Mesitylnitrile Oxide Research Articles

Design, Synthesis and Antiproliferative Evaluation of Bis-Indole Derivatives with a Phenyl Linker: Focus on Autophagy

This work deals with the study of the synthesis of new bis-indole analogues with a phenyl linker derived from indole phytoalexins. Synthesis of target bis-indole thiourea linked by a phenyl linker was achieved by the reaction of [1-(tert-butoxycarbonyl)indol-3-yl]methyl isothiocyanate with p-phenylenediamine. By replacing the sulfur of the thiocarbonyl group in bis-indole thiourea with oxygen using mesityl nitrile oxide, a bis-indole homodimer with a urea group was obtained. A cyclization protocol utilizing bis-indole thiourea and methyl bromoacetate was applied to synthesize a bis-indole homodimer with a thiazolidin-4-one moiety. Bis-indole homodimers derived from 1-methoxyspirobrassinol methyl ether were prepared by bromospirocyclization methodology. Among the synthesized analogues, compound 49 was selected for further study. To evaluate the mode of the mechanism of action, we used flow cytometry, Western blot, and spectroscopic analyses. Compound 49 significantly inhibited the proliferation of lung cancer cell line A549 with minimal effects on the non-cancer cells. We also demonstrated that compound 49 induced autophagy through the upregulation of Beclin-1, LC3A/B, Atg7 and AMPK and ULK1. Furthermore, chloroquine (CQ; an autophagy inhibitor) in combination with compound 49 decreased cell proliferation and induced G1 cell cycle arrest and apoptosis. Compound 49 also caused GSH depletion and significantly potentiated the antiproliferative effect of cis-platin.

Spontaneous cyclization of (acridin-9-ylmethyl)thioureas to spiro [dihydroacridine-9′(10′H),5-imidazolidine]-2-thiones, a novel type of acridine spirocycles

Novel acridine spirocompounds, spiro[dihydroacridine-9′(10′H),5-imidazolidine]-2-thiones have been prepared by the spontaneous cyclization of 1-substituted 3-(acridin-9-ylmethyl)thioureas, which were obtained from 1-(acridin-9-yl)methanamine, N-(acridin-9-ylmethyl)propan-1-amine, and N-(acridin-9-ylmethyl)benzylamine and alkyl/aryl isothiocyanates, as continuation of our previous studies on new acridine spirocycles. Imidazolidine-2-thiones thus obtained were subsequently transformed with mesitylnitrile oxide to imidazolidine-2-one analogues, some of which partly reopened to the corresponding (acridin-9-ylmethyl)ureas. An unusual spirocyclization via a CH carbanion instead of the N-1 nitrogen has been found for 3-(acridin-9-ylmethyl)-1-(acridin-9-yl)thioureas possessing two acridine rings. Structural modifications in positions 1, 3, and 4 of the spiro ring together with 1H, 13C, and 15N NMR spectroscopy and X-ray crystallography have been employed to rationalize a general propensity of various 9-substituted acridines to undergo easy spirocyclization.

Thermodynamic and Kinetic Study of Cleavage of the N–O Bond of N-Oxides by a Vanadium(III) Complex: Enhanced Oxygen Atom Transfer Reaction Rates for Adducts of Nitrous Oxide and Mesityl Nitrile Oxide

Thermodynamic, kinetic, and computational studies are reported for oxygen atom transfer (OAT) to the complex V(N[t-Bu]Ar)3 (Ar = 3,5-C6H3Me2, 1) from compounds containing N-O bonds with a range of BDEs spanning nearly 100 kcal mol(-1): PhNO (108) > SIPr/MesCNO (75) > PyO (63) > IPr/N2O (62) > MesCNO (53) > N2O (40) > dbabhNO (10) (Mes = mesityl; SIPr = 1,3-bis(diisopropyl)phenylimidazolin-2-ylidene; Py = pyridine; IPr = 1,3-bis(diisopropyl)phenylimidazol-2-ylidene; dbabh = 2,3:5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene). Stopped flow kinetic studies of the OAT reactions show a range of kinetic behavior influenced by both the mode and strength of coordination of the O donor and its ease of atom transfer. Four categories of kinetic behavior are observed depending upon the magnitudes of the rate constants involved: (I) dinuclear OAT following an overall third order rate law (N2O); (II) formation of stable oxidant-bound complexes followed by OAT in a separate step (PyO and PhNO); (III) transient formation and decay of metastable oxidant-bound intermediates on the same time scale as OAT (SIPr/MesCNO and IPr/N2O); (IV) steady-state kinetics in which no detectable intermediates are observed (dbabhNO and MesCNO). Thermochemical studies of OAT to 1 show that the V-O bond in O≡V(N[t-Bu]Ar)3 is strong (BDE = 154 ± 3 kcal mol(-1)) compared with all the N-O bonds cleaved. In contrast, measurement of the N-O bond in dbabhNO show it to be especially weak (BDE = 10 ± 3 kcal mol(-1)) and that dissociation of dbabhNO to anthracene, N2, and a (3)O atom is thermodynamically favorable at room temperature. Comparison of the OAT of adducts of N2O and MesCNO to the bulky complex 1 show a faster rate than in the case of free N2O or MesCNO despite increased steric hindrance of the adducts.

