[Au]-Catalyzed Cyclization of Propargyl-Tethered Ene-Amides: Substrate-Dependent Access to Tetrasubstituted Pyrroles, Aminophenols, and Dihydropyridines.

[Au]-catalyzed and substrate-dependent intramolecular cyclization of sulfonyl ene-amides with a pendant propargyl group afford tetrasubstituted pyrroles, o-aminophenols, or 1,6-dihydropyridine carbaldehydes. While the pyrroles and aminophenols are formed when the propargylic alkyne is terminal, dihydropyridines are formed when internal alkyne is present. Internal alkyne substrates with 2-thienyl and 3-thienyl groups give different types of dihydropyridines. The dihydropyridines so obtained can be readily converted to nicotinaldehydes with concomitant sulfonyl migration upon heating in xylene.

δ-Acetoxy Allenoate as a 5C-Synthon in Domino-Annulation with Sulfamidate Imines: Ready Access to Coumarins.

A DMAP-catalyzed sequential benzannulation and lactonization strategy in which δ-acetoxy allenoate functions as a 5C-synthon in its reaction with cyclic sulfamidate imines is reported. This platform delivers π-extended coumarin frameworks under metal-free conditions via allylic elimination followed by Mannich coupling, proton shifts, C-N bond cleavage, and lactonization as key steps. The driving force for this domino reaction is the formation of the diene-ammonium intermediate and O-S bond cleavage. ESI-HRMS has been useful in gaining insights into the reaction pathway.

Cu(II)-Catalyzed Decarboxylative (4 + 2) Annulation of Coumarin-3-Carboxylic Acids with In Situ Generated α,ß-Unsaturated Carbonyl Compounds from tert-Propargylic Alcohols.

Cu(II)-catalyzed decarboxylative oxidative (4 + 2) annulation of coumarin-3-carboxylic acids with tert-propargylic alcohols, via the in situ generated α,ß-unsaturated carbonyl compounds by the Meyer-Schuster rearrangement, has been developed. This protocol involving indirect C-H functionalization offers access to diverse naphthochromenone architectures with good to excellent yields.

DBU-Catalyzed Ring Expansion or Ene-amine Formation Involving δ-Acetoxy Allenoates and N-Sulfonyl Hydrazides.

DBU-catalyzed spiro-annulation and concomitant ring expansion/domino reaction of δ-acetoxy allenoates with cycl-2-ene-N-sulfonyl hydrazides afford ring-expanded (5 → 6, 6 → 7, and 7 → 8) products. By contrast, cycl-3-ene/ane-N-sulfonyl hydrazones under similar conditions deliver pyrazole cores with the same allenoate that involves allylic elimination in which δ-acetoxy allenoate serves as 3C-synthon. The key spirocyclic intermediates, as well as dienyl-amine intermediates, are isolated and characterized. An extension to (R)-(-)-carvone-derived sulfonyl hydrazide also led to ring expansion and gave pyrazoloazepine.

Divergent Reactivity of Phosphorylated and Related Allenes: [4 + 2] Cycloaddition with 3,6-Diphenyltetrazine, Self-Addition Leading to Dimers and [Pd]-Complex Formation.

Phosphorus-based naphthalenes are formed by self-dimerization-cum-cyclization of α-aryl allenylphosphonates or allenylphosphine oxides using catalytic Pd(OAc)2in the presence of PPh3 and Et3N . This reaction involves [4 + 2]-cycloaddition with the (ß,γ) double bond of one allene as the dienophile; the double bonds at the α-aryl-(ß',γ') group and (α,ß)-carbons of the second allene act as the diene part. A subsequent proton shift also takes place. Upon treating allenylphosphine oxides with Pd(OAc)2 [stoichiometry 2:1] in the presence of PPh3/Ag2CO3, a [Pd]-complex is isolated and structurally characterized. This complex can be used as a catalyst for C-C bond-forming reactions of phosphorus-based allenes with 2-iodophenol. Densely substituted 3,6-diphenylpyridazines are conveniently obtained in excellent yields by a thermally induced regioselective Inverse Electron Demand Diels-Alder (IEDDA) reaction of allenes with 3,6-diphenyltetrazine, followed by a [1,3]-H shift.

