Annulation Process Research Articles

Synthesis of isoindolo[2,1-alpha]indoles by the palladium-catalyzed annulation of internal acetylenes.

A wide variety of substituted isoindolo[2,1-alpha]indoles have been prepared via annulation of internal alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This methodology provides an extremely efficient route for the synthesis of these tetracyclic heterocycles from readily available starting materials. The mechanism of this interesting annulation process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) addition of the resulting vinylic palladium intermediate to the C-N double bond of the imine, (4) either electrophilic palladation of the resulting sigma-palladium intermediate onto the adjacent aromatic ring derived from the internal alkyne or oxidative addition of the neighboring aryl carbon-hydrogen bond, and (5) reduction of the tetracyclic product and Pd(0). A variety of internal acetylenes have been employed in this annulation process in which the aromatic ring of the alkyne contains either a phenyl or a heterocyclic ring.

Solid-Phase Synthesis of Bis(guanidines) Based on an Aza Wittig/Carbodiimide-Mediated Annulation Process

Solid-Phase Synthesis of Bis(guanidines) Based on an Aza Wittig/Carbodiimide-Mediated Annulation Process

Synthesis of Isoindolo[2,1-a]indoles by the Palladium-Catalyzed Annulation of Internal Alkynes

A wide variety of substituted isoindolo[2,1-a]indoles have been prepared in good to excellent yields by the palladium-catalyzed annulation of internal alkynes by imines derived from o-iodoanilines and benzaldehydes. The mechanism of this interesting annulation process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) addition of the resulting vinylic palladium intermediate to the C−N double bond of the imine, (4) either electrophilic palladation of the resulting σ-palladium intermediate onto the adjacent aromatic ring originating in the internal alkyne or oxidative addition of the neighboring aryl carbon−hydrogen bond, and (5) reductive elimination of the tetracyclic product and Pd(0).

ChemInform Abstract: Sequenced Reactions with Samarium(II) Iodide. A Complementary Annulation Process Providing Access to Seven‐, Eight‐, and Nine‐Membered Carbocycles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Isoquinolines and Pyridines by the Palladium- and Copper-Catalyzed Coupling and Cyclization of Terminal Acetylenes

3-Substituted isoquinolines have been synthesized by the coupling of aryl- and alkenyl-substituted terminal acetylenes with the tert-butylimine of o-iodobenzaldehyde in the presence of a palladium catalyst. Alkyl-substituted acetylenes fail to undergo this annulation process. However, the intermediate iminoalkynes containing aryl, alkenyl, and alkyl substituents produced from these palladium-catalyzed reactions undergo copper-catalyzed cyclization in excellent yields and short reaction times. Isoquinolines and pyridines have thus been prepared in a one-pot synthesis via coupling of aryl-, alkenyl-, and alkyl-substituted terminal acetylenes with the tert-butylimines of o-iodobenzaldehydes or 3-halo-2-alkenals in the presence of a palladium catalyst and subsequent copper-catalyzed cyclization of the resulting iminoalkynes. The total synthesis of the isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall yield by employing this palladium-catalyzed coupling/cyclization...

Sequenced Reactions with Samarium(II) Iodide. A Complementary Annulation Process Providing Access to Seven-, Eight-, and Nine-Membered Carbocycles

Samarium(II) iodide promotes an efficient one-pot annulation reaction between ω-iodo esters and 2-(ω-chloroalkyl)cycloalkanones. An initial intermolecular carbonyl addition reaction between the iodo ester and the ketone generates a lactone intermediate. The lactone undergoes a subsequent nucleophilic acyl substitution reaction with an organosamarium derived from the chloride. Nickel(II) iodide is an efficient catalyst for the first step of the process, and light is utilized to promote the second step. Seven-, eight-, and nine-membered rings can be accessed by this sequential dianionic process. This annulative approach to carbocycles is complementary to previously reported procedures.

Palladium-Catalyzed Annulation of Internal Alkynes by Arene-Containing Vinylic Iodides and Triflates

In the presence of a palladium catalyst, internal alkynes undergo carboannulation by cyclic and acyclic vinylic iodides and triflates bearing a neighboring aromatic ring to produce a variety of carbocycles. For example, a number of 9,10-disubstituted-1,2,3,4-tetrahydrophenanthrenes have been prepared in good yields through the palladium-catalyzed annulation of internal alkynes by 2-phenyl-1-cyclohexenyl triflate (1) or 1-iodo-2-phenylcyclohexene (2). This annulation process is fairly general and highly regioselective. The process appears to involve oxidative addition of the vinylic substrate to Pd(0) to produce a vinylic palladium intermediate, which adds the carbon moiety to the less hindered end and the palladium to the more hindered end of the alkyne, followed by intramolecular ring closure onto the neighboring aryl group. The scope and limitations of this methodology are discussed.