Synthesis, structure, and thermochemistry of adduct formation between N-heterocyclic carbenes and isocyanates or mesitylnitrile oxide

Reaction of N-heterocyclic carbenes (NHCs) with isocyanates yields stable zwitterionic imidates/amidates in toluene solution. These compounds were fully characterized and the crystal structures of several species were determined by X-ray crystallography. The thermochemistry of binding of these and related species was studied by solution calorimetry. Comparison is made of the enthalpies of binding of NHC to isocyanates (RNCO) and isomeric nitrile oxides (RCNO) as well as CO2. DFT calculations were performed to additionally assess the nature of bonding in these compounds.

Thermodynamic, Kinetic, and Mechanistic Study of Oxygen Atom Transfer from Mesityl Nitrile Oxide to Phosphines and to a Terminal Metal Phosphido Complex

The enthalpies of oxygen atom transfer (OAT) from mesityl nitrile oxide (MesCNO) to Me(3)P, Cy(3)P, Ph(3)P, and the complex (Ar[(t)Bu]N)(3)MoP (Ar = 3,5-C(6)H(3)Me(2)) have been measured by solution calorimetry yielding the following P-O bond dissociation enthalpy estimates in toluene solution (±3 kcal mol(-1)): Me(3)PO [138.5], Cy(3)PO [137.6], Ph(3)PO [132.2], (Ar[(t)Bu]N)(3)MoPO [108.9]. The data for (Ar[(t)Bu]N)(3)MoPO yield an estimate of 60.2 kcal mol(-1) for dissociation of PO from (Ar[(t)Bu]N)(3)MoPO. The mechanism of OAT from MesCNO to R(3)P and (Ar[(t)Bu]N)(3)MoP has been investigated by UV-vis and FTIR kinetic studies as well as computationally. Reactivity of R(3)P and (Ar[(t)Bu]N)(3)MoP with MesCNO is proposed to occur by nucleophilic attack by the lone pair of electrons on the phosphine or phosphide to the electrophilic C atom of MesCNO forming an adduct rather than direct attack at the terminal O. This mechanism is supported by computational studies. In addition, reaction of the N-heterocyclic carbene SIPr (SIPr = 1,3-bis(diisopropyl)phenylimidazolin-2-ylidene) with MesCNO results in formation of a stable adduct in which the lone pair of the carbene attacks the C atom of MesCNO. The crystal structure of the blue SIPr·MesCNO adduct is reported, and resembles one of the computed structures for attack of the lone pair of electrons of Me(3)P on the C atom of MesCNO. Furthermore, this adduct in which the electrophilic C atom of MesCNO is blocked by coordination to the NHC does not undergo OAT with R(3)P. However, it does undergo rapid OAT with coordinatively unsaturated metal complexes such as (Ar[(t)Bu]N)(3)V since these proceed by attack of the unblocked terminal O site of the SIPr·MesCNO adduct rather than at the blocked C site. OAT from MesCNO to pyridine, tetrahydrothiophene, and (Ar[(t)Bu]N)(3)MoN was found not to proceed in spite of thermochemical favorability.

ChemInform Abstract: Synthesis of Modified Homo‐N‐Nucleosides from the Reactions of Mesityl Nitrile Oxide with 9‐Allylpurines and Their Influence on Lipid Peroxidation and Thrombin Inhibition.

