Ruthenium‐catalyzed synthesis of quinolines via reductive heteroannulation of nitroarenes with 3‐amino‐1‐propanols

Nitroarenes are reductively cyclized with 3‐amino‐1‐propanols in dioxane/H₂O in the presence of a ruthenium catalyst and tin(II) chloride dihydrate together with isopropanol to afford the corresponding quinolines. A reaction pathway involving initial reduction of nitroarenes to anilines, propanol group transfer from 3‐amino‐1‐propanols to anilines, N‐alkylation of anilines by 3‐anilino‐1‐propanols and heteroannulation of 1,3‐dianilinopropanes is proposed.     

Homologous SNV Reaction: Synthesis of l‐Methyl‐4‐[4′‐phenylsulfonyl‐1′,3′‐butadienyl]pyridinium Iodide and Its Reactivity with Thiol Groups Giving Rise to the Chromophoric Thioether

Thioether 4‐[(1′E,3′E)‐4′‐phenylsulfanyl‐1,3′‐butadienyl]pyridine 8 and sulfone 4‐(4′‐phenylsulfonyl‐1′,3′‐butadienyl)pyridine 14 were prepared by reaction of the carbanions derived from allylic thioether or allylic sulfone with isonicotinaldehyde. The reaction with the sulfonyl carbanion occurred at the α position and on heating the alcolate gave the dienic sulfone 14 . The corresponding pyridinium iodide 10 and 15 were prepared by reaction with methyl iodide, respectively, on pyridine derivates 8 and 14 . The dienic pyridinium thioether 10 showed a long wavelength absorption band centered at 420 nm. The reaction of dienic pyridinium sulfone 15 with thiophenol gave the dienic pyridinium thioether 10 by a nucleophilic vinylic substitution. The reaction of sulfone 15 with glutathione was of second order and the rate constant was 8.5 M^?1s^?1 at 30°C and pH 7, about 500 times smaller than the rate constant observed with (E)‐1‐methyl‐4‐(2‐methylsulfonyl‐1‐ethenyl)pyridinium iodide 1 . The dienic pyridinium thioether 10 was a negative solvatochrome.     

Reactions of nitroarenes with secondary and tertiary carbanions bearing both a leaving group and electron‐withdrawing group: An approach to dihydronaphth[2,1‐c]isoxazole N‐oxides and dihydroisoxazolo[4,3‐f]quinoline N‐oxides

2‐Nitronaphthalene (1) and 6‐nitroquinoline (2) underwent direct cyclocondensation with secondary and tertiary carbanions derived from a methylene and methine group bearing both a leaving group and electron‐withdrawing group (e.g., methyl chloroacetate, ethyl chloroacetate, chloroacetonitrile, methyl 2‐chloropropionate, ethyl 2‐chloropropionate and 2‐chloropropionitrile) in the sodium hydride/N,N‐dimethylformamide system at low temperature, giving the corresponding dihydronaphth[2,1‐c]isoxazole N‐oxides 3 and dihy‐droisoxazolo[4,3‐f]quinoline N‐oxides 4 . On the other hand, nitroarenes 1 and 2 reacted with secondary carbanions in the sodium hydride/tetrahydrofuran system to yield the corresponding conventional vicarious nucleophilic substitution (VNS) products 5 and 6 .     

1,2,4-Triazines in Organic Synthesis. 9. Synthesis of 3-(3-Ethylindol-2-yl)-5,6,7,8-tetrahydroisoquinoline Using the Fischer Reaction under the Usual Conditions and with Microwave Irradiation

The nucleophilic substitution of hydrogen in 3-methylthio-1,2,4-triazine by the carbanions of nitrobutane and 4-nitrobut-1-ene gave oximes, the selective fission of which using sodium dithionite gave ketones in the case of compounds with a saturated carbon chain. Ketones in Diels-Alder reaction with 1-pyrrolidinocyclohex-1-ene gave 3-acyl-1-methylthio-5,6,7,8-tetrahydroisoquinolines. Phenylhydrazones of the compounds obtained underwent Fischer reaction under usual conditions and also when using microwave irradiation on a solid support. The final 3-(3-ethylindol-2-yl)-5,6,7,8-tetrahydroisoquinoline was obtained via reductive desulfuration using Raney nickel in ethanol.     

