Elimination Of HNO2 Research Articles

The first example of fluoro-Meinwald rearrangement

Novel fluorinated norbornadienes were synthesized in up to 95% yield by the base-induced elimination of HNO2 from 5-fluoro-5-nitro-6-arylbicyclo[2.2.1]hept-2-enes prepared, in turn, by the Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclopentadiene. The subsequent epoxidation initiated the Meinwald type rearrangement affording 6-aryl-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid fluorides as individual (1SR,5RS,6RS)-diastereomers. The transformation is the first example of fluoro-Meinwald rearrangement to form the corresponding acyl fluorides.

Organocatalyst-mediated, pot-economical total synthesis of latanoprost.

The enantioselective total synthesis of latanoprost, an antiglaucoma agent, has been accomplished with excellent diastereo- and enantioselectivities in a pot-economical manner using six reaction vessels. An enantioselective Krische allylation was conducted in the first pot. In the second pot, olefin metathesis, silyl protection, and hydrogenolysis proceeded efficiently. In the third pot, an organocatalyst-mediated Michael reaction proceeded with excellent diastereoselectivity. The fourth pot involved a substrate-controlled Mukaiyama intramolecular aldol reaction and elimination of HNO2 to afford a methylenecyclopentanone, also with excellent diastereoselectivity. The fifth pot involved a Michael reaction of vinyl cuprate. In the sixth pot, three reactions, a cis-selective olefin metathesis, diastereoselective reduction, and deprotection, afforded latanoprost. Nearly optically pure latanoprost was obtained, and the total yield was 24%.

Organocatalyst-mediated five-pot synthesis of (–)-quinine

In this work, the enantioselective total synthesis of (–)-quinine has been accomplished in a pot-economical manner using five reaction vessels. In the first pot, reactions involve the diphenylprolinol silyl ether-mediated Michael reaction, aza-Henry reaction, hemiaminalization, and elimination of HNO2 (five reactions), affording a chiral tetrahydropyridine with excellent enantioselectivity. In the second pot, five reactions proceed with excellent diastereoselectivity to afford a trisubstituted piperidine with the desired stereochemistry. A further five reactions are carried out in the last one-pot sequence.

Mechanistic Aspects on [3+2] Cycloaddition (32CA) Reactions of Azides to Nitroolefins: A Computational and Kinetic Study.

[3+2] cycloadditions of nitroolefins have emerged as a selective and catalyst-free alternative for the synthesis of 1,2,3-triazoles from azides. We describe mechanistic studies into the cycloaddition/rearomatization reaction sequence. DFT calculations revealed a rate-limiting cycloaddition step proceeding via an asynchronous TS with high kinetic selectivity for the 1,5-triazole. Kinetic studies reveal a second-order rate law, and 13 C kinetic isotopic effects at natural abundance were measured with a significant normal effect at the conjugated olefinic centers of 1.0158 and 1.0216 at the α and β-carbons of β-nitrostyrene. Distortion/interaction-activation strain and energy decomposition analyses revealed that the major regioisomeric pathway benefits from an earlier and less-distorted TS, while intermolecular interaction terms dominate the preference for 1,5- over 1,4-cycloadducts. In addition, the major regioisomer also has more favorable electrostatic and dispersion terms. Additionally, while static DFT calculations suggest a concerted but highly asynchronous Ei-type HNO2 elimination mechanism, quasiclassical direct-dynamics calculations reveal the existence of a dynamic intermediate.

Divergent Synthesis of Substituted Amino-1,2,4-triazole Derivatives

AbstractA divergent efficient assembly of disubstituted 1,2,4-triazoles was established by cyclization of readily accessible N′-nitro-2-hydrocarbylidene-hydrazinecarboximidamides with moderate to excellent yields under mild reaction conditions. This divergent synthetic strategy was achieved simply by varying the reaction conditions. Under acidic conditions, amino-1,2,4-triazoles were obtained by an intramolecular redox reaction involving the NO2 group. Control experiments and DFT studies revealed that this transformation proceeds via an intramolecular 1,3-hydride transfer pathway leading to HNO2 elimination. Under neutral conditions with water as the solvent, nitroimino-1,2,4-triazoles were obtained by oxidative intramolecular annulation under air.