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Synthesis of modified homo- N-nucleosides from the reactions of mesityl nitrile oxide with 9-allylpurines and their influence on lipid peroxidation and thrombin inhibition

9-(3-Mesityl-4,5-dihydroisoxazol-5-yl) homo- N-nucleosides were prepared from the 1,3-dipolar cycloaddition reactions of mesityl nitrile oxide with 9-allyl derivatives of 6-chloropurine, 6-piperidinylpurine, 6-morpholinylpurine, 6-pyrrolidinylpurine, and 6- N, N-dibenzoyladenine. The new compounds were tested in vitro for their ability: (i) to interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (ii) to inhibit lipid peroxidation, (iii) to scavenge the superoxide anion, (iv) to inhibit the activity of soybean lipoxygenase, and (v) to inhibit in vitro thrombin. Most of them found to be potent thrombin inhibitors and to inhibit in vitro lipid peroxidation. The majority of the compounds showed significant lipoxygenase inhibitory activity.

Experimental and theoretical push‐pull Chemo‐ and regioselectivity in 1,3‐Dipolar cycloaddition reactions: the case of benzotriazepin‐5‐one with mesitylnitrile oxide

AbstractA novel heterocyclic compound 3‐mesityl‐5‐methyl‐4,5,11,11a‐tetrahydro‐6H‐[1,2,4]oxadiazolo [5,4‐b][1,3,4]benzotriazépin‐6‐one 4 has been synthesised by a 1,3 dipolar cycloaddition (13DC) reaction of 1,3,4‐benzotriazepin‐5‐one 1 with mesitylnitrile oxide 3. The reaction, beside its synthetic interest, has shown to be completely chemo‐ and regioselective. The structure of the compound was determined by X‐ray crystallography and analysed by spectral methods (NMR and mass spectrometry). The molecular mechanism for the reaction has been studied using quantum mechanical calculations at the B3LYP/6‐31G* theory level. Two mechanisms are possible for the formation of the cycloadduct 4. The first one involves a 13DC reaction between 1, as dipolarophile and 3, as dipole. Analysis of the results indicates that it takes place along asynchronous concerted bond‐formation process with a very low polar character. The regioselectivity obtained from the calculations are in complete agreement with the unique formation of the cycloadduct 4. The second mechanism is initiated by the nucleophilic attack of the N3 nitrogen of the tautomer form of 2, to the C5 carbon of the nitrile oxide 3 to yield an amidoxime. However, the large energy involved in this addition prevents this mechanism. The large energy difference between the tautomers 1 and 2, makes that only the CN site of benzotriazepin‐5‐one 1 could act as a dipolarophile site. This fact makes the 13DC reaction to be chemoselective. The analysis of global electrophilicity of the reagents allows explaining the low polar character of these 13DC reactions. Copyright © 2007 John Wiley & Sons, Ltd.

Stereochemistry, tautomerism, and reactions of acridinyl thiosemicarbazides in the synthesis of 1,3‐thiazolidines

Abstractmagnified imageAcridin‐9‐yl hydrazine upon treatment with various isothiocyanates (RNCS, R = methyl, allyl, phenyl, p‐methoxy phenyl, and p‐nitro phenyl) yielded the corresponding thiosemicarbazides with acridine substituted on the carbazide‐type side. The alkyl‐substituted compounds were present in solution as equilibria consisting of the major H‐10, H‐12 tautomer (either E or Z or both about the C13‐N14 bond) and the minor H‐10, SH tautomer (either E or Z or both). The major species for the aromatic‐substituted compounds was the H‐10, H‐12 E tautomer, with the evident minor species being the H‐10, H‐12 Z tautomer. The thiosemicarbazides were each quantitatively converted into the analogous semicarbazides upon treatment with mesitylnitrile oxide wherein all structures were present in solution as the H‐10 tautomers with Z conformation about the C13‐N14 bond. Methylation of the compounds with methyl iodide yielded S‐methylated compounds wherein the Z configuration dominated in each case over the E configuration along the N12‐C13 double bond. Treatment of the thiosemicarbazides with methyl bromoacetate resulted in the formation of 1′,3′‐thiazolidin‐4′‐ones wherein the Z configuration predominated in each case over the E configuration along the N12C13 double bond. With bromoacetonitrile as the bifunctional electrophile, the initial 1′,3′‐thiazolidin‐4′‐imines that formed spontaneously underwent Dimroth‐type rearrangement to the regiosiomeric 1′,3′‐thiazolidin‐4′‐imines.

