Search

The practical method tolerates a broad range of functionalized N,N-dimethyl and N-alkyl-N-methyl aniline derivatives, but fails using N-methylmorpholine, N-methyl-9H-carbazole or N-methylaniline as a substrate.

High selectivity is observed during a Friedel–Crafts acylation/demethylation cascade. In contrast to this cascade, oxygen-containing acylating reagents do not undergo the demethylation step. By the methodology elaborated here, an access is provided to important intermediates for the total synthesis of seminaphthorhodafluor (SNARF) dyes.

A simple and efficient synthesis of 2-aryl-3-hydroxythieno[3,2-b]pyridin-7(4H)-ones, 7-methoxy-2,3-diarylthieno[3,2-b]pyridines, and 2,3-diarylthieno[3,2-b]pyridin-7(4H)-ones is presented. The synthesis involves thioalkylation of methyl 4-methoxypicolinate at the 3-position, followed by cyclization in situ to give 2-aryl-7-methoxythieno[3,2-b]pyridin-3-ols. Demethylation of these compounds gives the corresponding 2-arylthieno[3,2-b]pyridin-7(4H)-ones. Further functionalization of 7-methoxy-2-aryl­thieno[3,2-b]pyridin-3-ols was achieved by converting the hydroxy group into the corresponding triflate, which underwent palladium-catalyzed cross-coupling to give 7-methoxy-2,3-di(het)arylthieno[3,2-b]pyridines. Subsequent demethylation of the 7-methoxy group gave the corresponding pyridinones.

An antiangiogenic homoisoflavanone, cremastranone, was synthesized for the first time. This scalable synthesis, which includes selective demethylation, could be used to develop lead molecules to treat angiogenesis-induced eye diseases. Synthetic cremastranone inhibited the proliferation, migration and tube formation ability of human retinal microvascular endothelial cells, important steps in pathological angiogenesis.

Various alkoxy-substituted heterocyclic stannanes provide access to the corresponding substituted ‘pyridone’ moieties via Stille cross-coupling. Both pyridyl and a series of diazinyl stannanes are prepared, and options for unmasking (via demethylation or debenzylation) of the pyridone unit are evaluated.

A two-step route to 5-carbapterocarpens, hydroxylated at different positions, is presented from tetralones and aryl bromides in good overall yields.

A short total synthesis, guided by biosynthetic considerations, of racemic merochlorin B is presented. The formation of its isomer, merochlorin A, was not observed under the conditions. Key steps include a directed ortho-metalation (DoM), a selective demethylation, an ortho-allylation, and an oxidative [3 + 2]-cycloaddition mediated by an iodine(III) reagent.

Benzofuran-containing spirolactones are formed by a copper-catalyzed heterodimerization of 1,2-diarylcyclopropenones followed by stepwise BBr3-promoted demethylation.

A rapid and selective method for the title reaction is applied to a wide range of substrates.

A simple and efficient method for the synthesis of the title compounds starting from readily available N-cyanoimidates is developed.

An efficient de novo synthesis of vineomycinone B2 methyl ester has been achieved. The longest linear route required only 14 steps from achiral commercially available starting materials (4.0% overall yield). The key transformations included the de novo asymmetric synthesis of two key fragments, which were joined by a convergent late stage Suzuki's glycosylation for the construction of the aryl β-C-glycoside. A subsequent BBr3 one-pot debenzylation, demethylation and air oxidation provided vineomycinone B2 methyl ester.

The synthesis of 3,5-dimethoxy-1,3,5-triazines (III) is developed: demethylation and N-methylation of these products is studied.

Title compounds are generated by a BCl3-mediated ring-opening/aromatization/demethylation process of oxabicyclo[3.2.1]octenes which are obtained from the cycloaddition of oxidopyrylium triflates (I) with various alkynes.

The polymer PSIF is used as reusable catalyst for O-demethylation of various aryl methyl ethers.

