O-quinone Methide Research Articles

Formal [4 + 1] cycloaddition of o-quinone methides: facile synthesis of dihydrobenzofurans

An efficient and straightforward method for the rapid synthesis of 2-substituted dihydrobenzofurans has been developed via reaction of sulfur ylides with o-quinone methides (o-QMs).

Enantioselective synthesis of dihydrocoumarin derivatives by chiral scandium(III)-complex catalyzed inverse-electron-demand hetero-Diels-Alder reaction.

An asymmetric inverse-electron-demand hetero-Diels-Alder reaction between o-quinone methides and azlactones to generate potentially pharmacological active dihydrocoumarins has been achieved efficiently by using a chiral N,N'-dioxide-Sc(III) complex as the catalyst. The desired products were obtained in high yields with excellent enantioselectivities and diastereoselectivities (up to 94% yield, 96% ee and >19 : 1 dr) under mild reaction conditions. A concerted reaction pathway was confirmed by Operando IR and control experiments.

Quinine-catalyzed highly enantioselective cycloannulation of o-quinone methides with malononitrile.

2-Amino-3-cyano-4H-chromenes show great potential as novel anticancer agents. Here we report a quinine-catalyzed highly enantioselective formal 4 + 2 cycloaddition of ortho-quinone methides and malononitrile, providing a unique approach to 4-arylvinyl, 4-aryl and 4-vinyl 2-amino-3-cyano-4H-chromenes with excellent yields and enantioselectivities. Moreover, this reaction can be performed in up to 6 mmol scale without any noticeable loss of yield and stereoselectivity.

Synthesis of uvarindole A

Procedure was developed for the synthesis of an alkaloid of indole series uvarindole A. The key step of the synthesis is a successive indole alkylation with salicylic alcohol catalyzed with ZnCl2. The presumed intermediates are o-hydroxybenzyl carbocation and o-quinone methide.

Synthesis of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives via domino aldol-type/hetero Diels–Alder reaction and their cytotoxicity evaluation

New chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives have been synthesized by domino aldol-type reaction/hetero Diels–Alder reaction generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones with resorcinols/naphthols in the presence of 20mol% ethylenediamine diacetate (EDDA), triethylamine (2mL) as co-catalyst in CH3CN under reflux conditions in good yields. The structures were established based on spectroscopic data, and further confirmed by X-ray diffraction analysis. The results showed that compounds 4h and 4j exhibited very potent cytotoxicity against human cervical cancer cell line (HeLa). Compound 4h displayed good inhibitory activity against both breast cancer cell lines, MDA-MB-231 and MCF-7. Further, the compound 4i exhibited good cytotoxicity against only MDA-MB-231, and compound 4j showed promising activity against human lung cancer cell line, A549 with IC50 value of 2.53±0.07μM, which was comparable to the standard doxorubicin (IC50=1.21±0.1μM).

ChemInform Abstract: Novel Synthesis of 3‐Substituted 2,3‐Dihydrobenzofurans via ortho‐Quinone Methide Intermediates Generated in situ.

A new method is presented for the regioselective one-pot synthesis of 3-substituted 2,3-dihydrobenzofurans from 2-bromo-1-{2-[(triisopropylsilyl)oxy]phenyl}ethyl nitrate by fluoride-induced desilylation leading to o-quinone methide generation, Michael addition of different C, N, O, and S nucleophiles, and intramolecular 5-exo-tet elimination of a bromide anion. The method has potential synthetic applications in drug discovery.

ChemInform Abstract: Metalloradical Approach to 2H‐Chromenes.

Cobalt(III)–carbene radicals, generated through metalloradical activation of salicyl N-tosylhydrazones by cobalt(II) complexes of porphyrins, readily undergo radical addition to terminal alkynes to produce salicyl–vinyl radical intermediates. Subsequent hydrogen atom transfer (HAT) from the hydroxy group of the salicyl moiety to the vinyl radical leads to the formation of 2H-chromenes. The Co(II)-catalyzed process can tolerate various substitution patterns and produces the corresponding 2H-chromene products in good isolated yields. EPR spectroscopy and radical-trapping experiments with TEMPO are in agreement with the proposed radical mechanism. DFT calculations reveal the formation of the salicyl–vinyl radical intermediate by a metalloradical-mediated process. Unexpectedly, subsequent HAT from the hydroxy moiety to the vinyl radical leads to formation of an o-quinone methide intermediate, which dissociates spontaneously from the cobalt center and easily undergoes an endocyclic, sigmatropic ring-closing re...

