Synthesis of 2-substituted-7-azaindoles from 2-amino-3-picolin

An easy route to the synthesis of 2-substituted-7-azaindole derivatives has been developed. The carbinol intermediate dissolved in DMF undergoes cyclization upon treatment with sodium hydride, trifluoroacetic anhydride, and trifluoroacetic acid at 120 °C in a straightforward and one-pot step. An alternative methodology using (CF₃SO₂)₂O in acetonitrile in basic media followed by the addition of CF₃COOH affords the expected 2-substituted azaindole in best yields.     

Cascade reaction of β,γ-unsaturated α-ketoesters with phenols in trityl chloride/TFA system. Highly selective synthesis of 4-aryl-2H-chromenes and their applications

The treatment of β,γ-unsaturated α-ketoesters with phenols in the presence of trityl chloride and 4 ? molecular sieves in refluxing trifluoroacetic acid afforded 4-aryl-2H-chromenes in high yields, in which a reverse of the regiochemistry of J?rgensen-Rutjes chromane synthesis was observed. The isolation of 4H-chromene intermediates, confirmed by single-crystal X-ray analysis, indicates that the early stage of the reaction involves a Friedel-Crafts alkylation/cyclodehydration processes. Stirring of the 4H-chromene intermediate with trityl chloride in deuterotrifluoroacetic acid under reflux afforded the 2H-chromene and triphenylmethane in high yields, which implies the late stage of the reaction involves a hydrogen transfer process. Highly selective derivation of the hydroxyl esters to the corresponding hydroxyl amides, amino acids, amino esters and Friedel-Crafts adducts was further accomplished. Our endeavors will lead to a better understanding of the controlling elements behind their structural motifs. The products were confirmed unambiguously from their spectra and by single-crystal X-ray analysis.     

Transformations of spirocyclodimers of 1,3-bis(ferrocenylmethylidene)-2-methylidenecycloalkanes in acid medium

An intramolecular homoannular alkylation of one ferrocenyl substituent in spirocyclodimers of 1,3-bis(ferrocenylmethylidene)-2-methylidenecyclohexanes and -cycloheptanes on treatment with trifluoroacetic acid, leading to the formation of polyfused products containing a three-petal system of six-membered rings in the molecule center, was found. The structure of 11-ferrocenyl-6,14-bis(ferrocenylmethylidene)-2,3-ferroceno-1,2-tetracyclo[8.8.0.0^5,10.0^13,18]octadeca-2,13(18)-diene was established by X-ray diffraction analysis.     

ALKOXYPHOSPHONIUM SALT INTERMEDIATES IN THE THIONO-THIOLO REARRANGEMENT OF PHOSPHYLTHIONATES IN PROTIC ACID MEDIA

Abstract

The thiono-thiolo rearrangement reaction of phosphylthionates 1 catalyzed by protic acids proceeds with the formation of two types of intermediate alkoxyphosphonium salts 2 and 3. The first of these is formed by the protonation of the substrate 1 at the sulfur atom. Formation of 2 is evident from the changes in chemical shifts in ³¹P NMR spectroscopy of phosphylthionates upon their interaction with trifluoroacetic acid and also from the appearance of electrical conductivity in the solutions of substrates in TFA. The extent of protonation is consistent with the expected substituent effect on the basicity of thiophosphoryl sulfur. The second type of alkoxyphosphonium salt is formed by the alkylation of neutral esters with 2. The formation of 3 is observed in both ¹H and ³¹PNMR spectra. 3 were identified by their spectroscopic comparison with alkoyxphosphonium salts produced by alkylation of 1 with strong alkylation agents. The relative reactivity of a model alkoxyphosphonium salt towards a neutral ester and a phosphylthioate anion was investigated. In the absence of acid the rate of alkylation of the anion exceeds that of the alkylation of a neutral ester by three orders of magnitude. The protonation of phosphylthioate anion under acidic conditions results in a dramatic decrease in the rate of alkylation thereby leading to accumulation of 3 in the acidic reaction media.     