Ring-Expansion Reactions of Epoxy Amides and Enamides: Functionalized Azetidines, Dihydrofurans, Diazocanes, or Dioxa-3-azabicyclonon-4-enes?

Functionalized azetidines, 2,3-dihydrofurans, or the unorthodox dioxa-3-azabicyclonone-4-ene motifs are the products from transition metal-free reaction between N-oxiranylmethyl benzenesulfonamide and ß-chloro-cinnamaldehyde, depending on whether one uses either NaI/K2CO3 or LiBr/K2CO3. These ring expansion reactions involve enamide (X-ray evidence) derived from N-oxiranylmethyl benzenesulfonamide and ß-chloro-cinnamaldehyde as an intermediate. The N-oxiranylmethyl benzenesulfonamide itself upon heating gives readily separable and crystalline isomeric diazocanes that can be characterized by X-ray crystallography.

Pyridine vs DABCO vs TBAB in Annulations of δ-Acetoxy Allenoates with Thioamides Leading to Dihydrothiophene, Thiopyran, and Thiazole Scaffolds.

The same δ-acetoxy allenoates and thioamides, under DABCO, pyridine, or tetra-n-butyl ammonium bromide (TBAB) catalysis, undergo distinctly different annulations giving chemoselective routes to dihydrothiophene, thiopyran, or thiazole motifs. Thus, using pyridine in [3 + 2] annulation, dihydrothiophenes are obtained as essentially single diastereomers. By contrast, under DABCO catalysis, allenoates deliver thiopyran motifs in good to high yields through 6-exo-dig cyclization. In the thiazole forming [3 + 2] annulation, tetra-n-butyl ammonium bromide (TBAB) facilitates addition-elimination and 5-exo-trig cyclization in which ß- and γ-carbons of allenoates participate to deliver thiazole cores exclusively with a Z-isomeric exocyclic double bond. A possible rationale for these observations is delved into.

Contrasting Carboannulation Involving δ-Acetoxy Allenoate as a Four-Carbon Synthon Using DABCO and DMAP: Access to Spiro-carbocyclic and m-Teraryl Scaffolds.

Spiro-annulation involving δ-acetoxy allenoate and alkyl benzoisothiazole dioxide (N-sulfonyl ketimine) triggered by DABCO/MeCO2H combination leads to an essentially single diastereomer via chemo- and regiospecific [4 + 2]-carboannulation and a new hydroxyl group is introduced. In contrast, DMAP-catalyzed benzannulation using the same reactants affords unsymmetrical m-teraryls via Mannich coupling, sequential proton transfers, and C-N bond cleavage. Here, δ-acetoxy allenoate serves as a 4C-synthon and the carboannulation is completely base dependent and mutually exclusive.

Advances in [4+3]-Annulation/Cycloaddition Reactions Leading to Homo- and Heterocycles with Seven-Membered Rings.

In this review, we summarize advances in [4+3] and a few other annulation/cycloaddition reactions for the construction of seven membered rings, with an emphasis on the literature subsequent to the year 2010. The type of products include the following: azepines, diazepines, benzazepinones, 1,2-diazepinones, oxazepinones, benzothiazepines, benzodiazepinones, benzoxopinones, cyclohepta[b]indoles, benzoxazepines, azepino-indoles, oxepines/oxazepanes, triazepines oxepinoindolones/azepinoindolones, oxadiazepines, azabicyclooctanes. Emphasis is also given to cover diverse types of annulations; possible intermediates are displayed in the illustrated schemes to aid future work.

Lewis Base-Switched [3 + 3] and [4 + 2] Annulation Reactions of δ-Acetoxy Allenoates with Cyclic N-Sulfonyl Imines: Divergent Synthesis of Functionalized α-Pyridyl Acetates and Teraryl Scaffolds.

Under metal-free conditions, δ-acetoxy allenoates react with cyclic N-sulfonyl imines (sulfamidate imines/sulfonyl imines) to afford functionalized 2-pyridinyl acetates (α-pyridyl acetates) or teraryl motifs by a simple Lewis base switch. Thus, while DBU/Na2CO3 combination-directed [3 + 3] annulation involves sulfonyl elimination via O-S or C-S bond cleavage, affording 2-pyridinyl acetates, Ph3P-catalyzed [4 + 2] annulation leads to functionalized teraryls via Mannich coupling and C-N bond cleavage with retention or cleavage of the sulfamoyloxy group depending on the reaction conditions.

