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3‐Nitro‐2H‐chromene and derivatives are the significant structural building blocks of many natural products and pharmacologically active compounds. So, great deals of effort have been made for the development and improvement of 3‐nitro‐2H‐chromene functionalized scaffolds by utilizing different methodologies. Among the various strategies, Michael/hetero‐Michael addition reactions to 3‐nitro‐2H‐chromene have been established as the most vibrant and unique research area for the construction of diverse C−C and C−X (X=heteroatoms) bonds providing versatile 2H‐chromene frameworks. In recent years, a broad range of efficient Michael donors has been explored extensively which motivates the scientific community to work on these useful 2H‐chromene frameworks in presence of different bases, transition metals, organocatalysts, and base/catalyst‐free conditions. Considering the importance of this research field, the present review highlights the major advancements of Michael/hetero‐Michael addition reaction to 3‐nitro‐2H‐chromenes utilizing various Michael donors from the year 2010 to 2022 in a comprehensive manner. [ABSTRACT FROM AUTHOR]

A regioselective method for the synthesis of ethyl 3,4-dihydrochromeno[3,4-c]pyrazole-1-carboxylates from 2-substituted 3-nitro-2Hchromenes and ethyl diazoacetate in 68–87% yields was developed. This approach involves an AgOAc-catalyzed 1,3-dipolar cycloaddition of ethyl diazoacetate to nitrochromenes followed by elimination of HNO2 by the action of DBU. [ABSTRACT FROM AUTHOR]

A diastereoselective method was developed for the synthesis of 4-trifluoromethyl- and 4-phenyl-substituted 3a-nitro-2,3,3a,9b-tetrahydro-4H-thieno[3,2-c]chromen-3-ols having cis configuration of substituents at the C-3, C-3a, C-4 atoms and the 9b-CH hydrogen atom from the available starting materials – 3-nitro-2H-chromenes and 2,5-dihydroxy-1,4-dithiane in 80–92% yields. This approach relied on a tandem of Michael and Henry reactions between 3-nitro-2H-chromenes and in situ generated mercaptoacetaldehyde in Et2O at room temperature over 4–6 h, using Et3N as catalyst. [ABSTRACT FROM AUTHOR]

A regioselective one-pot method for the synthesis of 1-ethyl 2,4-dihydrochromene[3,4-c]pyrroles in 63–94% yields from available 2-phenyl-, 2-trifluoro(trichloro)methyl- or 2-phenyl-2-(trifluoromethyl)-3-nitro-2H-chromenes and ethyl isocyanoacetate through the Barton–Zard reaction in ethanol at reflux for 0.5 h, using K2CO3 as a base, has been developed.

The AgOAc-catalysed reaction of 3-nitro-2-phenyl-2H-chromenes with stabilized azomethine ylides generated from the imines based on methyl glycinate and arylaldehydes leads to a mixture of endo and endo’ isomers of the corresponding chromeno[3,4-c]pyrrolidines in a ratio of 2.0–2.3:1 in 85–93% total yields as a result of a Michael addition/Mannich reaction sequence. In a similar reaction involving 2-trifluoromethyl-3-nitro-2H-chromenes, only endo chromeno[3,4-c]pyrrolidines are formed in 85–94% yields. 3-Nitro-2-(trichloromethyl)-2H-chromenes under the same conditions react with these azomethine ylides to give the corresponding Michael adducts as individual anti-isomers with the cis,trans-configuration of the chromane ring in 40–67% yields. Some 4-CF3-substituted chromano[3,4-c]pyrrolidines exhibited high cytotoxic activity against HeLa human cervical carcinoma cells.

(3+2) Cycloaddition of azomethine ylide generated in situ from 11H-indeno[1,2-b]quinoxalin-11-one and proline to 3-nitro-2-trifluoro- (trichloro)methyl- and 3-nitro-2-phenyl-2H-chromenes upon heating in EtOH proceeded regio- and stereoselectively, resulting in the formation of spiro[chromeno[3,4-a]pyrrolizine-11,11'-indeno[1,2-b]quinoxalines]. An analogous reaction using ylide derived from sarcosine under the conditions of kinetic control led to preferential formation of diastereomeric spiro[chromeno[3,4-c]pyrrolidine-3,11'-indeno[1,2-b]quinoxalines] with different configuration of the spiro atom, which were transformed upon heating in DMSO into the thermodynamically more stable spiro[chromeno[3,4-c]pyrrolidine-1,11'-indeno[1,2-b]quinoxalines]. [ABSTRACT FROM AUTHOR]