Etudees en série indolique—VI : Transformation des alcaloïdes du type vobasine en alcaloïdes du type dehydroervatamine Analyse aux rayons X de l'ervatamine

N-oxides of vobasine alkaloids lead to dehydroervatamine alkaloids on treatment with trifluoroacetic anhydride (modified Polonovski reaction) followed by reduction of the intermediate immonium. X-ray analysis of ervatamine shows that the reported configurations of the ethyl chain of both dregamine and tabernaemontanine should be revised.     

Enantioselective synthesis of aroylalanine derivatives

In this paper we report the development of a highly enantioselective method for the synthesis of aroylalanines. The approach described employs a protected 2-amino-4-bromopent-4-enoic acid, generated via the asymmetric phase-transfer catalyzed alkylation of a glycine imine, as a key intermediate. Suzuki coupling with an aryl boronic acid followed by ozonolysis of the resulting styrene provides efficient access to the aroylalanine derivatives. The utility of this methodology is illustrated by the synthesis of l-kynurenine along with several aroylalanine inhibitors of the kynurenine pathway.     

Synthesis of 10-thia-5-deazafolic acid and 2-desamino-2-oxo-10-thia-5-deazafolic acid

The folate analogue, 10-thia-5-deazafolic acid, was obtained via a multistep synthetic sequence beginning with the known intermediate, 2,4-diaminopyrido[2,3-d]pyrirnidine-6-carboxaldehyde. Reduction of this aldehyde with sodium borohydride gave 2,4-diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine, which when heated in base gave 2-amino-3,4-dihydro-6-(hydroxymethyl)-4-oxopyrido[2,3-d]pyrimidine. Treatment of the latter compound with phosphorus tribromide in tetrahydrofuran afforded 2-amino-6-(bromomethyl)-3,4-dihydro-4-oxopyrido[2,3-d]pyrimidine, thus constituting the first successful synthesis of this elusive intermediate. The aforementioned bromomethyl compound reacted smoothly with the sodium salt of ethyl 4-mercaptobenzoate, and the resulting ester was saponified to give 10-thia-5-deazapteroic acid. Conventional peptide bond coupling to di-tert-butyl L-glutamate followed by treatment with trifluoroacetic acid afforded the target compound in respectable yield. Attempts to prepare its 5,6,7,8-tetrahydro derivative by catalytic hydrogenation were unsuccessful.     

Synthesis of 1,2,3-triarylpyrroles from 1-benzylbenzotriazoles via [1 + 2 + 2] annulation

1,2,3-Triarylpyrroles 7 have been synthesized by sequential lithiation and alkylation of 1-benzylbenzo-triazoles 1 with 2-bromoacetaldehyde diethyl acetal (2) and N-benzylideneaniline (4), followed by treatment with formic acid in ethanol.     

Protic acid-induced intramolecular reactions of 2-cyclopropylazobenzenes

Treatment of 2-cyclopropylazobenzenes with concentrated sulfuric acid affords the intramolecular N- and C-alkylation products. Treatment of azobenzenes with trifluoroacetic acid results in quantitative rearrangement to arylindazoles via the intermediate formation of acid-stable indazolium ions. It is suggested that the formation of indazolium ions in trifluoroacetic acid results from the synchronous opening of the cyclopropane ring and stabilization of the developing carbocation by an internal nucleophile (the azo-group).Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1063–1068, August, 1987.     

New routes to N-alkylated cyclic sulfamidates

BOC- and dibenzosuberyl-protected chiral and hindered cyclic sulfamidates ([1,2,3]-oxathiazolidine-2,2-dioxides) were synthesized and subsequently deprotected using trifluoroacetic acid. The resulting crystalline sulfamidates were then used in several alkylation reactions involving benzyl bromide and alcohols in a versatile route to cyclic sulfamidates with differing N-alkyl substituents.     