Regioselective Annulation of Alicyclic−Aromatic Dienes with 3-Halo-3-cyclobutene-1,2-diones. Synthesis of Annulated α-Halobenzocyclobutenones1

4-(1-Cycloalken-1-yl)-1,2-dialkoxybenzenes 8, 10, and 11 and 5-(1-cycloalken-1-yl)-1,3-benzodioxoles 12−15 react with the semisquaric halides 5a and 5b in a dehydrative annulation process to give the annulated α-halobenzocyclobutenones 9a,b and 16a,b−21a,b in poor to good yields (20−76%). The reaction failed with alicyclic−aromatic dienes having no or only one alkoxy group in the benzene ring. The dehydrative annulation process could be extended to 4-(3,4-dimethoxyphenyl)-1,2-dihydronaphthalene (24), affording the highly annulated α-chlorobenzocyclobutenone 25 in 50% yield. In the case of 5-(1-cyclobuten-1-yl)-1,3-benzodioxole (22), reaction with the semisquaric halides 5a,b yielded the dicyclobutanaphthodioxole-1,2-dione (23) as the sole product in a dehydrochlorinative annulation process. A reaction pathway has been suggested for the dehydrative annulation process. Several of the annulated α-halobenzocyclobutenones prepared were submitted to selected chemical transformations. Thus, the reaction with tri...

4‐Methyl‐3,4‐dihydrospiro[cycloheptane‐1′,2(1H)‐quinoline] and 4‐methyl‐3,4‐dihydrospiro[cyclooctane‐1′,2(1H)‐quinoline]. synthesis of derivatives and chemical transformations

AbstractNew derivatives of 3,4‐dihydrospiro[cycloalkane‐1′,2(1H)‐quinolines] were obtained from cycloheptanone and cyclooctanone via facile three steps hetero spiro annulation process. Their nitro derivatives were prepared through electrophilic substitution reactions.

ChemInform Abstract: A Novel Synthesis of the Pyrazolo(1,5‐a)quinoline Ring System. New N1‐ C2 Bridged DNA Gyrase Inhibitors via a Novel Tandem 1,4‐Conjugate Addition‐Michael (3 + 2) Annulation Process.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A novel synthesis of the pyrazolo[1,5- a]quinoline ring system. New N1-C2 bridged DNA gyrase inhibitors via a novel tandem 1,4-conjugate addition-Michael [3+2] annulation process

A novel tandem 1,4-conjugate addition-intramolecular Michael addition [3+2] annulation process for synthesis of the pyrazolo[1,5- a]quinoline ring system is described. Reaction of N-methylaminoquinolones with various acrylate derivatives in the presence of NaH leads to pyrazolo[1,5- a]quinolines in excellent yield. Transformation of the adducts into novel N1-C2 bridged tricyclic DNA gyrase inhibitors is also described.

2,3-Bis(phenylsulfonyl)-1,3-butadiene: Substrate for Michael Donor/Acceptors in a Novel Synthesis of Fused Cyclopentenes.

The reaction of 2,3-bis(phenylsulfonyl)-1,3-butadiene with the anion of various 1-substituted dimethyl 1-pentenedioates has been investigated with the purpose of devising a tandem conjugate addition-[3 + 2]-anionic cyclization route for the synthesis of bicyclo[3.3.0]octenes. The reaction proceeds with complete stereospecificity as was evidenced by treating (E)- and (Z)-dimethyl (3-cyano-2-propenyl)propanedioate with NaH in the presence of the bis(phenylsulfonyl)diene. In both cases only a single cycloadduct was obtained with no detectable signs of the other diastereomer. The overall process involves a series of three sequential conjugate additions followed by benzenesulfinate ion ejection. The success of the method is dependent on the electrophilicity of the proximal pi-bond. When 2-((5-oxo-2,5-dihydrofuranyl)methyl)malonic acid dimethyl ester was used, a mixture of the tricyclic adduct as well as an allene was obtained. In this case, elimination of the benzenesulfinate group from the initially formed sulfone-stabilized carbanion is competitive with the intramolecular [3 + 2]-annulation process. The base-induced reaction of dimethyl 2-(methoxycarbonyl)-2-pentenedioate with the bis(phenylsulfonyl)diene was also studied. Even though the position of the acceptor moiety on the pi-bond was altered, the tandem Michael reaction sequence still occurs. The course of the reaction is dependent upon the length of the tether as well as the relative placement of the electron-withdrawing group on the olefin. Reaction with gamma-substituted beta,gamma-alkenyl derivatives leads to bicyclo[3.3.0]octenes, whereas beta-substituted beta,gamma-alkenyl reagents provide bicyclo[3.3.0]octenes derived from a novel alpha-elimination reaction.

The Synthesis and Some Manipulations of Dialkyl 6-Aryl (or Alkyl)-2-oxotetrahydro-2H-pyran-3,5-dicarboxylates

A new, one-pot annulation process, involving conjugate addition of the sodium salts of dimethyl (or dibenzyl ) malonate to alkyl 2-(1- hydroxyalkyl ) propenoates, produces a mixture of dialkyl 6-aryl(or alkyl)-2-oxotetrahydro-2H-pyran-3,5-dicarboxylates. Alkylations of the cis-isomers were found to be highly stereoselective . The ntroduction of unsaturation into these molecules is also described.