Cu(I)-Catalyzed Ligand-Free Tandem One-Pot or Sequential Annulation via Knoevenagel Intermediates: An Entry into Multifunctional Naphthalenes, Phenanthrenes, Quinolines, and Benzo[b]carbazoles.

A simple but efficient one-pot or sequential copper-catalyzed protocol using 2-bromoaldehydes and active methylene group containing substrates that affords multifunctional naphthalenes, phenanthrenes, quinolines, and benzo[b]carbazoles via Knoevenagel condensation, C-arylation, and decarboxylation, followed by aromatization, is developed. The reaction utilizes the potential of Knoevenagel intermediates and does not require any ancillary ligand. The phenanthrene products thus obtained show moderate fluorescence activity. Structural elaboration of the products to obtain dihydrobenzoquinazolines is also highlighted.

Reaction of Indole Carboxylic Acid/Amide with Propargyl Alcohols: [4 + 3]-Annulation, Unexpected 3- to 2- Carboxylate/Amide Migration, and Decarboxylative Cyclization.

1-Methylindole-3-carboxamides react with substituted propargyl alcohols to afford lactams by [4 + 3]-annulation and carboxamide group migration to the indole-2-position. In contrast, indole-2-carboxylic acids/amides form fused seven-membered lactones/lactams (oxepinoindolones/azepinoindolones) upon treatment with substituted propargyl alcohols using catalytic Cu(OTf)2. Decarboxylative cyclization of 1-methylindole-2- or indole-3-carboxylic acids with substituted propargyl alcohols under Lewis (for 1-methylindole-2-carboxylic acid) or Brønsted (for 1-methylindole-3-carboxylic acid) acid catalysis gives the same 3,4-dihydrocyclopentaindoles, demonstrating 3- to 2-carboxylate migration in the latter case.

Transition-Metal-Free, Brønsted Acid-Mediated Cascade Sequence in the Reaction of Propargyl Alcohols with Sulfonamido-indoles/-indolines: Highly Substituted δ- and α-Carbolines.

Brønsted acid-mediated, transition-metal-free reaction of propargyl alcohols with sulfonamido-indoles/-indolines under mild conditions affords highly substituted δ- or α-carbolines in good to excellent yields. This protocol involves cascade reaction sequences of Friedel-Crafts alkylation/ [1,5]-hydrogen shift/electrocyclization/elimination/ [1,2]-aryl migration followed by aromatization. An unexpected regioselective tosyl group migration from indole 2- to 6-position and arene elimination leading to α-carbolines has also been discovered.

Palladium-Catalyzed Decarboxylative ortho-Amidation of Indole-3-carboxylic Acids with Isothiocyanates Using Carboxyl as a Deciduous Directing Group.

Palladium-catalyzed ortho-amidation of indole-3-carboxylic acids with isothiocyanates by using the deciduous directing group nature of carboxyl functionality to afford indole-2-amides is demonstrated. Both C-H functionalization and decarboxylation took place in one pot, and hence, this carboxyl group served as a unique, deciduous (or traceless) directing group. This reaction offers a broad substrate scope as demonstrated for several other heterocyclic carboxylic acids like chromene-3-carboxylic acid, imidazo[1,2- a]pyridine-2-carboxylic acid, benzofuran-2-carboxylic acid, pyrrole-2-carboxylic acid, and thiophene-2-carboxylic acid. In the reaction using 2-naphthoic acid, of the two possible isomers, only one isomer of the amide was exclusively formed. The indole-2-amide product underwent palladium-catalyzed C-H functionalization to afford the diindole-fused 2-pyridones by combining two molecules of the indole moiety, with the elimination of an amide group from one of them, attached at the C3-position for the C-C/C-N bond formation. The structures of key products are confirmed by X-ray crystallography.

Synthesis of thiazolidine-thiones, imino-thiazolidines and oxazolidines via the base promoted cyclisation of epoxy-sulfonamides and heterocumulenes.

Epoxy-sulfonamides react with heterocumulenes (carbon disulfide/isothiocyanates/isocyanates) in the presence of a base to afford ring expansion products in good to high yields with excellent regioselectivity. N-(2-Bromoethyl)-sulfonamides can also be employed as substrates. This reaction proceeds through a 5-exo-tet pathway without forming aziridine intermediates.

