline‐2,4(1H,3H)‐diones ( 1 ) with 1,3‐diphenylurea or by the transformation of 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) and 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ) in boiling AcOH. The latter were converted into 1,3‐bis[2‐(2‐oxo‐2,3‐dihydro‐1H‐imidazol‐4‐yl)phenyl]ureas ( 5 ) by treatment with triphosgene. All compounds were characterized by ¹H‐ and ¹³C‐NMR and IR spectroscopy, as well as atmospheric pressure chemical‐ionisation mass spectra.     

A Copper(I)‐Catalyzed Enantioselective γ‐Boryl Substitution of Trifluoromethyl‐Substituted Alkenes: Synthesis of Enantioenriched γ,γ‐gem‐Difluoroallylboronates

The first catalytic enantioselective γ‐boryl substitution of CF₃‐substituted alkenes is reported. A series of CF₃‐substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the corresponding optically active γ,γ‐gem‐difluoroallylboronates in high enantioselectivity. The thus obtained products could be readily converted into the corresponding difluoromethylene‐containing homoallylic alcohols using highly stereospecific allylation reactions.     

金属参与的N-酰基腙的偕二氟烯丙基化反应：高效合成偕二氟高烯丙基胺

金属铟参与醛衍生的N-酰基腙 1a-1q,4a-4g与3-溴-3,3-二氟丙烯 2 的反应,分别高效得到α, α-二氟高烯丙基肼 3a-3q,5a-5g。该反应条件温和,操作简便。硝基,酚羟基,苄氧基,α, β-不饱和醛的碳-碳双键等官能团对该反应具有良好的官能团兼容性。通过用锌粉代替铟粉, 酮衍生的N-酰基腙 6a-6d 也能发生偕二氟烯丙基化反应,以中等产率得到α, α-二氟高烯丙基肼 7a-7d。裂解肼3a的 N-N键顺利得到偕二氟高烯丙基胺 8,化合物 8 经丙烯酰化,随后进行RCM关环反应,可以方便的转化为偕二氟-γ-取代α, β-不饱和内酰胺 11。     

Hydriodic Acid‐Mediated Cyclization of α‐Substituted Secondary 2‐Ethenylbenzamides: Synthesis of 2‐Substituted 2,3‐Dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones and 3,3‐Disubstituted (E)‐1‐(Arylimino)‐1,3‐dihydroisobenzofurans

A new and facile method for the preparation of 2‐substituted 2,3‐dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones 3 and 3,3‐disubstituted (E)‐1‐(arylimino)‐1,3‐dihydroisobenzofurans 6 has been developed. Thus, treatment of N‐alkyl(or aryl)‐2‐(1‐methylethen‐1‐yl)benzamides 2 with concentrated hydriodic acid (HI) in MeCN at room temperature afforded 3 . Similar treatment of N‐aryl‐2‐(1‐phenylethen‐1‐yl)benzamide 5 with concentrated HI at 0° afforded 6 .     

Cyclization vs. Elimination Reactions of 5‐Aryl‐5‐hydroxy 1,3‐Diones: One‐Pot Synthesis of 2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones

2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones were prepared in one step by cyclocondensation of 1,3‐diketone dianions with aldehydes. The use of HCl (10%) for the aqueous workup proved to be very important to avoid elimination reactions of the 5‐aryl‐5‐hydroxy 1,3‐diones formed as intermediates. The TiCl₄‐mediated cyclization of a 2‐aryl‐2,3‐dihydro‐4H‐pyran‐4‐one with 1,3‐silyloxybuta‐1,3‐diene resulted in cleavage of the pyranone moiety and formation of a highly functionalized benzene derivative.     

Synthesis of 2‐Aryl‐1‐arylmethyl‐1H‐1,3‐benzimidazole Derivatives Using Silica‐bonded Propyl‐S‐sulfonic Acid as Recyclable Solid Acid Catalyst

A highly selective synthesis of 2‐aryl‐1‐arylmethyl‐1H‐1,3‐benzimidazoles from the reaction of o‐phenylenediamine and aromatic aldehydes in the presence of silica‐bonded propyl‐S‐sulfonic acid (SBSSA) at 80°C in water in good to excellent yields was developed.     