One‐Pot Synthesis of 3‐(2‐Fluoroalkenyl)indoles

An unprecedented one‐pot synthesis of 3‐(fluoroalkenyl)indoles was developed. This process involves a catalyst‐free Michael addition of β‐fluoro‐β‐nitrostyrenes to indoles in neat followed by elimination of HNO2 using DBU as a base. The effectiveness of this approach was demonstrated through the preparation of variety of target products in up to 75 % isolated yield.

Catalytic Kinetic Resolution by Enantioselective Aromatization: Conversion of Racemic Intermediates of the Barton-Zard Reaction into Enantioenriched 3-Arylpyrroles.

Racemic 3,4-dihydro-2H-pyrroles, hypothetical intermediates of the Barton-Zard reaction, were synthesized in a highly diastereoselective manner and fully characterized for the first time. Kinetic resolution of the dihydropyrroles with a quinine-derived thiourea afforded the (+)-3-arylpyrrole products and recovered (+)-3,4-dihydro-2H-pyrroles with high efficiency (s-factor up to 153). The resolved (+)-3,4-dihydro-2H-pyrroles underwent subsequent aromatization with a quinidine-derived thiourea catalyst to afford (-)-3-arylpyrroles with excellent central-to-axial chirality transfer. In contrast to the well-accepted Barton-Zard mechanism, the aromatization of the 3,4-dihydro-2H-pyrroles in the presence of a bifunctional catalyst is believed to proceed by an unprecedented sequence involving syn elimination of HNO2 and aromatization.

Catalytic Kinetic Resolution by Enantioselective Aromatization: Conversion of Racemic Intermediates of the Barton–Zard Reaction into Enantioenriched 3‐Arylpyrroles

AbstractRacemic 3,4‐dihydro‐2H‐pyrroles, hypothetical intermediates of the Barton–Zard reaction, were synthesized in a highly diastereoselective manner and fully characterized for the first time. Kinetic resolution of the dihydropyrroles with a quinine‐derived thiourea afforded the (+)‐3‐arylpyrrole products and recovered (+)‐3,4‐dihydro‐2H‐pyrroles with high efficiency (s‐factor up to 153). The resolved (+)‐3,4‐dihydro‐2H‐pyrroles underwent subsequent aromatization with a quinidine‐derived thiourea catalyst to afford (−)‐3‐arylpyrroles with excellent central‐to‐axial chirality transfer. In contrast to the well‐accepted Barton–Zard mechanism, the aromatization of the 3,4‐dihydro‐2H‐pyrroles in the presence of a bifunctional catalyst is believed to proceed by an unprecedented sequence involving syn elimination of HNO2 and aromatization.

Facile synthesis of polysubstituted furans and dihydrofurans via cyclization of bromonitromethane with oxodienes

A series of polysubstituted furans and dihydrofurans have been prepared from readily available oxodienes and bromonitromethane in modest to excellent yields. This facile synthetic method is developed on the basis of proprietary properties of nitro group such as strong electron-withdrawing ability and cleavability. The conversion of nitro-substituted dihydrofurans to furans is presumably realized by elimination of HNO2 under the aid of DABCO.

ChemInform Abstract: Tertiary‐Amine‐Catalyzed Asymmetric [3 + 2] Annulations of Morita—Baylis—Hillman Carbonates of Isatins with Nitroolefins to Construct Spirooxindoles.

An enantioselective [3+2] annulation of nitroolefins with racemic Morita–Baylis–Hillman carbonates of isatins catalyzed by α-isocupreine has been developed. Chiral spirocyclic 2-oxindoles bearing an unusual cyclopentadiene motif were produced in excellent enantioselectivity (up to 98% ee) after the tandem elimination of HNO2 in the presence of DIPEA.

ChemInform Abstract: Tandem Organocatalyzed Knoevenagel Condensation/1,3‐Dipolar Cycloaddition Towards Highly Functionalized Fused 1,2,3‐Triazoles.