ChemInform Abstract: Potassium Trinitromethanide as a 1,1‐Ambiphilic Synthon Equivalent: Access to 2‐Nitroarenofurans.

The first example of the use of potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent for the construction of a benzofuran moiety mediated by triethylamine has been developed. The method tolerates a variety of functional groups on the starting quaternary ammonium salt and has been successfully extended to polysubstituted benzofurans. Formation of an o-quinone methide intermediate is postulated as a key to the mechanism of this cascade process.

β-Nitroso-o-quinone methides: potent intermediates in organic chemistry and biology. The impact of the NO group on their structure and reactivity profile: a theoretical insight

The structure and reactivity profiles of prototype o-quinone methides 1, 2 and their β-nitroso analogues 6–9 have been investigated by means of DFT and MP2 calculations. These highly reactive unstable species are generated by oxidative dearomatization of their precursor oximes. The destabilization of their structure is more pronounced in the β-nitroso congeners 7–9. There is only a weak π conjugation across the nitrosoalkene arm. The latter gives rise to E and Z conformations and causes some distortion on the ring σ-frame, while the π-frame is weakly perturbed. The Z conformation is the most stable in all structures. Their geometry is also affected by the o-quinone ring and the 1,2-(7 and 8) and 2,3-(9) isomer pattern. The stability of these conformations is rationalized in terms of ortho- or peri- ring formations. The impact of their geometry profile on their reactivity pattern has been studied by means of reactivity descriptors such as Fukui and Parr functions, chemical potential and hardness, HOMO and LUMO energies and their separation (HOMO–LUMO gap) as well as aromaticity indices such as HOMA and out-of-plane deformability. All descriptors consistently demonstrate that the reactivity is dominated by an E/Z-controlled intramolecular ortho- or peri-cyclization mode to fused 1,2-oxazoles or 1,2-oxazines vs indoles, respectively. Intermolecular primary reactions can occur at the quinone alkene bond or that of the nitrosoalkene arm.

Novel Synthesis of 3-Substituted 2,3-Dihydrobenzofurans via ortho-Quinone Methide Intermediates Generated in Situ

A new method is presented for the regioselective one-pot synthesis of 3-substituted 2,3-dihydrobenzofurans from 2-bromo-1-{2-[(triisopropylsilyl)oxy]phenyl}ethyl nitrate by fluoride-induced desilylation leading to o-quinone methide generation, Michael addition of different C, N, O, and S nucleophiles, and intramolecular 5-exo-tet elimination of a bromide anion. The method has potential synthetic applications in drug discovery.

Potassium Trinitromethanide as a 1,1-Ambiphilic Synthon Equivalent: Access to 2-Nitroarenofurans

The first example of the use of potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent for the construction of a benzofuran moiety mediated by triethylamine has been developed. The method tolerates a variety of functional groups on the starting quaternary ammonium salt and has been successfully extended to polysubstituted benzofurans. Formation of an o-quinone methide intermediate is postulated as a key to the mechanism of this cascade process.

Metalloradical approach to 2H-chromenes.

Cobalt(III)-carbene radicals, generated through metalloradical activation of salicyl N-tosylhydrazones by cobalt(II) complexes of porphyrins, readily undergo radical addition to terminal alkynes to produce salicyl-vinyl radical intermediates. Subsequent hydrogen atom transfer (HAT) from the hydroxy group of the salicyl moiety to the vinyl radical leads to the formation of 2H-chromenes. The Co(II)-catalyzed process can tolerate various substitution patterns and produces the corresponding 2H-chromene products in good isolated yields. EPR spectroscopy and radical-trapping experiments with TEMPO are in agreement with the proposed radical mechanism. DFT calculations reveal the formation of the salicyl-vinyl radical intermediate by a metalloradical-mediated process. Unexpectedly, subsequent HAT from the hydroxy moiety to the vinyl radical leads to formation of an o-quinone methide intermediate, which dissociates spontaneously from the cobalt center and easily undergoes an endocyclic, sigmatropic ring-closing reaction to form the final 2H-chromene product.

ChemInform Abstract: Synthesis of Chromeno[2,3‐b]chromenes from 2‐Dimethylaminophenols and Malononitrile.

AbstractA new method for the synthesis of chromenochromenes (III) is developed based on the cycloaddition of o‐quinone methides, generated in situ from phenolic Mannich bases (I), to 2‐aminochromene‐3‐carbonitrile intermediates derived from Mannich bases (I) and malononitrile.