Synthesis of 3‐Aryl‐2,5‐Dihydro‐1‐Benzoxepines from Phenol via Ring‐Closing Metathesis

In this paper, the synthesis of 3‐aryl‐2,5‐dihydro‐1‐benzoxepines is described. While the reaction was started from phenol and based on the sequential reactions such as Claisen rearrangement, O‐alkylation, Wittig reaction, and ring‐closing metathesis (RCM), a series of new 3‐aryl‐1‐benzoxepines were prepared in good overall yields.     

Asymmetric reaction of diethylzinc with aldehydes catalyzed by l‐menthopyrazole derivatives

N‐Hydroxyalkyl‐1‐menthopyrazoles acted as a chiral catalyst for the diethylzinc ( 1 ) addition to aromatic aldehydes, and 1‐aryl‐1‐propanols were afforded enantioselectively. These reactions were carried out optimally in toluene at 40 °C in the presence of 30 mol% of (2′S)‐2‐(2‐phenyl‐2‐hydroxyethyl)‐3‐phenyl‐1‐men‐thopyrazole ((S)‐ 16d ) to afford optically active 1‐aryl‐1‐propanols up to 70% ee (S).     

Gas‐phase pyrolytic reaction of 3‐phenoxy and 3‐phenylsulfanyl‐1‐propanol derivatives: Kinetic and mechanistic study

3‐Phenoxy‐1‐propanols 1a–c and 3‐phenylsulfanyl‐1‐propanols 2a–c containing primary, secondary, and tertiary alcohols were prepared and subjected to gas‐phase pyrolysis in a static reaction system. Pyrolysis of 4‐phenyl‐1‐butanol 3 , 2‐methyl‐3‐phenyl‐1‐propanol 4 , and 2‐methyl‐3‐phenylpropanoic acid 5 was also studied, and results were compared with those obtained for compounds 1–3 . The pyrolytic reactions were homogeneous and followed a first‐order rate equation. Analysis of the pyrolysate showed the products to be phenol (from 1a to 1c ), thiophenol (from 2a to 2c ), and toluene (from 3 to 5 ) and carbonyl compounds. The kinetic results and product analysis of each of the nine investigated compounds are rationalized in terms of a plausible transition state for the elimination pathway. © 2007 Wiley Periodicals, Inc. 40: 51–58, 2008     

Regioselectivity of the Base-Induced Ring Cleavage of 1-Oxygenated Derivatives of Cyclobutabenzene

Oxy anions 3 generated from 1,2-dihydrocyclobutabenzen-1-ones 1 through addition of a charged nucleophile or from 1-hydroxy-1,2-dihydrocyclobutabenzenes 2 by deprotonation with base lead to stable products through distal and/or proximal cleavage of the strained four-membered ring via benzyl carbanion 4 and/or aryl carbanion 5. A systematic study of this process reveals the relative stability of the two isomeric carbanions 4 and 5 as a key factor in determining the course of the ring-cleavage reaction. While benzyl carbanions 4 can be trapped with carbon electrophiles, attempts at trapping aryl carbanions 5 with electrophiles other than H⁺ failed. In protic solvents, the magnesium salt of the tertiary alcohol 2 shows an increased rate of proximal cleavage as compared to its alkali salts. From this, we conclude that, in contrast to benzyl carbanions 4 , free aryl carbanions 5 are of transient existence only. Proximal C,C-bond cleavage seems to occur either through protonation of 5 from a fast, reversible equilibrium 3 ? 5 in which 3 strongly predominates, or in protic solvents possibly even through a rate-limiting protonation of 3 at the aromatic C-atom, bypassing free anion 5 altogether. Thus, additional factors other than just the relative stability of isomeric carbanions 4 and 5 are of importance in determining the regiochemistry of the base-induced C,C-bond cleavage in ketones 1 and in alcohols 2 .     