A 5-methylthiopenicillin analog and its transformation to novel bicyclic β-lactams

Reaction of methoxyacetyl chloride with 2-methylthio-2-thiazoline resulted in the stereoselective production of one isomer of 6-methoxy-5-methylthiopenam which underwent rearrangement to 6-methoxy-7-methylthio-5-oxo-2,3,4,5-tetrahydro-1,4-thiazepine when treated with trifluoroacetic acid. Subsequent thioamidation and alkylation with methyl iodide provided 5,7-bismethylthio-6-methoxy-2,3-dihydro-1,4-thiazepine which reacted with methoxyacetyl chloride and triethylamine to give a novel 1,4-thiazabicyclo[5.2.0]non-5-ene. Other substituted bicyclic β-lactams of similar structure have also been synthesized.     

Synthesis of key fragments of amphidinolide Q--a cytotoxic 12-membered macrolide

β-hydroxy aldehyde and alkyl ketone moieties were effectively synthesized as key intermediates of amphidinolide Q, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp.. The asymmetric center of the former derivative was produced by Sharpless asymmetric epoxidation, followed by E-selective 1,4-addition to give the sp2 methyl group. Derivatization of the L-ascorbic acid derivative by Evans asymmetric alkylation and Peterson olefination provided the latter intermediate. The coupling reaction of the segments was examined.     

Conversion of nocathiacin I to nocathiacin acid by a mild and selective cleavage of dehydroalanine

Thiazolyl peptide antibiotic nocathiacin I (1) was converted to nocathiacin acid (4) in high yield by treatment with trifluoroacetic anhydride and pyridine in THF at room temperature. Two equipotent water-soluble amide analogues of nocathiacin I were readily prepared from this important and versatile carboxylic acid intermediate under mild peptide coupling conditions. The present method is useful for chemical derivatization of complex natural products that contain C-terminal dehydroalanine.     

Phase transitions of native celluloses from evolutionarily different sources into polymorph IV

A procedure was suggested for preparing cellulose polymorph IV by dissolution of native celluloses from evolutionarily different sources in trifluoroacetic acid to molecularly dispersed state, followed by regeneration and treatment under hydrothermal conditions.     

Synthesis of 4,6-dimethyl-tetrahydro- and hexahydro-dibenzothiophene

2-Bromo-3-methylcyclohexanone was synthesized by conjugate addition of trimethylaluminium to 2-bromo-2-cyclohexen-1-one with copper bromide as catalyst, coupled with 2-methylthiophenol and annulated with the aid of polyphosphoric acid to 4,6-dimethyl-1,2,3,4-tetrahydrodibenzothiophene. The latter was hydrogenated to 4,6-dimethyl-1,2,3,4,4a,9b-hexahydrodibenzothiophene, another intermediate in the hydrodesulfurization of 4,6-dimethyldibenzothiophene, by zinc and trifluoroacetic acid, and dehydrogenated to 4,6-dimethyldibenzothiophene.     

Synthetic studies toward ecteinascidin 743

An efficient synthesis of a fully functionalized tetracycle (A-B-C-H) 7 containing a 1,4-bridged 10-membered lactone was developed. Phenolic aldol condensation between 2-methylsesamol (15) and Garner's aldehyde provided the protected amino diol 16, which was converted to free amine 11 in excellent yield. A Pictet-Spengler reaction between 11 and ethyl glyoxylate under carefully controlled conditions (LiCl, toluene, 1,1,1,3,3,3-hexafluoro-2-propanol, room temperature) provided the acid-sensitive tetrahydroisoquinoline (18) in high yield, which was converted to the amino alcohol 9. Enantioselective alkylation of a glycine template in the presence of a catalytic amount of chiral cinchonidium salt was the key step for the access of enantiomerically pure amino aldehyde 10. Union of the two fragments 9 and 10 via oxazolidine intermediate afforded amino nitrile 39, which upon esterification of the primary alcohol with (R)-N-(S-4,4',4' '-trimethoxyltrityl) Cys (42) afforded 43. Cyclization of 43 (1% trifluoroacetic acid in trifluoroethanol) provided compound 44 by a domino process involving (a) unmasking of the S-trimethoxytrityl group, (b) fragmentation of dioxane assisted by an electron-rich aromatic ring, and (c) formation of a 1,4-bridged 10-membered lactone via formation of a sulfide linkage. Treatment of 7, obtained in two steps from 44b, under acidic conditions (0.5% methyl sulfonic acid in acetonitrile) afforded the pentacyclic compound 51 via fragmentation of the 10-membered cyclic sulfide followed by an intramolecular Pictet-Spengler reaction.     