Base-catalyzed Schmittel cycloisomerization of o-phenylenediyne-linked bis(arenol)s to indeno[1,2-c]chromenes

We describe the transition metal-free base-catalyzed Schmittel cycloisomerization reactions of o-phenylene-linked bis(arenol)s to indeno[1,2-c]chromene derivatives through prototropic rearrangement (tautomerization) to a putative vinylidene o-quinone methide intermediate with an enyne-allene system followed by a formal inverse-electron-demand hetero Diels–Alder cycloaddition. The preliminary results on catalytic asymmetric cycloisomerization with chiral bases are also disclosed.

Natural-product-based drug design against Leishmania: Addition of thiols to o-quinone methide for the synthesis of new 2-Hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones

Natural naphthoquinones as lapachol have been used as scaffold for the synthesis of antiparasitic compounds. Visceral Leishmaniasis (VL) is a fatal neglected disease caused by the protozoan Leishmania; widespread in 68 countries, VL victimizes 60,000 people per year. Considering the limited and highly toxic therapy and the increasing number of resistance, the need for novel drugs is imperative. The objective of this work was the development of a reaction involving three components for the preparation of phenylsulfanylmethyl-[1,4]-naphthoquinone, via o-quinone methide, structurally related with lapachol and its evaluation against Leishmania infantum. Thirty six new phenylsulfanylmethyl-[1,4]-naphthoquinones were obtained by a three component reaction of lawsone, formaldehyde and thiols adequately substituted. These reactions explored the in situ generation of o-quinone methides (o-QM) via the Knoevenagel condensation. The 50% Inhibitory Concentration (IC50) of compounds was in vitro determined against Leishmania infantum promastigotes (MTT assay) and intracellular amastigotes (light microscopy). The cytotoxicity was determined in NCTC cells by the MTT assay. Among the thirty six synthetic naphthoquinones, 75% (27 compounds) showed activity against L. infantum promastigotes, with IC50 values in a range between 8 to 188µM. Intracellular amastigotes were also susceptible to compounds; 38% (14 compounds) showed activity with IC50 values in a range between 12 to 57µM. Considering the selectivity index (S.I.), compounds (1) and (2) were the most promising (S.I.> 8).

NHC-Catalyzed [4+3] Annulation of Enals and o-Quinone Methides

NHC-Catalyzed [4+3] Annulation of Enals and o-Quinone Methides

Synthesis of chromeno[2,3-b]chromenes from 2-dimethylaminophenols and malononitrile

5a-Amino-5aH,11H-chromeno[2,3-b]chromene-11a(12H)-carbonitriles were synthesized from malono-nitrile and o-quinone methides, generated in situ by the thermolysis of phenolic Mannich bases in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. It was also shown that this heterocyclic system can be obtained from 2-amino-4H-chromene-3-carbonitriles and the aforementioned o-quinone methides.

A Dual Lewis Base Activation Strategy for Enantioselective Carbene-Catalyzed Annulations

A dual activation strategy integrating N-heterocyclic carbene (NHC) catalysis and a second Lewis base has been developed. NHC-bound homoenolate equivalents derived from α,β-unsaturated aldehydes combine with transient reactive o-quinone methides in an enantioselective formal [4 + 3] fashion to access 2-benzoxopinones. The overall approach provides a general blueprint for the integration of carbene catalysis with additional Lewis base activation modes.

Biomimetic Total Synthesis of ent-Penilactone A and Penilactone B

The total synthesis of ent-penilactone A and penilactone B has been achieved via biomimetic Michael reactions between tetronic acids and o-quinone methides. A five-component cascade reaction between a tetronic acid, formaldehyde, and a resorcinol derivative that generates four carbon-carbon bonds, one carbon-oxygen bond, and two stereocenters in a one-pot synthesis of penilactone A is also reported.

N‐Heterocyclic Carbene Catalyzed [4+3] Annulation of Enals and o‐Quinone Methides: Highly Enantioselective Synthesis of Benzo‐ε‐Lactones

Enantioselectivity through H bonding: An unprecedented [4+3] annulation of enals with o-quinone methides catalyzed by N-heterocyclic carbenes (NHCs) to give benzo-ε-lactones is described. High to excellent enantioselectivity was achieved by using a chiral triazolium NHC having a free OH group, which participates in a hydrogen-bonding interaction with the substrate.