Organophosphorus Compounds, Part 168;1,3-Dipolar Cycloaddition Reactions of 1,3,5-Triphosphinines with Nitrile Oxides

Phenylnitrile oxide as well as mesitylnitrile oxide underwent 1,3-dipolar cycloaddition reactions with the 1,3,5-triphosphinines 2 under mild conditions to furnish the condensed heterocyclic compounds 9 and 11, respectively. Oxadiphospholes 14 were accessible by fragmentation reactions of 11.

A study of the reactivity of a tetraphosphadeltacyclene*

AbstractThe selective deselenation of the recently described tetraphosphatetracycle 4a leads to the tetraphosphabishomoprismane 6 in high yield. Triethylphosphine is used as a deselenating reagent. A further example for a selective decomposition of 4a is performed by mesitylnitrile oxide (9), yielding the 1,2,4‐oxazaphosphole 10. Bromine and iodine furnish tetracyclic rearrangement products 13a,b. Finally, the applicability of the tetracycle 4a as a ligand in transition metal chemistry is evaluated by complexation with tungsten (14) and, respectively, iron (15) carbonyl fragments.Side aspects of this article are the first synthesis of 3,5‐dimesityl‐1,2,4‐selenadiphosphole 2e starting from mesitylphosphaalkyne 1e, as well as the first report on a mixed substitution at a cage compound of type 4. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:406–413, 2001

Unusual reversal of stereoselectivity of 1,3-dipolar cycloaddition in the presence of Lewis acids

The addition of Lewis acids to dipolar cycloaddition reactions of mesityl nitrile oxide with α,β-unsaturated 2-acyl-1,3-dithiane 1-oxides affects and can even reverse the sense of induced stereoselectivity. The addition of Lewis acids to dipolar cycloaddition reactions of mesityl nitrile oxide with a,b-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.

Retention of Configuration and E/Z Stereoselectivity in the Photolysis of cis ‐ and trans ‐Tetraalkyl‐4‐methylene‐1‐pyrazolines

The isomeric 4-methylene-1-pyrazolines cis- and trans-2 are synthesized by a Wittig reaction from the pyrazolin-4-ones cis- and trans-1, respectively. Direct irradiation with 350-nm light of cis-2 affords the alkylidenecyclopropanes cis-8, (E)- and (Z)-9 (64: 17: 19) besides molecular nitrogen and small amounts of the 4-methylenepyrazolidine cis-7 as a result of photoreduction. Under the same conditions, trans-2 is converted into trans-8 as well as (E)- and (Z)-9 (64: 14: 22). The configurations of cis- and trans-8 have been established by means of a 1,3-dipolar cycloaddition with mesityl nitrile oxide which furnishes two cycloadducts from cis-8, e.g. cis-14A and B, but only one cycloadduct from trans-8, viz. trans-14. The configurations of (E)- and (Z)-9 have been assigned on the basis of homoallylic 1H,1H coupling constants and nuclear Overhauser experiments. The results demonstrate that, on the least-motion paths leading to cis- and trans-8, the configuration of the ring substituents in cis- and trans-2 is completely retained. Of the non-least-motion products (E)- and (Z)-9 the latter is favoured regardless of the configuration of the precursors cis- and trans-2 though the extent of (Z) selectivity depends on that configuration. The results are interpreted in terms of bis-orthogonal trimethylenemethane diradicals as primary intermediates from which irreversible paths bifurcate. Cyclization yields cis-8 (from cis-2) or trans-8 (from trans-2) and 90°-bond rotations afford two diastereomeric mono-orthogonal trimethylenemethane diradicals [(E)- and (Z)-18] which eventually cyclize to the corresponding non-least-motion products (E)-9 and (Z)-9.

ChemInform Abstract: Cycloaddition Reactions of 2,3‐Dihydro‐1H‐1,4‐diazepines with Nitrile Oxides and Imines. Synthesis of Bis(1,2,4)oxadiazolo‐ and Bis(1,2,4)triazolo(1,4)diazepine Derivatives.

New heterotricyclic systems, 6,10a,11,11a-tetrahydro-5H-bis[1,2,4]oxadiazolo[4,5-d:5′,4′-g][1,4]diazepines 6,7,9-11 and 5,6,10,10a,11,11a-hexahydro-1H-bis[1,2,4]triazolo[4,3-d:3′,4′-g][1,4]diazepines 8,12 have been obtained by double site- and regie-specific 1,3-dipolar cycloaddition of mesitylnitrile oxide (1) or diphenylnitrile imine (2) to 5,7-disubstituted 2,3-dihydro-1H-1,4-diazepines 3-5. The structure of the synthesized bis-adducts 6-12 shows that the hetero double bonds are much more reactive than the olefinic ones in the dipolarophiles under study. No evidence for the formation of mono-adducts was obtained.

