Acid 1b Research Articles

Reactivity studies on 4‐aminopyrones: Access to benzimidazole and benzimidazolone derivatives

AbstractReaction of pyrone 1a or tetronic acid 1b with o‐phenylenediamine derivatives gave enaminone compounds 2. When reacting with different electrophiles, these intermediates allowed versatile access to different heterocyclic structures: when DMA derivatives or triphosgene was used, cyclization occurred through nitrogen, leading to benzimidazoles 3 and benzimidazolones 4, respectively, while reaction with benzaldehyde yielded benzodiazepines 5.

Synthesis of combinatorial libraries based on terpenoid scaffolds.

Triterpenoid-based scaffolds betulinic acid (1a) and ursolic acid (1b), have been used for the generation of combinatorial libraries in parallel format using solid phase organic synthesis method. These templates have the potential for the synthesis and amplification of triterpenoid-based compounds with one and two-point diversity. This has been demonstrated by the synthesis of two small libraries comprising 18 derivatives each of betulinic acid and ursolic acid with structural diversity at C-3 and C-28 positions. The primary screening of antimalarial activity of these libraries against P. falciparum in vitro led to the identification of four compounds with 5 fold increase in the activity compared to betulinic and ursolic acids.

Orthoamide, LVIII . Kondensationsreaktionen von CH2-aciden Verbindungen mit Orthoamiden von Carbonsäuren und Alkincarbonsäuren / Orthoamides, LVIII . Condensation Reactions of CH2-Acidic Compounds with Orthoamides of Carboxylic Acids and Alkyne Carboxylic Acids

The orthoamide derivatives 1s and 2e were prepared from the guanidinium salt 7a and the appropriate carbanions. Cleavage of the orthoamide 2e with benzoyl chloride affords the amidinium salt 10a, which can be transformed into the amidinium salt 10b by an anion exchange reaction. The enamines 11a-i, 12a-c, 13a, b, 14a-c, 15a, b, 16, 17a, b, 18a, b, 19a, b, 20 were prepared by condensation of CH2-acidic compounds with the carboxylic acid orthoamides 2a-j. The orthoamide 2d reacts with 1-nitropropane to give the amidinium salt 27a which is transformed into the salt 27b. From benzyl cyanide and orthoamides 2g, i the enamines 30 and 32 were obtained. Similar condensation reactions were performed with the orthoamides of alkyne carboxylic acids 1b, 1c, 1d, 1e, 1p, 1s, giving the push-pull-butadiene derivatives 35a-f, 36a-f, 37a-j, 38a, b, 39a, b, 40a, b. Crystal structure analyses of the butadiene derivatives 37a, 39a, b, 40a, b and 42 were performed, showing that in 37a, 39b, 40a, b by far the shortest bond distance is between C-2 and C-3 of the butadiene system. In 39a the bonds between C1-C2, C2-C3 and C3-C4 are nearly of equal length, whereas in the 1,3-diene unit of 42 the shortest bonds are between C1-C2 and C3-C4.

(dppe)Pt(OTf)2 and (R-BINAP)Pt(OTf)2 Lewis Acids Catalyze the Diels−Alder Reaction by Different Mechanisms

In situ observation, by 31P and 1H NMR at 195−240 K, of acryloyl-N-oxazolidinone (4)/cyclopentadiene (HCp) Diels−Alder reactions catalyzed by the Pt(II) Lewis acids P2Pt(OTf)2 (2; P2 = dppe (a), R-BINAP (b)) revealed that the ditriflate catalysts are consumed by HCp at different rates to produce the catalytically inactive 18-electron complexes [P2Pt(η5-Cp)]+[OTf]- (9). Mechanistic studies point to formal loss of HOTf from the proposed intermediate diene complex [P2Pt(HCp)]2+[OTf]-2, facilitated by a necessary second equivalent of HCp; ill-defined HCp/HOTf byproducts, whose 1H NMR resonances include a broad singlet at 12.7 ppm, are also formed. Both catalyst decomposition and Diels−Alder catalysis proceeded faster in reactions involving dppe Lewis acid 2a than in those involving R-BINAP Lewis acid 2b. In the 2b reaction at 195 K, Pt-bound dienophile 4 was immediately converted to the Pt-bound Diels−Alder adduct 2S-5 on addition of HCp; however, no turnover occurred and no η5-Cp complex was detected until the temperature was raised to 225 K. At this temperature, no low-field resonances were observed by 1H NMR, a highly enantiopure Diels−Alder adduct was obtained, and TOFs less than the rates of ligand exchange were observed. These data are consistent with catalysis by a chiral [P2Pt]2+ Lewis acid, in which ligand substitution is the turnover-limiting step of the catalytic cycle. In contrast, 9a and Diels−Alder adduct rac-5 formed rapidly at 195 K in the 2a reaction. The observation of low-field HCp/HOTf resonances (1H NMR) and TOFs greater than the rates of ligand exchange together suggest that, in this case, the Diels−Alder reaction is catalyzed primarily by a Brønsted acid mechanism involving the HCp/HOTf byproduct of 2a decomposition, rather than by [(dppe)Pt]2+.

