Annulation Strategy Research Articles

ChemInform Abstract: Tandem Thien‐ and Benzannulations of α‐Alkenoyl‐α‐Alkynyl Ketene Dithioacetals with Cyanoacetates: Synthesis of Functionalized Benzo[b]thiophenes.

AbstractA novel domino annulation strategy for the construction of benzo[b]thiophenes is presented which occurs in the presence of Cs2CO3 and Ag2CO3.

ChemInform Abstract: Synthesis of Spiropyrrolidines via Five‐Component 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Olefinic Dipolarophiles Generated in situ Simultaneously.

AbstractThe introduced method allows 1,3‐dipole azomethine ylides and olefinic dipolarophiles to be simultaneously generated in situ, which makes this novel annulation strategy both practical and attractive with the advantages of direct use of commercially available and inexpensive reagents, simple experimental and work‐up procedures, and mild reaction conditions.

New Convenient Strategy for Annulation of Pyrimidines to Thiophenes or Furans via the One-pot Multistep Cascade Reaction of 1H-Tetrazoles with Aliphatic Amines.

A versatile, convenient, efficient and high-yield synthetic method for 2-R(3),R(4)-amino-5-R(1)-6-R(2)-thieno[2,3-d]pyrimidin-4(3H)-ones, 2-R(3),R(4)-amino-5-R(1)-6-R(2)-thieno[3,2-d]pyrimidin-4(3H)-ones, and benzofuro[3,2-d]pyrimidin-4(3H)-ones preparation has been developed. The reaction proceeded without using solvents and included several steps. A variety of thieno[2,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives with substituents of different nature were obtained in high yields from substituted alkyl 2-(1H-tetrazol-1-yl)thiophene-3-carboxylates, 3-(1H-tetrazol-1-yl)thiophene-2-carboxylates, and 3-(1H-tetrazol-1-yl)benzofuran-2-carboxylate after their treatment with aliphatic amines.

Tandem Thien- and benzannulations of α-alkenoyl-α-alkynyl ketene dithioacetals with cyanoacetates: synthesis of functionalized benzo[b]thiophenes.

A novel domino annulation strategy for the construction of benzo[b]thiophenes has been developed. In the presence of Cs2CO3 and Ag2CO3, a wide range of α-alkenoyl-α-alkynyl ketene dithioacetals readily react with cyanoacetates in CH3CN at 110 °C under N2 to afford multisubstituted benzo[b]thiophenes efficiently via tandem thien- and benzannulations. A plausible mechanism is also proposed.

ChemInform Abstract: Iodine‐Promoted Sequential C(sp3)—H Functionalization Reactions: An Annulation Strategy for the Construction of 3‐Methylthio‐4‐arylmaleimides.

AbstractMethylthio‐substituted maleimides are synthesized by a novel annulation strategy from methyl ketones, actetamides, and DMSO in the presence of I2 via an iodination/Kornblum oxidation/amidation/cyclization sequence.

Inter- and Intramolecular Annulation Strategies to a Cyclopentanone Building Block Containing an All-Carbon Quaternary Stereogenic Center

Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone methyl ester (1S)-1 has been achieved by both inter- and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral bis-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center.

Synthesis of benzofused 1,4-azaborinols via [4 + 2] annulation strategy and its application in indole synthesis

The first general synthesis of benzofused 1,4-azaborinols via [4 + 2] annulation strategy and its application in indole synthesis.

One pot synthesis of tetrasubstituted thiophenes: [3 + 2] annulation strategy

A simple, efficient and economical synthesis of dimethyl 3-amino-5-(2-oxo-2-arylethyl)thiophene-2,4-dicarboxylates has been reported by ring opening of methyl 3-amino-6-aryl-4-oxo-4H-thieno[3,2-c]pyran-2-carboxylates by alkoxide ions.