• New 2-glyco-6-halo-3-nitro-2 H -chromenes have been synthesized using DBU as catalyst. • Antiproliferative activity and cytotoxicity of new compounds have been studied. • Carbohydrate moiety at C-2 modulates the antiproliferative activity of the chromenes. 3-nitro-2 H -chromenes and derivatives are compounds with diverse biological activity, among them, new 2-glyco-3-nitro-2 H -chromenes have been prepared by one-pot oxa -Michael-Henry-dehydration reactions between carbohydrate-derived nitroalkenes and several salicylaldehydes, using a minimal amount of solvent and DBU as catalyst. The antiproliferative activity of these new compounds has been evaluated against a panel of six human solid tumor cell lines, and compared to pharmacological reference compounds, finding that their activities are in the low micromolar range and that some of them are more effective than the standards. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Various (R)-2-alkyl-3-nitro-2 H -chromenes are synthesized via a Henry/Michael/dehydration domino reaction. • High to excellent enantioselectivities are achieved. • Most of R enantiomers exhibit moderate to excellent inhibition activities. • The absolute configuration and substitution pattern have significant influence on the antimicrobial activity. • (R)-ethyl-2-(6,8-dibromo-3-nitro-2 H -chromene) acetate is the best potential antibacterial agent. Abstract A one-pot organocatalytic domino Henry/Michael/dehydration sequence of various salicylaldehyde derivatives with nitromethane as a dual-nucleophile is disclosed. This straightforward strategy assembles the optically active (R)-2-alkyl 3-nitro-2 H -chromenes with good to excellent enantioselectivities (up to 93% ee) and a broad substrate scope. Preliminary in vitro antibacterial evaluation revealed most of the chiral 3-nitro-2 H -chromene derivatives exhibit antibacterial activities against four Gram-positive bacteria. Compound 3p with two bromine substituents on the core scaffold was shown to be the best antibacterial agent in the series against S. aureus , B. subtilis and Bacillus cereus with minimal bactericidal concentration (MBC) values of 4 μg/mL, and against Staphylococcus epidermidis with a MBC value of 8 μg/mL. [ABSTRACT FROM AUTHOR]

A one-pot synthesis of substituted (dihydro)thieno[2,3- c]chromene derivatives was developed through a Lewis base catalyzed domino Michael addition/intramolecular cyclization reaction between 3-nitro-2H-chromenes and thioamides. The desired (dihydro)thieno[ 2,3-c]chromene derivatives were prepared with a large substrate scope (22 examples) and excellent diastereoselectivity in moderate to excellent yields. [ABSTRACT FROM AUTHOR]

Cascade oxa-Michael-Henry reactions of salicylaldehyde derivatives with â-nitrostyrenes catalyzed by potassium carbonate via solvent- free ball milling are demonstrated. The corresponding 3-nitro-2Hchromene products were obtained in moderate to excellent yields. This method offers significant advantages, particularly in terms of high yields, short reaction times and mild conditions. [ABSTRACT FROM AUTHOR]

The AgOAc-catalysed reaction of 3-nitro-2-phenyl-2 H -chromenes with stabilized azomethine ylides generated from the imines based on methyl glycinate and arylaldehydes leads to a mixture of endo and endo ' isomers of the corresponding chromeno[3,4- c ]pyrrolidines in a ratio of 2.0-2.3:1 in 85-93% total yields as a result of a Michael addition/Mannich reaction sequence. In a similar reaction involving 2-trifluoromethyl-3-nitro-2 H -chromenes, only endo chromeno[3,4- c ]pyrrolidines are formed in 85-94% yields. 3-Nitro-2-(trichloromethyl)-2 H -chromenes under the same conditions react with these azomethine ylides to give the corresponding Michael adducts as individual anti -isomers with the cis , trans -configuration of the chromane ring in 40-67% yields. Some 4-CF 3 -substituted chromano[3,4- c ]pyrrolidines exhibited high cytotoxic activity against HeLa human cervical carcinoma cells.

A regioselective one-pot method for the synthesis of 1-ethyl 2,4-dihydrochromene[3,4- c ]pyrroles in 63-94% yields from available 2-phenyl-, 2-trifluoro(trichloro)methyl- or 2-phenyl-2-(trifluoromethyl)-3-nitro-2 H -chromenes and ethyl isocyanoacetate through the Barton-Zard reaction in ethanol at reflux for 0.5 h, using K 2 CO 3 as a base, has been developed.

Abstract: Reactions of 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes, including 2-unsubstituted derivatives, with N-alkyl-α-amino acids (sarcosine, proline) and paraformaldehyde proceed diastereoselectively to give 1-benzopyrano[3,4-c]pyrrolidines in good yields as a result of a 1,3-dipolar cycloaddition of the intermediate nonstabilized azomethine ylide at the Δ3-bond of the chromene system. [Copyright &y& Elsevier]

The conjugate addition of aldehydes and ketones to 3-nitro-2H-chromenes under basic conditions has been explored. A series of inorganic and organic bases were examined. Proline combined with NaOAc was found to act as an efficient catalyst for the reaction. A number of substituted 3-nitro-2H-chromenes, aldehydes, and ketones are applicable for this transformation. trans-3-Nitro-4-substituted chromanes were sometimes obtained in good yields and with excellent diastereoselectivities. trans-2-Methyl-2-(3-nitrochroman-4-yl)propanal could be transformed into cis-2,3-dihydro-1,1-dimethyl-1H-chroman[3,4-b]pyrrole in one step. [ABSTRACT FROM AUTHOR]

Abstract: Reactions of 3-nitro-2H-chromenes with aminoenones derived from acetylacetone and cyclic amines proceed diastereoselectively to give functionalized 2,3,4-trisubstituted chromanes as a result of nucleophilic addition of the vinylogous β-methyl group at the C-4 atom of the chromene system. From these compounds, under acidic conditions, 5-(trifluoromethyl)-5H-chromeno[3,4-b]pyridines and 4-acetoacetonyl-3-nitro-2-(trichloromethyl/phenyl)chromanes, depending on the substituent at the 2-position, were obtained in moderate to good yields. [Copyright &y& Elsevier]

As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10µM, the ortho-aminoanilide series and the d-Phe derived α-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and 12b, 14 and 15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho-aminoanilides 9b, 9c, 10b, 10c, 11b, and the α-aminoamides 16a and 16b were potent HADC1 inhibitors with the IC 50 values in the nanomolar ranges. The ortho-aminoanilides 10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2., (Copyright © 2017 Elsevier Ltd. All rights reserved.)