Asymmetric synthesis of trans-2,3-piperidinedicarboxylic acid and trans-3,4-piperidinedicarboxylic acid derivatives.

Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz protected analogues 8a,b and 17a,b are described. Enantiomerically pure 1b has been synthesized in five steps starting from L-aspartic acid beta-tert-butyl ester. Tribenzylation of the starting material followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1 diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde 7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%. Optically pure 2b has been synthesized beginning with N-Cbz-beta-alanine. The synthesis involves the induction of the first stereogenic center using Evans's chemistry and sequential LDA-promoted alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and reductive amination affords 2b in an overall yield of 28%.

A CONVENIENT SYNTHESIS OF 2-ALKYL-8-QUINOLINE CARBOXYLIC ACIDS

ABSTRACT 2-Methyl-8-quinoline carboxylic acid 1 was readily synthesized by the improved Doebner–Miller reaction using anthranilic acid and crotonaldehyde in a two phase system containing 5 mol% PTC. By alkylation of methyl group in 1, other 2-alkyl-8-quinoline carboxylic acids (2a and 2b) have been easily prepared.

CHEMOSPECIFICITY IN ARYLATIONS OF δ- AND γ-KETOCARBOXYLIC ACIDS WITH P2O5–MsOH, TfOH, AND RELATED ACIDIC MEDIA

ABSTRACT Remarkable contrast between chemospecificities in acid-mediated arylation of δ- and γ-ketocarboxylic acids was revealed: in the presence of P2O5–MsOH, TfOH, PPA, and MsOH, arylation of δ-ketocarboxylic acid 1A with arenes takes place at the carboxycarbonyl carbon, while that of γ-ketocarboxylic acid 1B takes place at the ketone carbonyl carbon, specifically.

Novel Columnar Tetraphenylethenes via McMurry Coupling

Several tetraphenylethenes 2a, 4a–i with lipophilic side chains were synthesized and their mesomorphic properties were investigated. The most promising candidates turned out to be tetrakis[4-(trisalkyloxybenzoyloxy)phenyl]ethenes 4e–i with chain lengths between C7 and C12. Compounds 4 were prepared by a convergent strategy employing a McMurry coupling of 4,4′-dimethoxybenzophenone 1c, followed by demethylation and subsequent esterification of 2c with either 4-decyloxybenzoic acid 3a, 3,4-didecyloxybenzoic acid 3b, or O-alkylated gallic acids 3c–i. Despite the twisting of the central tetraphenylethene moiety compounds 4c–i display hexagonal columnar mesophases according to differential scanning calorimetry (DSC), polarizing microscopy, and X-ray diffraction studies.

Precursors to oak lactone: synthesis of gallate ester derivatives of 3-methyl-4-hydroxyoctanoic acid

(3 R,4 R- and 3 S,4 S)-3-Methyl-4-(3′- O-methylgalloyloxy)octanoic acid ( 2b ), the corresponding methyl ester ( 2c ) and the straight galloyl derivative, (3 R,4 R- and 3 S,4 S)-3-methyl-4-galloyloxyoctanoic acid ( 2a ) were synthesised from cis-oak lactone ( 1 ). Analysis by TLC and mass spectrometry established that the original assignment of structure ( 2c ) to a methylated natural oak component was in error.

An alternative stereoselective synthesis of trans-(2 R,3 R)-3-hydroxypipecolic acid

The enantioselective synthesis of trans-(2 R,3 R)-3-hydroxypipecolic acid 1b is presented, starting from O-protected methyl mandelate as chiral source. The synthesis involved a regioselective intramolecular nucleophilic substitution of an azido epoxide as the key step .

Effect of cyclodextrin on the intramolecular catalysis of amide hydrolysis.