Ruthenium-Catalyzed Oxidative Annulation and Hydroarylation of Chromene-3-carboxamides with Alkynes via Double C-H Functionalization.

Ruthenium-catalyzed oxidative annulation of 2H-chromene-3-carboxamides with alkynes has been achieved by using the directing group nature of amide in the presence of Cu(OAc)2·H2O as an oxidant and AgNTf2 as an additive. This reaction offers a broad substrate scope, and both symmetrical and unsymmetrical alkynes can be harnessed. High regioselectivity was achieved in the case of unsymmetrical alkynes. In addition, we have also accomplished double C-H activation by employing an excess of alkyne, where both annulation and hydroarylation took place regio- and stereoselectively in one pot, with the catalyst playing a dual role. While the first C-H functionalization could involve Ru-N covalent bond, the second C-H functionalization most likely involves Ru-O coordinate bond. The structures of key products are confirmed by X-ray crystallography.

Rhodium(III)-Catalyzed ortho-Alkylation of Phenoxy Substrates with Diazo Compounds via C-H Activation: A Case of Decarboxylative Pyrimidine/Pyridine Migratory Cyclization Rather than Removal of Pyrimidine/Pyridine Directing Group.

An efficient Rh(III)-catalyzed ortho-alkylation of phenoxy substrates with diazo compounds has been achieved for the first time using pyrimidine or pyridine as the directing group. Furthermore, bis-alkylation has also been achieved using para-substituted phenoxypyrimidine and 3 mol equiv of the diazo ester. The ortho-alkylated derivatives of phenoxy products possessing the ester functionality undergo decarboxylative pyrimidine/pyridine migratory cyclization (rather than deprotection of pyrimidine/pyridine group) using 20% NaOEt in EtOH affording a novel class of 3-(pyrimidin-2(1H)-ylidene)benzofuran-2(3H)-ones and 6-methyl-3-(pyridin-2(1H)-ylidene)benzofuran-2(3H)-one. The ortho-alkylated phenoxypyridine possessing ester functionality also undergoes decarboxylative pyridine migratory cyclization using MeOTf/NaOMe in toluene providing 6-methyl-3-(1-methylpyridin-2(1H)-ylidene)benzofuran-2(3H)-one.

Transition Metal-Free Cascade Cyclization of Epoxy-Ynamides: To Go for 1,3-Oxazines or 1,4-Oxazines?

An approach to both 1,3- and 1,4-oxazines is developed by the cascade cyclization of epoxy ynamides under transition metal-free conditions. Thus, while 1,3-oxazines are obtained in a regio- and stereoselective manner by using base, cyclization of epoxy ynamides with sodium azide as a nucleophile results in 1,4-oxazines. Deuterium-labeling experiment demonstrates the role of water as a proton source in the formation of 1,4-oxazines. Epoxy tethered alkyne precursors provide 1,4-oxazines that undergo click reaction.

Exploring the gold mine: [Au]-catalysed transformations of enynals, enynones and enynols.

Gold catalysed synthesis of carbo-/hetero-cyclic compounds is currently a topic of intense activity thanks to the unique properties bestowed upon gold by relativistic effects, the potential of which has been realised mainly during the past two decades. This review will dwell upon the reactions involving gold catalysis in which enynal, enynone or enynol is one of the reacting partners. Most often these reactions lead to fused hetero-/homo-cycles under mild conditions with environmentally benign byproducts. Thus an opportunity for the organic community to develop new methodologies, efficient asymmetric variants, and application in total synthesis by [Au]-catalysis has emerged.

Regioselective carboannulation of electron-deficient allenes with dialkyl (2-formylphenyl)malonates leading to multisubstituted naphthalenes.

An efficient base-catalysed regioselective carboannulation of allenoates (or allenylphosphonates) with dialkyl 2-(2-formylphenyl)malonates that leads to multi-substituted naphthalenes in high yields has been developed. This cascade reaction proceeds through Michael addition, cyclisation, dealkoxycarboxylation and tautomerisation. By using an allenylphosphine oxide, a species analogous to one of the intermediate species in the mechanistic pathway has been isolated.