Cycloaddition reactions of 2,3‐dihydro‐1H‐1,4‐diazepines with nitrile oxides and imines. Synthesis of bis[1,2,4]oxadiazolo‐and bis[1,2,4]triazolo[1,4]diazepine derivatives

AbstractNew heterotricyclic systems, 6,10a,11,11a‐tetrahydro‐5H‐bis[1,2,4]oxadiazolo[4,5‐d:5′,4′‐g][1,4]diazepines 6,7,9‐11 and 5,6,10,10a,11,11a‐hexahydro‐1H‐bis[1,2,4]triazolo[4,3‐d:3′,4′‐g][1,4]diazepines 8,12 have been obtained by double site‐ and regie‐specific 1,3‐dipolar cycloaddition of mesitylnitrile oxide (1) or diphenylnitrile imine (2) to 5,7‐disubstituted 2,3‐dihydro‐1H‐1,4‐diazepines 3‐5. The structure of the synthesized bis‐adducts 6‐12 shows that the hetero double bonds are much more reactive than the olefinic ones in the dipolarophiles under study. No evidence for the formation of mono‐adducts was obtained.

1,3‐Dipolar Cycloadditions of 1,1‐Difluoroallene, Nitrones, Nitrile‐Oxides and Carbonyl Ylides

AbstractThe 1,3‐dipolar cycloadditions of C,N‐diphenylnitrone, C‐phenyl‐N‐methylnitrone, triphenylnitrone, mesitylnitrile oxide and tetracyanocarbonyl ylide with 1,1‐difluoroallene (DFA) are reported and discussed with respect to regiochemistry. Each of the dipoles adds exclusively to the C2—C3, non‐fluorine‐substituted π‐bond of DFA. The nitrones all undergo regiospecific reactions while mesitylnitrile oxide does not. The results are discussed with respect to FMO theory and other factors which can give rise to regiochemical variation.

Studies on diazepines. XXI. Photochemical synthesis of 1H-2,4-benzodiazepines from 4-azidoisoquinolines.

Irradiation of 4-azidoisoquinolines (1a-e) in the presence of sodium methoxide resulted in ring-expansion to give 5-methoxy-1H-2, 4-benzodiazepines (10) : the structures of the products were confirmed by the following chemical studies as well as spectral analyses. Treatment of the diazepines (10) with hydrochloric acid or acidic alumina in methanol resulted in ring-contraction to afford 1-aminoisoindolenines (14), and treatment with acetic anhydride gave the ring-opened products (16). The diazepines (10) were also converted to 1-methoxyisoindolenines (19) by further irradiation and to the diazepin-3-one (21) by treatment with either mesitylnitrile oxide or lead tetraacetate.

Conversion of ω-terminal-acetylenic sugar derivatives into acetylenic glycosides and nucleosides, and formation of “double-headed nucleoside” analogs

3,5-Di- O-acetyl-6,7-dideoxy-1,2- O-isopropylidene-β- L- ido- and α- d- gluco-hept-6-ynofuranose were separately deacetonated, and the products acetylated, to give the 1,2,3,5-tetra- O-acetyl analogs ( 2 and 6). Fusion of compounds 2 and 6 with 2,6-dichloropurine under acid catalysis produced 2,6-dichloro-9-(2,3,5-tri- O-acetyl-6,7-dideoxy-α- L- ido-hept-6-ynofuranosyl)-9 H-purine ( 3) and its β- d- gluco analog 7, respectively. Methanolic ammonia converted 3 in good yield into 2-chloro-9-(6,7-dideoxy-α- L- ido-hept-6-ynofuranosyl)-6-methoxy-9 H-purine. Treatment of compound 3 with mesityl nitrile oxide gave a “double-headed nucleoside” analog. Upon treatment with phenyl azide, the d- gluco derivative 7 produced another “double-headed nucleoside”. Fusion of 2 and 6 with p-nitrophenol yielded the respective p-nitrophenyl glycosides. The stereochemistry and regiospecificity of the reactions were verified spectroscopically.