Trifluoroacetic anhydride-mediated solid-phase version of the Robinson-Gabriel synthesis of oxazoles

A traceless solid-phase synthesis of oxazoles 4 via Robinson-Gabriel reaction of solid-supported alpha-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield alpha-methoxyphenyl (MAMP) resin with an alpha-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with alpha-keto aldehydes; reaction of MAMP resin with alpha-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.     

Preparation and X-ray crystal study of benziodoxaborole derivatives: new hypervalent iodine heterocycles

A series of heterocyclic compounds containing trivalent iodine, oxygen, and boron in a five-membered ring were prepared and structurally investigated by X-ray crystallography. 1-Chloro-4-fluoro-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol was synthesized by chlorination of 2-fluoro-6-iodophenylboronic acid followed by treatment of the intermediate iododichloride with water. 1-Acetoxy-4-fluoro-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol, 1-acetoxy-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol, and similar 1-substituted trifluoroacetate derivatives of benziodoxaborole were prepared the hypochlorite oxidation of 2-fluoro-6-iodophenylboronic acid or 2-iodophenylboronic acid in acetic or trifluoroacetic acid, respectively. 1-Acetoxy substituted benziodoxaborole can be further converted to the respective trifluoroacetate by treatment with trifluoroacetic acid or to the 1-hydroxy derivative by basic hydrolysis with aqueous NaHCO(3). X-ray structural studies of 1-chloro- and 1-trifluoroacetoxy substituted benziodoxaboroles 13, 17, and 18 have shown the presence of a planar five-membered heterocyclic ring with unusually short endocyclic I-O bond distance of 2.04-2.09 ?. Slow crystallization of 4-fluoro-1-trifluoroacetoxy-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol-3-ol from methanol resulted in the formation of a tetrameric macrocyclic structure 21 resulting from self-assembly of the initially formed 4-fluoro-1,3-dimethoxy-1H-1λ(3)-benzo[d][1,2,3]iodoxoborol. Structural parameters of the five-membered iodoxoborol ring, such as the planar geometry and the short B-O and O-I bonds lengths in 13, 17, and 18 compared to those in 21 and known benziodoxoles are indicative of partially aromatic character of this ring. Density functional theory (DFT) predicted NIST (0) and NIST (1) indexes for 1-chloro- and 1-trifluoroacetoxy substituted benziodoxaboroles, however, are indicative of significantly lower aromaticity compared to the classic aromatic systems.     

Solid-phase synthesis of a library of hydroxyproline derivatives

The synthesis of a library of N-alkylated O-arylated hydroxyproline derivatives has been achieved on solid phase. The choice of O-protection and the optimization of the Mitsunobu reaction involving a secondary alcohol were key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-O-THP-hydroxyproline was accomplished readily. Subsequent deprotection of the Fmoc and reductive amination with different aldehydes resulted in the tertiary amine intermediate. The deprotection of the THP group by p-toluenesulfonic acid was followed by a Mitsunobu reaction with a series of phenols. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 200 member library.     

Ouverture acide de bis-(alkylthio)-2,2 cyclopropanols: Une nouvelle methode d'homologation et d'extension de cycle

Solvolysis of 2,2-bis(alkylthio) cyclopropanols by aqueous trifluoroacetic acid occurs easily to yield conjugated α-alkylthio emone and/or β-oxo-S alkylthioesters. The formation of the former most probably involves a disrotary rink opening concerted with the departure of the alkylthio group trans to hydoxyl, or, alternatively with monocyclic compounds, a 1,2-emigration of the same akylthio group synchronous with OH departure and cleavage. A nucleophilic substitution at the thioacetal centre followed by oxidative opening of the intermediate cyclopropandiol accounts for the formation latter. In 70% aqueous perchloric acid the formation of enones in favoured.