Palladium-Catalyzed Reaction of o-Ethynylphenols, o-((Trimethylsilyl)ethynyl)phenyl Acetates, and o-Alkynylphenols with Unsaturated Triflates or Halides: A Route to 2-Substituted-, 2,3-Disubstituted-, and 2-Substituted-3-acylbenzo[b]furans

The reaction of o-ethynylphenols 3 with a wide variety of unsaturated halides or triflates 6 in the presence of Pd(OAc)2(PPh3)2, CuI, and Et3N (procedure A) gives 2-vinyl- and 2-arylbenzo[b]furans 7, in good to high yield, through a palladium-catalyzed coupling followed by an in situ cyclization step. Small amounts of 2,3-disubstituted-benzo[b]furans 8 are usually isolated as side products. In some cases, however, compounds 8 are generated in significant yield or even as the main products. The formation of 8 can be prevented by employing alternative procedures (B and C) that use o-((trimethylsilyl)ethynyl)phenyl acetates 5 as starting building blocks. Procedure B is based on the palladium-catalyzed reaction of 5 with 6 in the presence of Pd(PPh3)4, Et3N, and n-Bu4NF, followed by the hydrolysis of the resultant coupling derivative 12 under basic conditions. Procedure C affords 7 through an in situ coupling/cyclization of 5 with 6 in the presence of Pd(PPh3)4 and KOBut. The utilization of o-alkynylphenols 9 as the starting alkynes in the palladium-catalyzed reaction with 6 leads to the formation of 2,3-disubstituted-benzo[b]furans 13 through an annulation process promoted by σ-vinyl- and σ-arylpalladium complexes generated in situ. The best results in this case are obtained by using KOAc and Pd(PPh3)4. In the presence of KOAc and Pd(PPh3)4, and under an atmosphere of carbon monoxide, the reaction of o-alkynylphenols with 6 provides 2-vinyl- and 2-aryl-3-acylbenzo[b]furans 14.

Palladium−Cobalt-Mediated Double Annulation Process: A New Strategy to Chiral and Polysubstituted Bis-Cyclopentanoids on Carbohydrate Precursors

Palladium−Cobalt-Mediated Double Annulation Process: A New Strategy to Chiral and Polysubstituted Bis-Cyclopentanoids on Carbohydrate Precursors

A General Synthesis of Methylenecyclopentanes by a Stereoselective [3 + 2] Approach

The [3 + 2] cyclopentanation involving 3-(phenylsulfonyl)-2-(bromomethyl)-1-propene (1) and representative (E) α,β-unsaturated acyclic esters and ketones has been studied. High yields and complete stereoselectivity were observed in all reactions leading to tri- or tetrasubstituted methylenecyclopentanes. The anti-diastereoselectivity in the first, Michael addition step is rationalized by a chelation-controlled transition state in which MO interactions of the two π systems are involved. The Michael reactions of methallyl sulfone 8 with (E) enoates in the absence and presence of HMPA confirms the influence of chelation on the diastereomeric ratio of adducts. Cyclopentanations involving 1 with cyclohexenone, 2(5H)-furanone, and 5,6-dihydro-2-pyranone, respectively, were also studied with emphasis on the factors influencing the stereochemical outcome of the annulation process.

An iminophosphorane-mediated efficient synthesis of the alkaloid leucettamine B of marine origin

The first synthesis of the alkaloid Leucettamine B, by a four-step sequence in a overall yield of 50%, is discribed. The key step, formation of the 2-aminoimidazole ring, involves a tandem aza-Wittig/carbodiimide-mediated annulation process.

A convenient annulation process involving a tandem alkylation-Michael addition sequence

Malonic esters, β-keto-ester and other methylene-active compounds react withthe 7-iodo-2-heptenoic acid methyl ester 2 in presence of cesium carbonate to give six-membered ring products 5, through a tandem alkylation-Michael addition reaction.

Dilithiated 2-(Chloromethyl)-3-tosylpropene: A New γ-Chlorinated Allyl Sulfone Dianion in Organic Synthesis

Dilithiation of 2-(chloromethyl)-3-tosylpropene ( 1) with n-butyllithium at −90°C in the presence of DMPU affords the allylic dianion 2 which reacts with deuterium oxide or very reactive alkylating agents to give α,α-disubstituted products 3 or 4, respectively. Monoalkylation at the α-position followed by cyclopropanation reaction takes place with n-alkyl bromides to provide tosylated methylenecyclopropanes 5. The reaction of dianion 2 with aldehydes or electrophilic olefins occurs at the α-position followed by the corresponding annulation process obtaining tosylated 2,5-dihydrofurans 6 or cyclopentenes 8, respectively. When ketones are used as electrophiles, dianion 2 reacts at the γ-position yielding 3-(tosylmethylene)tetrahydrofurans 7. Reductive desulfonylation of compounds 5-8 with sodium amalgam or samarium(II) iodide to afford the corresponding desulfonylated derivatives 22-26 has been also studied.

Reputation and Reality in the ICSID Annulment Process: Understanding the Distinction Between Annulment and Appeal

Reputation and Reality in the ICSID Annulment Process: Understanding the Distinction Between Annulment and Appeal