Studies on Hydroiodination and Deconjugation of 5—Aryloxy—（thiophenyl）—3—pentyn—2—one

One-pot hydroiodination and deconjugation of 5-aryloxy(or thiophenyl)-3-pentyn-2-one with a reagent system of sodium iodide/trimethylsilyl chloride/water in acetonitrile at 25℃ have been described.The plasuible mechanism was discussed.The reaction provided a simple and useful method for the preparation of (Z)-β-substituted β，γ-enones and (Z)-β-substituted α，β-unsaturated ketones.     

One‐pot Synthesis of Fused Dipyranocoumarins from Dihydroxycoumarins and Propargyl Chlorides under Microwave Irradiation

Dipetalolactone and 4‐methyldipetalolactone are prepared in excellent yield by a one‐pot tandem propargylation/Claisen rearrangement/cyclization reaction of the corresponding 5,7‐dihydroxycoumarins with 3‐chloro‐3‐methylbut‐1‐yne in the presence of Cs₂CO₃ under microwave irradiation. The analogous reactions of propargyl chloride with esculetins or 5,7‐dihydroxycoumarins led to dipropargyloxy derivatives. The later by treatment with gold nanoparticles supported on TiO₂ or BF₃.Et₂O in N,N‐dimethylformamide (DMF) under microwave irradiation resulted in very good to excellent yield to the corresponding fused dipyranocoumarins. The reactions of esculetins with 3‐chloro‐3‐methylbut‐1‐yne gave mainly exomethylene fused dioxino[g]coumarins.     

Electrophilic Reactivities of 1,2‐Diaza‐1,3‐dienes

The kinetics of the reactions of 1,2‐diaza‐1,3‐dienes 1 with acceptor‐substituted carbanions 2 have been studied at 20 °C. The reactions follow a second‐order rate law, and can be described by the linear free energy relationship log k(20 °C)=s(N+E) [Eq. (1)]. With Equation (1) and the known nucleophile‐specific parameters N and s for the carbanions, the electrophilicity parameters E of the 1,2‐diaza‐1,3‐dienes 1 were determined. With E parameters in the range of ?13.3 to ?15.4, the electrophilic reactivities of 1 a–d are comparable to those of benzylidenemalononitriles, 2‐benzylideneindan‐1,3‐diones, and benzylidenebarbituric acids. The experimental second‐order rate constants for the reactions of 1 a – d with amines 3 and triarylphosphines 4 agreed with those calculated from E, N, and s, indicating the applicability of the linear free energy relationship [Eq. (1)] for predicting potential nucleophilic reaction partners of 1,2‐diaza‐1,3‐dienes 1 . Enamines 5 react up to 10² to 10³ times faster with compounds 1 than predicted by Equation (1), indicating a change of mechanism, which becomes obvious in the reactions of 1 with enol ethers.     

Potassium tert‐Butoxide Catalyzed Synthesis and Characterization of Novel 3‐Aryl‐3‐(phenylthio)‐1‐(thiophen‐3‐yl)propan‐1‐one Derivatives

A series of thiophenyl‐containing 3‐thiophene derivatives ( 4a – 4i ) were prepared via the reaction of chalcone‐analogua compounds ( 3a – 3i ) and thiophenol in the presence of catalytic amount of KOBu‐t in CH₂Cl₂ with moderate to high yields. The mechanistic pathway of the reaction was explained by the Michael‐type addition of thiophenol to chalcone derivatives ( 3a – 3i ).     

Synthesis,characterization, and antidiabetic activity of 6‐methoxyimidazo[1,2‐b]pyridazine derivatives