The regioselective demethylation of podophyllotoxin (I) is smoothly achieved using methionine and methylsulfonic acid in TFA or in acetone/water.

Demethylation of aryl methyl ethers and subsequent acetylation of the resulting boronic acid intermediates is successfully applied to directly afford acetoxybenzene derivatives.

Condensation of 3,5-dimethoxyphenol with activated fluorobenzenes and subsequent demethylation provides an efficient and scalable method for the preparation of the desired structures (IV) as analogues of the cannabinoid partial agonist BAY59-3074 (V).

The synthesis of nalbuphine (VI) from oripavine (I) requires only five chemical transformations and is conducted with an overall yield of 45%, in contrast to current methods requiring seven to ten steps.

Attempted selective demethylation of substrate (Ia) during the synthesis of pestalone affords instead a cyclized product (IIa).

A new and efficient method for the demethylation of aryl as well as hetaryl methyl ethers using a combination of LiCl and TosOH is described.

However, all of these methods invariably suffered from one or more drawbacks such as harsh reaction conditions, long reaction times, difficulty of manipulation, use of exotic reagents, and low reaction yields. Furthermore, in the most of known methods for demethylation of aryl methyl ethers, use of large excess amounts of demethylating agents have been generally required. Thus, it is highly desirable to develop an improved convenient and efficient procedure for demethylation reactions of aryl methyl ethers.Magnesium iodide etherate, MgI

Under Polonovski-type conditions ferrocene is found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes.

N-Oxides, readily obtained by oxidation of the N-methylated substrate with MCPBA, are subjected to treatment with elemental iron.

Hypervalent iodine compounds are useful reagents in the dearomatization of phenols and in the chemo- and regioselective demethylation of 2-methoxyphenols into catechols.

The described method is easy, high-yielding and avoids the use of corrosive or moisture-sensitive reagents.

An efficient demethylation of methyl aryl ethers using an ionic liquid, 1-n-butyl-3-methylimidazolium bromide ([bmim][Br]) has been developed. Methyl aryl ethers are successfully cleaved by the halide anion of [bmim][Br], without aid of any other activating agents. In this reaction, microwave irradiation was found to be crucial for the effective conversion. The newly developed protocol is a very attractive green chemical process as it utilizes minimal amount of cleaving reagents and does not require additional activating agents or solvents. Under the conditions described herein, a broad range of methyl aryl ethers were converted to the corresponding phenolic compounds in moderate to excellent yields in a short time.

Two pairs of novel triptycene-derived calix[6]arenes 4a,b and 5a,b have been efficiently synthesized through both one-pot and two-step fragment-coupling strategies starting from 2,7-bis(hydroxymethyl)-1,8-dimethoxytriptycene 1. Subsequent demethylation of 4a,b and 5a,b with BBr(3) in dry dichloromethane gave the macrocyclic compounds 6a,b and 7a,b. Treatment of either 4a or 6a with AlCl(3) resulted in the same debutylated product 8, while 9 was similarly obtained from either 5a or 7a. Structural studies revealed that all of the macrocycles have well-defined structures with fixed conformations both in solution and in the solid state owing to the introduction of the triptycene moiety with a rigid three-dimensional (3D) structure, making them very different from their classical calix[6]arene counterparts. As a consequence, it was found that all of these the triptycene-derived calix[6]arenes could encapsulate small neutral molecules in their cavities in the solid state. Moreover, it was also found that the macrocycles 4b and 5b showed highly efficient complexation abilities toward fullerenes C(60) and C(70), forming 1:1 complexes with association constants ranging from (5.22+/-0.20) x 10(4) to (8.68+/-0.30) x 10(4) M(-1).

Aryl methyl ethers which are ortho-substituted with electron-withdrawing groups are selectively demethylated in the presence of aluminum chloride.