New domino‐reaction for the synthesis of N4‐(5‐aryl‐1,3‐oxathiol‐2‐yliden)‐2‐phenylquinazolin‐4‐amines and 4‐[4‐aryl‐5‐(2‐phenylquinazolin‐4‐yl)‐1,3‐thiazol‐2‐yl]morpholine

The model morpholine‐1‐carbothioic acid (2‐phenyl‐3H‐quinazolin‐4‐ylidene) amide (1) reacts with phenacyl bromides to afford N⁴‐(5‐aryl‐1,3‐oxathiol‐2‐yliden)‐2‐phenylquinazolin‐4‐amines (4) or N⁴‐(4,5‐diphenyl‐1,3‐oxathiol‐2‐yliden)‐2‐phenyl‐4‐aminoquinazoline ( 5 ) by a thermodynamically controlled reversible reaction favoring the enolate intermediate, while the 4‐[4‐aryl‐5‐(2‐phenylquinazolin‐4‐yl)‐1,3‐thiazol‐2‐yl]morpholine ( 8 ) was produced by a kinetically controlled reaction favoring the C‐anion intermediate. ¹H nmr, ¹³C nmr, ir, mass spectroscopy and x‐ray identified compounds ( 4 ), ( 5 ) and ( 8 ).     

Palladium(II) acetate catalyzed efficient synthesis of N‐aryl‐α,β‐unsaturated amides via carbonylative addition of aniline derivatives to aromatic alkynes

A series of new N‐aryl‐α,β‐disubstituted amides (gem or E1; trans or E2) were synthesized in good yields by carbonylative addition of aniline derivatives 1a–f to aromatic alkynes 2a,b catalyzed by Pd(OAc)₂ and 1,3‐bis(diphenylphosphino)propane. The catalytic synthesis of tertiary α,β‐unsaturated amides was also successfully achieved. Traces of products were observed in the absence of p‐toluenesulfonic acid used as an additive. The reaction is sensitive to the type of phosphine ligand and solvent. Copyright © 2002 John Wiley & Sons, Ltd.     

Rhodium‐Catalyzed Defluorinative Vinylation of gem‐Difluoroalkenes for the Synthesis of 2‐Fluoro‐1,3‐dienes

Herein, we present a strategy for the formation of 2‐fluoro‐1,3‐diene derivatives via rhodium‐catalyzed direct C(sp²)—C(sp²) cross‐coupling of gem‐difluoroalkenes and acrylamides. By merging Rh(III)‐catalyzed C(sp²)–H bond activation and nucleophilic addition/F‐elimination of gem‐difluoroalkene, an efficient defluorinative vinylation reaction is uncovered, which leads to the generation of 2‐fluoro‐1,3‐dienes in moderate to good yields with excellent stereoselectivity under mild conditions. Preliminary mechanistic study suggests unique effects of fluorine substituents which allow the reactivity profile not observed with the congeners bearing heavier halides.     

(E)‐2‐(1,3‐Benzothiazol‐2‐yl)‐3‐(4‐fluorophenyl)acrylonitrile: a chain of π‐stacked hydrogen‐bonded rings

The title compound, C₁₆H₉FN₂S, crystallizes as a nonmerohedral twin with twin rotation about the reciprocal‐lattice vector [10]*. The molecules are nearly planar and the dihedral angle between the planes of the two aryl rings is only 4.4 (2)°. The molecules are linked by pairs of C—H...N hydrogen bonds to form cyclic centrosymmetric R₂²(18) dimers, which are linked into chains by an aromatic π–π stacking interaction. Comparisons are made with some related 3‐aryl‐2‐thienylacrylonitriles.     