Asymmetric N-Heterocyclic Carbene Catalyzed Annulation of 2-Alkenylbenzothiazoles with α-Chloro Aldehydes

Diastereo- and enantioselective N-heterocyclic carbene catalyzed 1-azadiene Diels–Alder reactions of (E)-2-styrylbenzothiazoles with α-chloro aldehydes are reported. This annulation strategy provides an efficient access to medicinally important dihydrobenzothiazolopyridin-1-ones in good to excellent yields (44–97%) with very good to excellent stereoselectivities (up to 9:1 dr, 98% ee) and tolerates quite a range of substituents.

Iodine‐Promoted Sequential C(sp3)H Functionalization Reactions: An Annulation Strategy for the Construction of 3‐Methylthio‐4‐arylmaleimides

AbstractA new process has been developed for the iodine‐promoted sequential C(sp3)H bond functionalization of methyl ketones and acetamides. This reaction represents a novel annulation strategy for the synthesis of 3‐(methylthio)‐4‐aryl‐1H‐pyrrole‐2,5‐diones, and involves an α‐ketoimide as the key intermediate. Furthermore, DMSO was converted to DMS in situ, which served as the methylthiolation reagent in the reaction. This protocol constitutes an efficient and convenient method for the methylthiolation of substrates bearing a wide range of functional groups.magnified image

Interceptive [4 + 1] annulation of in situ generated 1,2-diaza-1,3-dienes with diazo esters: direct access to substituted mono-, bi-, and tricyclic 4,5-dihydropyrazoles.

In situ derived acyclic and cyclic 1,2-diaza-1,3-dienes (DDs) were engaged in interceptive [4 + 1] annulation strategy with diazo esters (DEs). The catalytic activity of inexpensive copper(II) chloride allows the direct synthesis of mono-, bi-, and tricyclic 4,5-dihydropyrazole-5-carboxylic acid derivatives in a process that circumvents the use of an anhydrous and inert atmosphere.

Highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence.

Stereoselective synthesis of a cyclopentane nucleus by convergent annulations constitutes a significant challenge for synthetic chemists. Though a number of biologically relevant cyclopentane natural products are known, more often than not, the cyclopentane core is assembled in a stepwise fashion due to lack of efficient annulation strategies. Herein, we report the rhodium-catalyzed reactions of vinyldiazoacetates with (E)-1,3-disubstituted 2-butenols generate cyclopentanes, containing four new stereogenic centers with very high levels of stereoselectivity (99% ee, >97 : 3 dr). The reaction proceeds by a carbene–initiated domino sequence consisting of five distinct steps: rhodium–bound oxonium ylide formation, [2,3]-sigmatropic rearrangement, oxy-Cope rearrangement, enol–keto tautomerization, and finally an intramolecular carbonyl ene reaction. A systematic study is presented detailing how to control chirality transfer in each of the four stereo-defining steps of the cascade, consummating in the development of a highly stereoselective process.

ChemInform Abstract: Synthesis of Benzocyclohepta[b]indoles by Lewis Acid Catalyzed Annulation of Two 3‐(1H‐Isochromen‐1‐yl)‐1H‐indoles.

A novel Lewis acid catalyzed annulation reaction has been established for the synthesis of benzocyclohepta[b]indoles. This method represents a new annulation strategy to a seven-membered carbocyclic ring system from two 3-(1H-isochromen-1-yl)-1H-indole molecules using Cu(OTf)2 catalyst; moreover, the products, benzocyclohepta[b]indoles, can be used as the rapid mercuric ion colorimetric detection reagents.

Stereocontrolled synthesis of bicyclic sulfamides via Pd-catalyzed alkene carboamination reactions. Control of 1,3-asymmetric induction by manipulating mechanistic pathways.

A new annulation strategy for the synthesis of trans-bicyclic sulfamides is described. The Pd-catalyzed alkene carboamination reactions of 2-allyl and cis-2,5-diallyl pyrrolidinyl sulfamides with aryl and alkenyl triflates afford the fused bicyclic compounds in good yields and with good diastereoselectivity (up to 13:1 dr). Importantly, by employing reaction conditions that favor an anti-aminopalladation mechanism, the relative stereochemistry between the C3 and C4a stereocenters of the products is reversed relative to related Pd-catalyzed carboamination reactions that proceed via syn-aminopalladation.