The present article describes the synthesis, characterization, and antidiabetic activity of 6‐methoxyimidazo[1,2‐b]pyridazine derivatives 7a‐l . The synthetic sequence for the preparation of these derivatives involves the following prominent reactions: (a) Step 1: involves the high‐pressure amination reaction; (b) Step 2: involves the Zinc oxide nanoparticle‐catalyzed cyclization reaction; (c) Step 3: involves the methoxylation; (d) Step 4: involves the bromination reaction; (e) Step 5: involves the Suzuki coupling reaction; (f) Step 6: involves the reduction of the –NO₂ group; (g) Step 7: involves Boc protection of the 1^o amino group (h) Step 8: involves diazotization of the amine group and finally the last of the synthesis (i) Step 9: involves the saponification of the ethyl ester group. Furthermore, the structures of the newly synthesized 6‐methoxyimidazo[1,2‐b]pyridazine derivatives 7a–l were determined using ¹H NMR, ¹³C NMR, and Mass and IR spectroscopic analyses. These derivatives were evaluated for their antidiabetic property and the results revealed that most of the compounds exhibited significant potency. It is worth mentioning that compounds 7b (69.87%), 7f (69.0%), 7h (68.79%), and 7l (68.61%) with substitution R = para‐NH₂, para‐COOH, meta‐NH₂, and meta‐COOH, respectively, showed significant (good) hypoglycemic activity when compared to the standard drug insulin (50 mg/kg b.w) in reducing the blood glucose level.     

Reactions of Chlorosulfanyl Derivatives of Cyclobutanones with Different Nucleophiles

The reactions of 3‐chloro‐3‐(chlorosulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 2 ) with N, O, S, and P nucleophiles occur by substitution of Cl at the S‐atom. Whereas, in the cases of secondary amines, alkanols, phenols, thiols, thiophenols, and di‐ and trialkyl phosphates, the initially formed substitution products were obtained, the corresponding products with allyl and propargyl alcohols undergo a [2,3]‐sigmatropic rearrangement to give allyl and allenyl sulfoxides, respectively. Analogous substitution reactions were observed when 3‐chloro‐3‐(chlorodisulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 3 ) was treated with N, O, and S nucleophiles. The reaction of 3 with Et₃P led to an unexpected product via cleavage of the S? S bond (cf. Scheme 13). In the reactions of 2 with primary amines and H₂O, the substitution products react further via elimination of HCl to yield the corresponding thiocarbonyl S‐imides and the thiocarbonyl S‐oxide, respectively. Whereas the latter could be isolated, the former were not stable but could be intercepted by MeOH (Scheme 4) or adamantanethione (Scheme 5). The structures of some of the substitution products were established by X‐ray crystallography.     

Single and Consecutive Cyclization Reactions of Alkynyl Carbene Complexes and 8‐Azaheptafulvenes: Direct Access to Polycyclic Pyrrole and Indole Derivatives

The reactivity of alkynyl and enynyl Fischer carbene complexes towards 8‐azaheptafulvenes is examined. Alkynyl carbenes 1 a – f undergo regioselective [8+2] heterocyclization with 8‐aryl‐8‐azaheptafulvenes 2 a , b providing cycloheptapyrroles 3 and 4 with metal carbene or ester functionality at C3. Moreover, consecutive cyclization reactions are involved when enynyl carbenes are used. Thus, the cyclopenta[b]pyrrole framework 7 is formed by the consecutive [8+2] cyclization and cyclopentannulation reactions. The initially formed cyclopentannulation adduct can be intercepted through a Diels–Alder reaction with classic dienophiles to afford increasing structural complexity (compounds 8 and 9 ). More importantly, the construction of the indole skeleton is accomplished with a high degree of substitution and functionalization (compounds 11 – 15 ) by a one‐pot sequence that involves [8+2] cyclization, R? NC or CO insertion, and ring closure.     

Selective Double Functionalization of meso‐Tetraphenylporphyrin Complexes on the Same Pyrrole Unit by Tandem Electrophilic/Nucleophilic Aromatic Substitution

The mono‐nitrated meso‐tetraphenylporphyrin (TPP) complex 2 could be readily functionalized on the substituted pyrrole ring with yields of up to 83%. These transformations were achieved via aromatic substitution with carbanions generated from diverse functionalized compounds containing different leaving groups ( 3a – g , Scheme 1). The resulting TPP compounds 4a – g , bearing two different β‐substituents on the same pyrrole ring, may be further manipulated. This, in turn, should allow one to tune the solubility of TPP derivatives used in photodynamic cancer therapy.     