The hydrolysis reaction of phthalamic acids (HOOCArCONHR, R = p-NO(2)Ph 1a, Ph 1b, adamantyl 1c) and N-phenyl maleamic acid 2b was studied in the presence of hydroxypropyl-beta-cyclodextrin (HPCD) in acid solution. The reactions of 1a and 1b were studied also in the presence of beta-cyclodextrin (beta-CD). All the compounds formed inclusion complexes with HPCD, and the association constant was determined from the change in absorption of the substrate when the host is added in the case of 1a (90 M(-)(1)) and 2b (49 M(-)(1)). For 1c ( 4 x 10(4) M(-)(1)) a competition method was used, and for 1b the association equilibrium constant was obtained from the kinetic data (37 M(-)(1)) because it is too reactive for the spectrophotometric method. Both cyclodextrins strongly inhibited the reactions, and analysis of the kinetic data for HPCD indicated that the reactions of complexed 1a, 1b, and 2b are at least 10-30 times slower than in the bulk solution whereas 1c reacts only 4.6 times slower when it is complexed. The inhibition is attributed to changes in the geometry of the substrate due to interaction of the carboxylic group and/or the amide with the OH at the rim of the cyclodextrin. The differences in the relative effect observed for 1c are attributed to the formation of a tighter complex with this substrate.

Design, syntheses, and structure–Activity relationships of indan derivatives as endothelin antagonists; new lead generation of non-peptidic antagonist from peptidic leads

A new lead generation of non-peptidic ETA antagonists from two peptidic ETA-selective ones, BQ-123 and FR139317, was performed. Using computer assisted molecular modeling, a putative pharmacophore was constructed from the superposition of the reported three-dimensional structure of the cyclic peptide BQ-123 and a presumable β-turn active conformation of the linear peptide FR139317 formed by an intramolecular hydrogen bond. According to this model, a new series of indan derivatives were designed and synthesized. Among these, 5-isobutyrylamino-6-(1-naphthylmethyloxy)-3-(2-thienyl)-1-indancarboxylic acid (1b) showed a moderate ETA antagonistic activity (IC50=28 μM).

Facile synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid.

An SN2-type of substitution of (S)-bromide 4, which had been prepared from L-aspartic acid, with potassium thiobenzoate provided (R)-benzoylthio derivative 5 with complete inversion of the configuration. Compound 5 was converted, via iodide 6c, to (R)-4-amino-3-benzoylthiobutyric acid 8b. (R)-4-Mercapto pyrrolidine-2-thione 1 was readily obtained from 8b through cyclization with acetic anhydride, thionation with Lawesson's reagent and facile removal of the S-benzoyl group with sodium methoxide.

Synthesis, Hydrolysis, and Evaluation of 3-Acylamino-3,4-dihydro-2-oxo-2H-1,3-benzoxazinecarboxylic Acids and Linear Azadepsipeptides as Potential Substrates/Inhibitors of β-Lactam-Recognizing Enzymes

The title compounds can be considered as stabilized aza analogs of previously studied dihydrobenzopyranones and linear depsipeptides, which behave as substrates or inhibitors of β-lactamases. Treatment of substituted hydrazides 9b and 9b′ with a phosgene substitute resulted in a series of N-methylated 3-acylamino-3,4-dihydro-2-oxo-2H-1,3-benzoxazine-7- and -8-carboxylic acids 2b and 2b′. However, in the case of the corresponding free NH hydrazide 9a(m), a competitive cyclization gave instead a stable 4H-1,3,4-oxadiazol-5-one 10a. To avoid this unwanted cyclization, an N-(p-methoxy)benzylated hydrazide 9b′′ was prepared. After formation of the benzoxazinone ring with carbonyldiimidazole, the removal of this new N1-hydrazide protecting group was achieved with methanesulfonic acid in trifluoroacetic acid to give the expected 3-phenacetamido-3,4-dihydro-2-oxo-2H-1,3-benzoxazine-7-carboxylic acid 2a(m). The corresponding linear azadepsipeptides 5 were generally obtained by reaction of a hydrazide with 3-tert-butoxycarbonylphenyl chlorocarbonate. Hydrolysis of the title compounds in buffer at neutral pH was more rapid than anticipated because of the presence of mechanisms more facile than the classical BAC2. Hydrolysis of the cyclic azadepsipeptide 2a(m), for example, involved intramolecular nucleophilic participation by the amido side chain and a slowly hydrolyzing oxadiazolone intermediate (10a). These compounds, unlike their parent depsipeptides, were not substrates or inhibitors of β-lactamase or DD-peptidase. This result probably arises from a combination of the poor carbonyl electrophilicity and the close to planar geometry of the nitrogen atom of the oxazin-2-one ring.

