Raffaella Mancuso

A Simple and Mild Synthesis of 1H-Isochromenes and (Z)-1-Alkylidene-1,3-dihydroisobenzofurans by the Iodocyclization of 2-(1-Alkynyl)benzylic Alcohols

A variety of iodo-substituted isochromenes, dihydroisobenzofurans, and pyranopyridines are readily prepared in good to excellent yields under mild conditions by the iodocyclization of readily available 2-(1-alkynyl)benzylic alcohols or 2-(1-alkynyl)-3-(hydroxymethyl)pyridines. Reactions are carried out in MeCN at 25 degrees C with 3 equiv of I(2) as the iodine source and NaHCO(3) (3 equiv) as the base. The regiochemical outcome of the reaction strongly depends on the substitution pattern of the starting material. In particular, the 5-exo-dig cyclization mode, leading to dihydroisobenzofurans, is observed in the case of substrates bearing a tertiary alcoholic group, owing to the gem-dialkyl effect, while the 6-endo-dig cyclization mode, leading to isochromene or pyranopyridines, is the usually preferred pathway in the case of substrates bearing a primary or secondary alcoholic group.

Versatile Synthesis of Quinoline-3-Carboxylic Esters and Indol-2-Acetic Esters by Palladium-Catalyzed Carbonylation of 1-(2-Aminoaryl)-2-Yn-1-Ols

1-(2-Aminoaryl)-2-yn-1-ols, easily obtained by the Grignard reaction between 1-(2-aminoaryl)ketones and alkynylmagnesium bromides, were subjected to carbonylative conditions in the presence of the PdI2-KI catalytic system, in the presence and in the absence of an external oxidant. Under oxidative conditions (80 atm of a 4:1 mixture of CO-air, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), 1-(2-aminoaryl)-2-yn-1-ols bearing a primary amino group were selectively converted into quinoline-3-carboxylic esters in fair to good yields [45-70%, based on starting 1-(2-aminoaryl)ketones], ensuing from 6-endo-dig cyclization followed by dehydration and oxidative methoxycarbonylation. On the other hand, indol-2-acetic esters, deriving from 5-exo-dig cyclization followed by dehydrating methoxycarbonylation, were selectively obtained in moderate to good yields [42-88%, based on starting 1-(2-aminoaryl)ketones] under nonoxidative conditions (90 atm of CO, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), in the case of 1-(2-aminoaryl)-2-yn-1-ols bearing either a primary or secondary amino group and substituted with a bulky group on the triple bond.

Recent Advances in the Synthesis of Indanes and Indenes

Indanes and indenes are among the most important carbocycles. Many indane and indene derivatives have shown important pharmacological activities, and the indane and indene nuclei are structural motifs present in several natural products of biological relevance. In spite of their importance, only a few reviews on their preparation methods have appeared so far in the literature, the most recent ones being published about ten years ago. The present Review is aimed at filling this gap, presenting some of the most important and innovative approaches to indanes and indenes that have been published in the course of the last ten years (coverage: from 2005 to May, 2015).

An Iodocyclization Approach to Substituted 3-Iodothiophenes

A novel approach to 3-iodothiophenes by direct iodocyclization of alkynylthiol derivatives is presented. A variety of 1-mercapto-3-yn-2-ols 5 (readily available from alkynylation of the corresponding alpha-mercapto ketones or alpha-mercapto esters) were smoothly converted into the corresponding 3-iodothiophene derivatives 6 in good yields by reaction with molecular iodine in the presence of NaHCO(3) at room temperature in MeCN as the solvent.

A Novel Synthesis of 2-Functionalized Benzofurans by Palladium-Catalyzed Cycloisomerization of 2-(1-Hydroxyprop-2-ynyl)phenols Followed by Acid-Catalyzed Allylic Isomerization or Allylic Nucleophilic Substitution

A novel two-step synthesis of 2-hydroxymethylbenzofurans 3 and 2-alkoxymethylbenzofurans 4-6, based on palladium-catalyzed cycloisomerization of 2-(1-hydroxyprop-2-ynyl)phenols 1 under basic conditions to give 2-methylene-2,3-dihydrobenzofuran-3-ols 2, followed by acid-catalyzed isomerization or allylic nucleophilic substitution with alcohols as nucleophiles, is reported. Cycloisomerization reactions leading to 2 (80-98% yields) were carried out at 40 degrees C in MeOH as the solvent, in the presence of a base and catalytic amounts of PdX2 + 2KX (X = Cl, I). Isomerization reactions of 2 readily occurred at 25-60 degrees C in DME as the solvent, with H2SO4 as the proton source, to give 2-hydroxymethylbenzofurans 3 in 65-90% yields. In a similar manner, allylic nucleophilic substitution reactions of 2 with ROH as nucleophiles [carried out at 25-40 degrees C in ROH (R = Me) or ROH-DME mixtures (R = Bu, Bn) in the presence of H2SO4] afforded 2-alkoxymethylbenzofurans 4, 5, and 6 (R = Me, Bu, and Bn, respectively), in 65-98% yields.