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

An unprecedented tandem N‐alkylation–ionic aza‐Cope (or Claisen) rearrangement–hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N‐alkylation and subsequent microwave‐irradiated ionic aza‐Cope rearrangement–hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2‐reverse quaternary‐centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza‐Cope rearrangement reaction proceeds highly regioselectively to give the quaternary‐centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2‐reverse prenylated indoles, such as indolines, indole‐fused sultams and lactams, and the natural product bruceolline D.     

Syntheses of Chalcone‐Type Chlorophyll Derivatives Possessing a Bacteriochlorin,Chlorin or Porphyrin π‐System and Their Optical Properties

C3‐(Trans‐2‐arylethenyl)carbonylated chlorophyll derivatives possessing a bacteriochlorin or chlorin π‐system were synthesized by cross‐aldol (Claisen–Schmidt) condensation of methyl pyrobacteriopheophorbide‐a or 3‐acetyl‐3‐devinyl‐pyropheophorbide‐a bearing the C3‐acetyl group with p‐(un)substituted benzaldehydes under basic conditions. The corresponding porphyrin‐type chlorophyll derivatives were prepared by the oxidation (17,18‐didehydrogenation) of the chlorin‐type. Their Qy absorption and fluorescence emission maxima in dichloromethane correlated well with Hammett substituent constants of the p‐substituents. Several electron‐withdrawing p‐substituents suppressed the emission due to photoinduced electron transfer quenching in a molecule. The substitution sensitivities for their maxima and fluorescence quantum yields decreased in the order of bacteriochlorin‐, chlorin‐ and porphyrin‐type derivatives.     

VICARIOUS NUCLEOPHILIC SUBSTITUTION WITH SULFUR CONTAINING CARBANIONS

Abstract

Carbanions stabilized with sulfur containing substituents are versatile intermedi-ates in organic synthesis. The great value and importance of such carbanions is connected with specific properties of the sulfur atom which is capable to exist in a variety of valent states and to form many functional groups. These various sulfur-containing groups exert different carbanion stabilizing effects and can also serve as leaving groups in nucleophilic substitution or elimination reactions. Taking into account numerous types of sulfur containing functional groups and a variety of reactions they can promote, it is well understandable that reactions of sulfur-containing carbanions have been thoroughly studied and widely exploited in organic synthesis. The reactions of such carbanions with aliphatic electrophilic partners: alkylating agents, carbonyl compounds and Michael acceptors consist a major section of this field and were subject of numerous studies as well as many monographs.¹ Contrary to that, not very much was known about reactions of such carbanions with electrophilic aromatic compounds. Actually, there are only few reports on nitroarylation of sulfur-containing carbanions via replacement of halogen orfho- or para- to the nitro group in halonitrocornpounds.² There are also some reports on the alkylation of nitroarenes and heterocyclic compounds in the reaction with sulfonium3 and sulfoxonium4 ylides, dimethylsulfoxide carbanion,⁵ and dialkyl or alkyl aryl sulfones carbanions.⁶     

Brominated Trihalomethylenones as Versatile Precursors to 3‐Ethoxy, ‐Formyl, ‐Azidomethyl, ‐Triazolyl,and 3‐Aminomethyl Pyrazoles

5‐Bromo[5,5‐dibromo]‐1,1,1‐trihalo‐4‐methoxy‐3‐penten[hexen]‐2‐ones are explored as precursors to the synthesis of 3‐ethoxymethyl‐5‐trifluoromethyl‐1H‐pyrazoles from a cyclocondensation reaction with hydrazine monohydrate in ethanol. 3‐Ethoxymethyl‐carboxyethyl ester pyrazoles were formed as a result of a substitution reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3‐acetal‐pyrazole that was easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic substitution reaction with sodium azide to synthesize the 3‐azidomethyl‐5‐ethoxycarbonyl‐1H‐pyrazole from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction with phenyl acetylene furnishing the 3‐[4(5)‐phenyl‐1,2,3‐triazolyl]5‐ ethoxycarbonyl‐1H‐pyrazoles and to reduction conditions resulting in 3‐aminomethyl‐1H‐pyrazole‐5‐carboxyethyl ester. The products were obtained by a simple methodology and in moderate to good yields.