Facile synthesis of fused 1,2,3-triazoles by a proline-catalyzed reaction of an azido aldehyde and a nitroalkane is elaborated. The present tandem protocol proceeds via an organocatalytic Knoevenagel condensation of the azido aldehyde and nitroalkane followed by intramolecular azide–nitroalkene cycloaddition. The functionalized bicyclic triazole is obtained by elimination of HNO2 from the cycloadduct. Application of this strategy enabled us to synthesize a range of functionalised 5–7 membered ring fused triazoles. The reaction calls for mild conditions, affords high yields, and results in good regiospecificity while displaying excellent substrate scope.

ChemInform Abstract: Copper‐Catalyzed [3 + 2] Cycloaddition/Oxidation Reactions Between Nitro‐Olefins and Organic Azides: Highly Regioselective Synthesis of NO2‐Substituted 1,2,3‐Triazoles.

A new copper-catalyzed [3 + 2] cycloaddition/oxidation reaction of nitro-olefins with organic azides has been developed to afford 1,4(-NO2),5-trisubstituted 1,2,3-triazoles. This reaction sequence has a broad substrate scope and affords NO2-substituted 1,2,3-triazoles with high regioselectivities and in good to excellent yields. The involved oxidative process overcomes the elimination of HNO2 for general cycloaddition of nitro-olefins with organic azides, which shows a high atom economy and potential applications.

Tandem Organocatalyzed Knoevenagel Condensation/1,3‐Dipolar Cycloaddition towards Highly Functionalized Fused 1,2,3‐Triazoles

AbstractFacile synthesis of fused 1,2,3‐triazoles by a proline‐catalyzed reaction of an azido aldehyde and a nitroalkane is elaborated. The present tandem protocol proceeds via an organocatalytic Knoevenagel condensation of the azido aldehyde and nitroalkane followed by intramolecular azide–nitroalkene cycloaddition. The functionalized bicyclic triazole is obtained by elimination of HNO2 from the cycloadduct. Application of this strategy enabled us to synthesize a range of functionalised 5–7 membered ring fused triazoles. The reaction calls for mild conditions, affords high yields, and results in good regiospecificity while displaying excellent substrate scope.

Computational Study of the Rate Coefficients for the Reactions of NO2 with CH3NHNH, CH3NNH2, and CH2NHNH2

The reactions of NO2 with cis-/trans-CH3NHNH, CH3NNH2 and CH2NHNH2 have been studied theoretically by quantum chemical calculations and steady-state unimolecular master equation analysis based on RRKM theory. The barrier heights for the roaming transition states between nitro (RNO2) and nitrite (RONO) isomerization reactions and those for the concerted HONO and HNO2 elimination reactions from RNO2 and RONO, affect the pressure dependences of the product-specific rate coefficients. At ambient temperature and pressure, the dominant product of the reactions of NO2 with cis-/trans-CH3NHNH and CH2NHNH2 would be expected to be HONO with trans-CH3NNH and CH2NNH2, respectively, whereas it is CH3N(NH2)NO2 for CH3NNH2 + NO2. The product-specific rate coefficients for the titled and related reactions on the same potential energy surfaces were proposed for kinetics modeling.

Copper-catalyzed [3 + 2] cycloaddition/oxidation reactions between nitro-olefins and organic azides: highly regioselective synthesis of NO2-substituted 1,2,3-triazoles.

A new copper-catalyzed [3 + 2] cycloaddition/oxidation reaction of nitro-olefins with organic azides has been developed to afford 1,4(-NO2),5-trisubstituted 1,2,3-triazoles. This reaction sequence has a broad substrate scope and affords NO2-substituted 1,2,3-triazoles with high regioselectivities and in good to excellent yields. The involved oxidative process overcomes the elimination of HNO2 for general cycloaddition of nitro-olefins with organic azides, which shows a high atom economy and potential applications.

The multieffects of DMF and DBU on the [5 + 1] benzannulation of nitroethane and α-alkenoyl ketene-(S,S)-acetals: hydrogen bonding and electrostatic interactions.