Synthesis of Benzothiophene Derivatives by Pd-Catalyzed or Radical-Promoted Heterocyclodehydration of 1-(2-Mercaptophenyl)-2-yn-1-ols

Novel and convenient approaches to benzothiophene derivatives 3 and 5 have been developed, based on heterocyclization reactions of 1-(2-mercaptophenyl)-2-yn-1-ols 2 or 4, respectively, readily available from alkynylation of 2-mercaptobenzaldehydes or 1-(2-mercaptophenyl) ketones 1. In particular, 1-(2-mercaptophenyl)-2-yn-1-ols 2, bearing a CH(2)R substituent on the triple bond (R = alkyl, aryl), were conveniently converted in fair to good yields (55-82%) into (E)-2-(1-alkenyl)benzothiophenes 3 when allowed to react in the presence of catalytic amounts (2 mol %) of PdI(2) in conjunction with KI (KI:PdI(2) molar ratio =10) at 80-100 °C in MeCN as the solvent, through a heterocyclodehydration process. On the other hand, 2-alkoxymethylbenzothiophenes 5 were selectively obtained in fair to excellent yields (49-98%) via a radical-promoted substitutive heterocyclodehydration process, by reacting 1-(2-mercaptophenyl)-2-yn-1-ols 4 (bearing an alkyl or aryl substituent on the triple bond) in alcoholic media at 80-100 °C in the presence of a radical initiator, such as AIBN.

A palladium iodide-catalyzed carbonylative approach to functionalized pyrrole derivatives.

A novel and convenient approach to functionalized pyrroles is presented, based on Pd-catalyzed oxidative heterocyclization-alkoxycarbonylation of readily available N-Boc-1-amino-3-yn-2-ols. Reactions were carried out in alcoholic solvents at 80-100 °C and under 20 atm (at 25 °C) of a 4:1 mixture of CO-air, in the presence of the PdI(2)-KI catalytic system (2-5 mol % of PdI(2), KI/PdI(2) molar ratio = 10). In the case of N-Boc-1-amino-3-yn-2-ols 3, bearing alkyl or aryl substituents, the carbonylation reaction led to a mixture of Boc-protected and N-unsubstituted pyrrole-3-carboxylic esters 4 and 5, respectively. This mixture could be conveniently and quantitatively converted into deprotected pyrrole-3-carboxylic esters 5 by a simple basic treatment. In the case of diastereomeric (3RS,4RS)- and (3RS,4SR)-N-Boc-3-amino-2-methyldec-5-yn-4-ol (syn-3f and anti-3f, respectively, whose relative configuration was determined by X-ray crystallographic analysis), no particular difference was observed in the reactivity of the two diastereomers between them and with respect to the diastereomeric mixture (3S,4S) + (3S,4R). Interestingly, N-Boc-2-alkynyl-1-amino-3-yn-2-ols 6, bearing an additional alkynyl substituent α to the hydroxyl group, spontaneously underwent N-deprotection under the reaction conditions and regioselective water addition to the alkynyl group at C-3 of the corresponding pyrrole-3-carboxylic ester derivative, thus directly affording highly functionalized pyrrole derivatives 7 in one step. In a similar manner, a novel functionalized dihydropyrrolizine derivative 9 was directly synthesized starting from (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8.

Solution-Phase Parallel Synthesis of a Diverse Library of 1,2-Dihydroisoquinolines

Synthesis of a 105 membered library of 1,2-dihydroisoquinolines is described. The 1,2-dihydroisoquinoline compounds have been prepared in good yields using a Lewis acid and organocatalyst-cocatalyzed multicomponent reaction of 2-(1-alkynyl)benzaldehydes, amines, and ketones. Various indoles have also been employed as pronucleophiles, furnishing 1-(3-indolyl)-1,2-dihydroisoquinolines. The halogen functionality present in some of the synthesized compounds allows for further diversification by palladium-catalyzed Suzuki−Miyaura and Sonogashira cross-couplings to give more diversified 1,2-dihydroisoquinoline derivatives.

Synthesis of Substituted Thiophenes by Palladium-Catalyzed Heterocyclodehydration of 1-Mercapto-3-yn-2-ols in Conventional and Nonconventional Solvents

A variety of readily available 1-mercapto-3-yn-2-ols 5 were conveniently converted into the corresponding thiophenes 6 in good to high yields in MeOH as the solvent at 50-100 °C in the presence of catalytic amounts (1-2%) of PdI(2) in conjunction with KI (KI:PdI(2) molar ratio = 10). The catalyst could be made recyclable employing an ionic liquid, such as BmimBF(4), as the solvent under suitable conditions.

Copper-catalyzed synthesis of substituted furans and pyrroles by heterocyclodehydration and tandem heterocyclodehydration-hydration of 3-yne-1,2-diols and 1-amino-3-yn-2-ol derivatives.

CuCl2-catalyzed heterocyclodehydration of readily available 3-yne-1,2-diols and 1-amino-3-yn-2-ol derivatives afforded substituted furans and pyrroles, respectively, in good to high yields (53-99%) under mild conditions (MeOH as the solvent, 80-100 °C, 1-24 h). In the case of 2,2-dialkynyl-1,2-diols, bearing an additional alkynyl substituent at C-2, a cascade process, corresponding to copper-catalyzed heterocyclodehydration followed by acid-catalyzed hydration of the triple bond, was realized when the reaction was carried out in the presence of both CuCl2 and TsOH, leading to 3-acylfurans in one step and high yields (75-84%). Under the same conditions, N-Boc-2-alkynyl-1-amino-3-yn-2-ols were converted into the corresponding N-unsubstituted 3-acylpyrroles in low to fair yields (19-59%). However, working in the presence of added water and a large excess of CO2 (40 atm), in addition to CuCl2 and TsOH, caused a significant improvement of the yields of 3-acylpyrroles (68-87%), thus making the method of general synthetic applicability.