Organocatalytic synthesis of substituted spirocyclohexane carbaldehydes via [4 + 2] annulation strategy between 2-arylideneindane-1,3-diones and glutaraldehyde.

An organocatalytic domino reaction between 2-arylideneindane-1,3-diones and glutaraldehyde has been devised that gives functionalized spirocyclohexane carbaldehydes with an all-carbon quaternary center. The reaction proceeds through a Michael/Aldol sequence in good-to-high chemical yields and with high levels of stereoselectivity (up to >95:5 dr and 99% ee) in the presence of the α,α-L-diphenylprolinol trimethylsilyl ether 3 (20 mol %) and DIPEA (20 mol %) in ether at 0 °C.

Synthesis of Benzocyclohepta[b]indoles by Lewis Acid Catalyzed Annulation of Two 3-(1H-Isochromen-1-yl)-1H-indoles

A novel Lewis acid catalyzed annulation reaction has been established for the synthesis of benzocyclohepta[b]indoles. This method represents a new annulation strategy to a seven-membered carbocyclic ring system from two 3-(1H-isochromen-1-yl)-1H-indole molecules using Cu(OTf)2 catalyst; moreover, the products, benzocyclohepta[b]indoles, can be used as the rapid mercuric ion colorimetric detection reagents.

Synthesis of highly substituted pyranonaphthalene spiroketals related to the griseusins using a Hauser–Kraus annulation strategy

The synthesis of an advanced pyranonaphthalene spiroketal as an intermediate for the total synthesis of griseusin B is described. A one-pot Hauser–Kraus annulation–methylation via reaction of a highly-substituted enone with a cyanophthalide was employed to construct the naphthalene framework. Other key steps include Sharpless asymmetric dihydroxylation of a (Z)-alkene and an HF-pyridine mediated double TBS deprotection-spirocyclisation.

Regioselective dehydrative intramolecular heteroannulation of β-allyl-β-hydroxy dithioesters: facile and straightforward entry to 2H-thiopyrans

β-Allyl-β-hydroxy dithioesters have been employed in the synthesis of hitherto unreported and synthetically demanding 2H-thiopyrans via regioselective intramolecular annulation strategy. Lewis acid BF3·Et2O efficiently mediates the regioselective dehydration followed by intramolecular thioannulation at room temperature. The attractive features of this protocol include mild conditions, high atom-economy and excellent yields with the elimination of water as the only by-product.

Annulations of α‐Carbamoyl Ketene Dithioacetals with Dicarboxylic Acid Dichlorides: Synthesis of Functionalized Pyrrolidinetriones and Piperidinetriones

AbstractAn annulation strategy based on ketene dithioacetals is described. Under very mild conditions, a number of pyrrolidinetriones 2 and piperidinetriones 3 have been synthesized by the cycloaddition reaction of α‐carbamoyl ketene dithioacetals 1 with di‐carboxylic acid dichlorides in good to excellent yields. Further application of this protocol is highlighted by the synthesis of a set of fused pyrimidine derivatives 4/5 from 2/3 and amidines.

ChemInform Abstract: Pd‐Catalyzed C—S Activation for [3 + 3] Annulation of 2‐(Methylthio)benzofuran‐3‐carboxylates and 2‐Hydroxyphenylboronic Acids: Synthesis of Coumestan Derivatives.

Pd-catalytic C–S activation was successfully applied to initiate the cross-coupling of (2-methylthio-3-ester)benzofurans with 2-hydroxyphenylboronic acids and sequential intramolecular transesterification process under Liebeskind-Srogl conditions. Thus, a novel [3 + 3] annulation strategy for efficient synthesis of coumestan derivatives has been developed from readily available starting materials.