A Three‐Component One‐Pot Synthesis of Functionalized 5,5‐Dicyanocyclopenta‐1,3‐dienes from Arylidene­malononitriles,Activated Acetylenes,and KCN or KSCN

The reaction of dialkyl acetylenedicarboxylates with arylidenemalononitriles in the presence of KSCN in MeCN led to a mixture of dialkyl (3E)‐4‐aryl‐3‐(arylideneamino)‐5,5‐dicyanocyclopenta‐1,3‐diene‐1,2‐dicarboxylates and dialkyl 4‐aryl‐5‐cyanothiophene‐2,3‐dicarboxylates. When these reactions were performed in the presence of KCN, only the functionalized 5,5‐dicyanocyclopenta‐1,3‐dienes were obtained.     

Studies on the Reaction of α‐Chloroformylarylhydrazine Hydrochloride with Imidazole and 1,2,4‐Triazole

α‐Imidazolformylarylhydrazine 2 and α‐[1,2,4]triazolformylarylhydrazine 3 have been synthesized through the nucleophilic substitution reaction of 1 with imidazole and 1,2,4‐triazole, respectively. 2,2′‐Diaryl‐2H,2′H‐[4,4′]bi[[1,2,4]‐triazolyl]‐3,3′‐dione 4 was obtained from the cycloaddition of α‐chloroformylarylhydrazine hydrochloride 1 with 1,2,4‐triazole at 60 °C and in absence of n‐Bu₃N. The inducing factor for cycloaddition of 1 with 1,2,4‐triazole was ascertained as hydrogen ion by the formation of 4 from the reaction of 3 with hydrochloric acid. 4 was also acquired from the reaction of 3 with 1 and this could confirm the reaction route for cycloaddition of 1 with 1,2,4‐triazole. Some acylation reagents were applied to induce the cyclization reaction of 2 and 3.1 possessing chloroformyl group could induce the cyclization of 2 to give 2‐aryl‐4‐(2‐aryl‐4‐vinyl‐semicarbazide‐4‐yl)‐2,4‐dihydro‐[1,2,4]‐triazol‐3‐one 6. 7 was obtained from the cyclization of 2 induced by some acyl chlorides. Acetic acid anhydride like acetyl chloride also could react with 2 to produce 7D . 5‐Substituted‐3‐aryl‐3H‐[1,3,4]oxadiazol‐2‐one 8 was produced from the cyclization reaction of 3 induced by some acyl chlorides or acetic acid anhydride. The 1,2,4‐triazole group of 3 played a role as a leaving group in the course of cyclization reaction. This was confirmed by the same product 8 which was acquired from the reaction of 1 , possessing a better leaving group: Cl, with some acyl chlorides or acetic acid anhydride.     

Synthesis of α,α‐Difluoromethylene Alkynes by Palladium‐Catalyzed gem‐Difluoropropargylation of Aryl and Alkenyl Boron Reagents

gem‐Difluoropropargyl bromides are versatile intermediates in organic synthesis, but have rarely been employed in transition‐metal‐catalyzed cross‐coupling reactions. The first palladium‐catalyzed gem‐difluoropropargylation of organoboron reagents with gem‐difluoropropargyl bromides is now reported. The reaction proceeds under mild reaction conditions with high regioselectivity; it features a broad substrate scope and excellent functional‐group compatibility and thus provides an attractive approach for the synthesis of complex fluorinated molecules, in particular for drug discovery and development.     

Synthesis of (4Z)‐4‐(Arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones by the Reaction of Ethyl (2Z)‐3‐Aryl‐2‐isothiocyanatoprop‐2‐enoates with Organolithium Compounds

A convenient one‐pot method for the preparation of (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones 2 and 3 from ethyl (2Z)‐3‐aryl‐2‐isothiocyanatoprop‐2‐enoates 1 , which can be easily prepared from ethyl 2‐azidoacetate and aromatic aldehydes, has been developed. Thus, these α‐isothiocyanato α,β‐unsaturated esters were treated with organolithium compounds, including lithium enolates of acetates, to provide 5‐substituted (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones, 2 , and 2‐[(4Z)‐(4‐arylmethylidene)‐5‐ethoxy‐2‐thioxo‐1,3‐oxazolidin‐5‐yl]acetates, 3 .     