Title compound (IV) is obtained in multigram quantities by a novel sequential one-pot procedure comprising imination/Pictet—Spengler cyclization/demethylation/Boc-protection.

New methods were developed for removal of two methyl groups from aryl methyl ethers. Treatment of an aryl methyl ether containing two methoxy units (i.e., 1, 3, 5, 7, 9, 11 or 13) with ∼2.5 equiv of Me 3 SiSNa in 1,3-dimethyl-2-imidazolidinone at 185°C in a sealed tube gave the corresponding aryl alcohol (i.e., 2, 4, 6, 8, 10, 12, or 14) in 78-96% yields after aqueous workup. Also, Me 3 SiSSiMe 3 was found useful for bis-O-demethylation of aromatic compounds containing one free hydroxyl group and two methoxy units (e.g., 11 and 13). Thus 11 and 13 reacted with 1.5 equiv of NaH and then with 1.5 equiv of Me 3 SiSSiMe 3 at 185°C in a sealed tube to afford triols 13 (75%) and 14 (72%), respectively. In these bis-O-demethylations, Me 3 SiSNa and Me 3 SiSSiMe 3 act as counterattack reagents

The reaction of 1,3-bisbromomethyl-2-methoxy benzene with diaza-15-crown-5 or diaza-18-crown-6 in acetonitrile gives the phenolic cryptands 6a and 6c; it is shown that the formation of 6a involves the methoxy cryptand salt 9 which undergoes efficient demethylation by bromide anion as a result of acid catalysis within the cavity of the cryptand system.

Four new 1,4-dithiafulvenyl substituted bianthrones 3 have been prepared with the aim of making a light-activated «molecular switch». Acylation of 10,10'-dimethoxy-9,9'-bianthracene (2) could be controlled to give 3-acyl- or 3,3'-diacyl-10,10'-dimethoxy-9;9'-bianthracenes 4 and 5, respectively. Demethylation and oxidation yielded 2-acylbianthrones 7. Horner-Emmons-type coupling of 4 and 6 with substituted 1,3-dithiole-2-phosphonate esters 8 and 11 gave 1,4-dithiafulvenyl-substituted bianthracenes 9 and 12. Demethylation and oxidation finally gave the 1,4-dithiafulvenyl-substituted bianthrones 3. The electrochemical properties and absorption spectra of these new molecules (3) have been investigated and compared to bianthrone

Development of an efficient synthesis of the C-D ring portion of streptonigrin is a key operation in the synthesis of this antibiotic and its analogues. A new method for the synthesis of 3-cyano-5,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-2-pyridone (14), a compound having the requisite functionality for conversion into a streptonigrin analogue, has been established. It involves treatment of 3,4,5-trimethoxybenzonitrile with ethylmagnesium bromide and malononitrile to give propylenemalononitrile derivative 7, which is condensed with trimethyl orthoacetate to give a mixture of 9 and pyridine derivative 12. Demethylation of 12 then affords 14. The overall yield for this route was 50%, allowing for conversion of 9 to 12.

The dimethyl ether of 1,1'-bi-2-naphthol crystallizes as a conglomerate and can be resolved without chiral auxiliaries by entrainment. The direct crystallization of a supersaturated solution of the title compound partially enriched by one enantiomer (ee∼2%) is conducted in anisole at 40 o C and gives, after one crystallization, a compound with ee>98%. Demethylation under nonracemizing conditions gives the enantiomeric 1,1'-bi-2-naphthol