A density functional theory (DFT) study was performed to elucidate the mechanism for the [5 + 1] benzannulation of nitroethane and α-alkenoyl ketene-(S,S)-acetals. The calculation results are consistent with experimental findings, showing that the reaction proceeds via deprotonation of nitroethane, nucleophilic addition, intramolecular cyclization, elimination of HNO2 , and the keto-enol tautomerization sequence. It was disclosed that N,N-dimethylformamide (DMF) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) act as not only solvent and nonnucleophilic base, respectively, but also catalysts in the reaction by stabilizing the transition states (TSs) and intermediates via intermolecular hydrogen bonds and electrostatic interactions. Besides, the effective orbital interaction of the reaction site in TS also contributes to the intramolecular cyclization step. The new mechanistic insights obtained by DFT calculations highlight that the hydrogen bonds and electrostatic interactions are key factors for the [5 + 1] benzannulation of nitroethane and α-alkenoyl ketene-(S,S)-acetals.

A versatile and efficient approach for the synthesis of chiral 1,3-nitroamines and 1,3-diamines via conjugate addition to new (S,E)-γ-aminated nitroalkenes derived from L-α-amino acids.

New chiral (S,E)-γ-N,N-dibenzylated nitroalkenes 2a–c were synthesized from natural L-(α)-amino acids in five steps with overall yields of 68–88%. The conjugate addition of hydride, methoxide, nitronate and azide nucleophiles to 2a–c led to the corresponding chiral 1,3-nitroamines in 74–90% yield. The conjugate addition of cyanide anion to 2a,b was followed by HNO2 elimination affording chiral aminated acrylonitriles (73–98%). On the other hand, the azide anion reacted with 2a, in acetonitrile, via a [3 + 2]-cycloaddition in which HNO2 was lost, providing the corresponding 1,2,3-triazole derivative. Direct reduction of 1,3-nitroamine derivatives 9a,b produced the corresponding 1,3-diamines in good yields.

ChemInform Abstract: Synthesis of Fused Isoindoles via 1,3‐Dipolar Cycloaddition of 1,3‐Oxazolium‐5‐olates (Muenchnones) with Nitro Benzazoles.

Abstract1,3‐Dipolar cycloaddition of in situ formed muenchnones (III) to nitro benzazoles leads to azolo‐fused isoindole derivatives of type (IV), (V), or (VIII) after elimination of HNO2 and CO2.

Regioselective Two-Component Synthesis of Polysubstituted Pyrazoles

A simple thermal or acid-catalyzed synthesis of polysubstituted pyrazoles by reaction of various hydrazones with nitroolefins is reported. An extensive screening of conditions showed that alcohols are the best solvents and acids as additives promote the reaction. In DMF and DMSO, for example, no reaction takes place. Choosing the right alcohol and acid proved to be crucial, since otherwise complex mixtures resulted. Lewis acids are not efficient in promoting the reaction. Two sets of reaction conditions were developed (A and B), which complement each other in terms of functional group compatibility. The substrate scope was extensively studied and the yields range from poor (electron-deficient hydrazones) to good (electron-rich hydrazones). A mechanistic pathway was considered involving tautomerization of the hydrazone to an azomethine imine, which undergoes a 1,3-dipolar cycloaddition with the nitroolefin. Subsequent oxidation by air followed by elimination of HNO2 furnishes the product. To differentiate between a stepwise or concerted cycloaddition mechanism, the stereocontrol during this step was studied, and the lack of it suggests a stepwise mechanism.

Reactivity of acetonyl anion with nitroaromatics: an atmospheric pressure chemical ionization study

AbstractNucleophilic attack by the acetonyl anion (CH3COCH) on highly electron‐deficient nitroaromatics such as trinitrotoluene (TNT) results in the carbon‐bonded anionic σ‐complexes (Meisenheimer complexes). The complexes are generated at atmospheric pressure with relatively low internal energy and do not dissociate under atmospheric pressure chemical ionization conditions, but can be dissociated upon collisional activation to produce characteristic nitrobenzyl‐substituted acetonyl anions via elimination of HNO2. Further fragmentation produces deprotonated nitrotoluene anions through the loss of CH2CO, while loss of CH2COCH3 and CH3COCH3 yields nitroaromatic molecular anions and their H‐loss counterparts. Hydrogen/deuterium (H/D) scrambling is observed in the fragmentation products of the [TNT · CD3COCD2]− complex to extents which vary for different fragmentation pathways. Selective Meisenheimer complex formation, together with its distinctive fragmentation pattern, supplies a highly discriminatory method for detection of TNT and related compounds. Copyright © 2005 John Wiley & Sons, Ltd.