Stereospecific synthesis of a family of novel (E)‐2‐aryl‐1‐silylalka‐1,4‐dienes or (E)‐4‐aryl‐5‐silylpenta‐1,2,4‐trienes via a cross‐coupling of (Z)‐silyl(stannyl)ethenes with allyl halides or propargyl bromide

Stereospecific synthesis of a family of novel (E)‐2‐aryl‐1‐silylalka‐1,4‐dienes or (E)‐4‐aryl‐5‐silylpenta‐1,2,4‐trienes via a cross‐coupling of (Z)‐silyl(stannyl)ethenes with allyl halides or propargyl bromide is described. In the reaction with allyl bromide, either a Pd(dba)₂? CuI combination (dba, dibenzylideneacetone) in DMF or copper(I) iodide in DMSO–THF readily catalyzes or mediates the coupling reaction of (Z)‐silyl(stannyl)ethenes at room temperature, producing novel vinylsilanes bearing an allyl group β to silicon with cis ‐disposition in good yields. Allyl chlorides as halides can be used in the CuI‐mediated reaction. CuI alone much more effectively mediates the cross‐coupling reaction with propargyl bromide in DMSO–THF at room temperature compared with a Pd(dba)₂? CuI combination catalysis in DMF, providing novel stereodefined vinylsilanes bearing an allenyl group β to silicon with cis ‐disposition in good yields. Copyright © 2008 John Wiley & Sons, Ltd.     

Generation of Aryl(2‐lithiophenyl)methanone O‐Methyl Oximes and Their Use for the Synthesis of N‐(3‐Alkyl‐1‐aryl‐ or 1,3‐diaryl‐1H‐isoindol‐1‐yl)‐O‐methylhydroxylamines via the Reaction with Nitriles

An efficient two‐step procedure for the preparation of a new type of 1H‐isoindoles, i.e., N‐(3‐alkyl‐1‐aryl‐ or 1,3‐diaryl‐1H‐isoindol‐1‐yl)‐O‐methylhydroxylamines 5 , from readily available aryl(2‐bromophenyl)methanones 1 has been developed. Aryl(2‐bromophenyl)methanone O‐methyloximes 2 , derived from the corresponding ketones, were treated with BuLi in Et₂O at 0° to generate novel lithium compounds, aryl(2‐lithiophenyl)methanone O‐methyloximes 3 , which were allowed to react with nitriles to give the desired products 5 in moderate‐to‐fair yields.     

Studies on 4‐Thiazolidinones: Scope of the Reactions of 3‐Aryl‐2‐thioxo‐1,3‐thiazolidin‐4‐ones with Cyanide and Cyanate Ions

Treatment of 3‐aryl‐2‐thioxo‐1,3‐thiazolidin‐4‐ones 1 with CN^? and NCO^? effected the ring cleavage providing [(cyanocarbonothioyl)amino]benzenes 4 and arylisothiocyanates 5 , respectively. Similar treatment of 5‐(2‐aryl‐2‐oxoethyl) derivatives 2 afforded 2,4‐bis(2‐aryl‐2‐oxoethylidene)cyclobutane‐1,3‐diones 6 along with each of the preceding products. Treatment of the respective (E,Z)‐5‐(2‐aryl‐2‐oxoethylidene) analogues 3b and 3c with CN^? gave 4b and 4c and 2‐(arylcarbonyl)‐2‐methoxy‐4‐oxopentanedinitriles 7b and 7c , in addition to 3,6‐bis[2‐(4‐chlorophenyl)‐1‐methoxy‐2‐oxoethylidene]‐1,4‐dithiane‐2,5‐dione 8c , which has been generated from 3c . Reactions of 3c or 3d with NCO^? provided 5c or 5d , together with 8c or 8d as pure isomers. In the formation of the MeO products 7 and 8 , the solvent (MeOH) has participated. Structures of these products are based on microanalytical and spectroscopic data. Rationalizations for the above transformations are given.