Oxidative coupling of 2,2′,4,4′-tetramethoxystilbene-3,3′-diol 51 gave a 51% yield of 1,3, 6,8-tetramethoxyphenanthrene-2,7-quinone 52, the first isolated example of a quinone of this type. Similar oxidation of the corresponding diphenylethane 55 gave the 9,10-dihydrophenanthrene-2,7-quinone 56. Attempts to synthesize the tetramethoxyphenanthrene-2, 7-diol 25 from a 2, 2′bis(hydroxymethyl)hexamethoxybiphenyl precursor 28 were thwarted by the ease of intramolecular cyclization to 2,3, 4,8,9,10-hexamethoxydibenz[c,e]oxepine 32. Selective demethylation of the 3-and 9-methoxy groups of this compound, and oxidation of the resulting diol 58 gave the dibenzoxepine quinone 59.The synthesis of 3,6-di-tert-butylphenanthrene-2, 7-diol 3 is also described, but this could not be oxidized to the quinone. However, the preparation of 3,6-di-tert-butyl-9,10-dihydrophenanthrene2,7-quinone 12 was successful.

The aldol condensation product (4) of 4- acetylpyridine (2) and diethyl mesoxalate (3) was converted to pyridazine- carboxylic acid hydrazide (6). Curtius reaction of 6 gave aminopyridazinone (7). The condensation of (4-pyridinyl)glyoxal (17) with aminomalonamide (9) yielded pyrazinecarboxamide (18) which was transformed to aminopyrazinone (19) by the Hofmann reaction. Curtius reaction of 1,2,4-triazinone-5-carboxylic acid (21b) gave aminotriazinone (22). Demethylation of methoxypyridine (29) prepared from methyl 2-methoxyformylacetate (25) and isonicotinamidine (26) gave pyrimidinol (30)

Nortropinone 5, prepared from 3 by N-demethylation with trichloroethyl chloroformate, followed by deprotection of carbamate 4 with zinc in acetic acid, served as a starting material to prepare the N-protected 6-acetoxy ketones 7 and 9–12, and alcohols 6 and 8. Nortropane 16 was prepared from 3 by decarbonylation via dithioketal 13 followed by N-demethylation, and from 10 by decarbonylation via dithioketal 14. When ethanol was used in the desulfurization of 14 instead of tetrahydrofuran, substantial amounts of the N-ethylated amine 17 were produced.

The synthesis and pharmacological characterization of a series of N-substituted 3-(4-fluorophenyl)tropane derivatives is reported. The compounds displayed binding characteristics that paralleled those of cocaine, and several had substantially higher affinity at cocaine recognition sites. Conjugate addition of 4-fluorophenyl magnesium bromide to anhydroecgonine methyl ester gave 2 beta-(carbomethoxy)-3 beta-(4-fluorophenyl)tropane (4a, designated CFT, also known as WIN 35,428) after flash chromatography. N demethylation of 4a was effected by Zn/HOAc reduction of the corresponding 2,2,2-trichloroethyl carbamate to give 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)nortropane (5), which was alkylated with allyl bromide to afford the N-allyl analogue, 6. The N-propyl analogue, 7, was prepared by catalytic reduction (Pd/C) of 6. The most potent analogue, 4a, was tritiated at a specific activity of 81.3 Ci/mmol. ({sup 3}H)4a bound rapidly and reversibly to caudate putamen membranes; the two-component binding curve typical of cocaine analogues was observed. Equilibrium was achieved within 2 h and was stable for at least 4 h. High- and low-affinity Kd values observed for ({sup 3}H)4a (4.7 and 60 nM, respectively) were more than 4 times lower than those for ({sup 3}H)cocaine, and the density of binding sites (Bmax = 50 pmol/g, high, and 290 pmol/g, low) for the two drugs were comparable. Nonspecific binding ofmore » ({sup 3}H)4a was 5-10% of total binding.« less

The reaction of ‘(C5Me5)Ru+’, produced by the protonation of [(C5Me5)RuOMe]2 by CF3SO3H, with various steroids leads to selective aromatization of the A ring via demethylation of the 19 methyl group and/or dehydration and/or dehydrogenation reactions.

Stable quaternary ammonium alkoxides, a new type of organic strong base, were obtained from unhindered tertiary alkanolamines and glycidol. At elevated temperatures, the 2-hydroxyethyl derivatives underwent intramolecular rearrangements and deoxyalkylation to form tertiary amine terminated 1,4-poly(3-hydroxyoxetanes). Demethylation was also observed. The 3-hydroxypropyl derivative underwent disproportionation and Hofmann elimination in addition

Since the strategy for the synthesis of 9-, 10- and 11-nitronoracronycine [3,4] could not be applied to the 8-nitronoracronycine 9, we here report the preparation of the latter by a fusion of methyl 2-amino-6-nitrobenzoate 2 and phloroglucinol 3. The fusion of 2 and 3 gave 1,3-dihydroxy-8-nitro-9(10H)-acridinone 6. Subsequent methylation, demethylation and reaction with 2-chloro-2-methyl-3-butyne afforded the desired 8-nitronoracronycine 9. Compound 9, 1,3-dimethoxy-10-methyl-8-nitro-9(10H)-acridinone 7 and 1,3-dihydroxy-10-methyl-8-nitro-9(10H)-acridinone 8 were tested by the National Cancer Institute (NCI) for possible anticancer activity.

Pummerer's ketone 1 is obtained with an overall yield of 55 % by the following sequence: Claisen rearrangement of an arylcyclohexylether 3; allylic oxidation of the methylcycloalkylphenolic derivative 4b, then spontaneous cyclisation during demethylation to give 2. 1 is obtained by dehydrogenation of 2. NMR data agree with a cis stereochemistry at C4a and C 9b.

The structure of the positional isomers of mono-O-demethylated metabolites ( V and VI ) of Tetraminol - trans -3-(2-hydroxyethylamino)-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol ( XIX ) - and the pairs of related derivatives was determined.

Two bacteria exhibiting resistance to toxic arsenic were isolated. These had been contaminated with arsenic in a Chlorella sp. culture medium containing arsenic. The two bacteria were identified as Klebsiella oxytoca and Xanthomonas sp., and grew well in a peptone medium at neutral pH at 30°C, reaching the stationary phase in ca 100h and 70h, respectively. The growth of the bacteria was not affected by arsenic(V) concentrations in the medium as high as 1000mg dm−3. The bacteria bioaccumulated arsenic, a part of the arsenic being methylated. The bioaccumulation exhibited its peak around the turing point from the log phase to the stationary phase. The relative content of methylated arsenic in the excrement was greater than that in the bacterial cells. Adaptation treatment of inorganic arsenic caused an increase in the bioaccumulation of inorganic arsenic by K. oxytoca. Such a situation was not observed in the case of Xanthomonas sp. The bacteria also bioaccumulated methylated arsenic compounds, and demethylation of these species was observed. When the bacteria were killed by ethanol, arsenic was not taken up by the cells.

The asymmetric 4a and symmetric conformers 4b of a trimethoxy[2.2.1]metacyclophane were isolated and the structures were established by 1H NMR spectroscopy and X-ray crystallography. The trihydroxy[2.2.1]-5 and dihydroxy(methoxy)[2.2.1]metacyclophane 6 were obtained by demethylation of isomers 4a and 4b, respectively. Treatment of compound 5 with ethyl bromoacetate afforded only the tris(ethoxycarbonylmethoxy)[2.2.1]metacyclophane 7. On the other hand the bis(ethoxycarbonylmethoxy)(methoxy)[2.2.1]-8 and ethoxycarbonylmethoxy(hydroxy)(methoxy)[2.2.1]metacyclophane 9 were obtained from compound 6. It was found that compounds 4a and 7 assume a ‘2,1-alternate’ conformation, whereas, on the other hand, compounds 4b, 6, 8 and 9 have a ‘2,2-alternate’ conformation. In the case of compound 5 both ‘2,1-alternate’ and ‘2,2-alternate’ conformers were detected by 1H NMR spectroscopy. The chiralities of compounds 4a and 9 were confirmed by their 1H NMR spectrum in the presence of Pirkle's reagent.