Synthesis, Hydrolysis, and Evaluation of 3-Acylamino-3,4-dihydro-2-oxo-2H-1,3-benzoxazinecarboxylic Acids and Linear Azadepsipeptides as Potential Substrates/Inhibitors of β-Lactam-Recognizing Enzymes

The title compounds can be considered as stabilized aza analogs of previously studied dihydrobenzopyranones and linear depsipeptides, which behave as substrates or inhibitors of β-lactamases. Treatment of substituted hydrazides 9b and 9b′ with a phosgene substitute resulted in a series of N-methylated 3-acylamino-3,4-dihydro-2-oxo-2H-1,3-benzoxazine-7- and -8-carboxylic acids 2b and 2b′. However, in the case of the corresponding free NH hydrazide 9a(m), a competitive cyclization gave instead a stable 4H-1,3,4-oxadiazol-5-one 10a. To avoid this unwanted cyclization, an N-(p-methoxy)benzylated hydrazide 9b′′ was prepared. After formation of the benzoxazinone ring with carbonyldiimidazole, the removal of this new N1-hydrazide protecting group was achieved with methanesulfonic acid in trifluoroacetic acid to give the expected 3-phenacetamido-3,4-dihydro-2-oxo-2H-1,3-benzoxazine-7-carboxylic acid 2a(m). The corresponding linear azadepsipeptides 5 were generally obtained by reaction of a hydrazide with 3-tert-butoxycarbonylphenyl chlorocarbonate. Hydrolysis of the title compounds in buffer at neutral pH was more rapid than anticipated because of the presence of mechanisms more facile than the classical BAC2. Hydrolysis of the cyclic azadepsipeptide 2a(m), for example, involved intramolecular nucleophilic participation by the amido side chain and a slowly hydrolyzing oxadiazolone intermediate (10a). These compounds, unlike their parent depsipeptides, were not substrates or inhibitors of β-lactamase or DD-peptidase. This result probably arises from a combination of the poor carbonyl electrophilicity and the close to planar geometry of the nitrogen atom of the oxazin-2-one ring.

Self-Assembly of Amphoteric Azopyridine Carboxylic Acids: Organized Structures and Macroscopic Organized Morphology Influenced by Heat, pH Change, and Light

In this paper, we describe the synthesis of novel amphoteric azopyridine carboxylic acids (2b, 3a, 3b, 4a, and 4b), having both a carboxyl group as a hydrogen donor and a pyridyl group as an acceptor at each molecular terminus, and their self-organization, which is markedly affected by external stimuli including heat, pH changes, and light. The amphoteric compounds form intermolecular hydrogen bonds between pyridyl and carboxyl groups in a head-to-tail manner in the solid state to give linear pseudopolymer structures, as supported by FT-IR analysis. Heating and cooling across their melting points induced thermoreversible supramolecular depolymerization to and polymerization from small molecular components of monomers and the corresponding carboxylic acid dimers. In alkaline aqueous media, these amphoteric compounds, dissolved as carboxylate anions, were gradually neutralized by atmospheric carbon dioxide, leading to their deposition as novel fibrous materials from 3b and 4b, substituted with a propyl grou...

Efficient synthesis of ( S)-(−)- and ( R)-(+)-enantiomers of 15-deoxyspergualin (15-DSG)

An efficient synthesis of the ( S)-(−)- and ( R)-(+)-enantiomers of 15-deoxyspergualin (15-DSG) is reported. The synthesis involves preparative HPLC separation and subsequent hydrogenolysis of two diastereoisomers 10a and 10b of fully protected 15-DSG penultimates. Alternatively, diastereomerically pure amide 10b (97% de) was also prepared from acid 8b (97% de), which was obtained via crystallization of a 1:1 diastereomeric mixture of 8a and 8b.

Photoisomerization of Azobenzene Chromophores in Organic/Inorganic Zirconium Phosphonate Thin Films Prepared Using a Combined Langmuir−Blodgett and Self-Assembled Monolayer Deposition

The photoinduced trans to cis isomerization of two new azobenzene-derivatized phosphonic acids, 4-(4‘-(3‘ ‘-pentyloxy)phenyl)azophenylbutylphosphonic acid (2a) and 4-(4‘-propoxyphenyl)azophenylbutylphosphonic acid (2b), has been studied in zirconium phosphonate thin films. Multilayer films were assembled using a three-step combined Langmuir−Blodgett (LB) and monolayer self-assembly procedure that forms a layered metal phosphonate lattice in the polar region of asymmetric bilayers which are composed of octadecylphosphonate and the azobenzene chromophore. Multilayer films containing 2a and 2b undergo rapid and reversible photoisomerization. For both molecules, thermal relaxation of the cis form shows both fast- and slow-relaxing components that arise from cis isomers experiencing different degrees of strain in the films. The relaxation rates and the ratio of fast/slow relaxing components can be changed through synthetic modification of the chromophore and by altering the thin-film architecture. When the cis form of 2a is deposited directly, virtually all of the fast-relaxing component is eliminated, and the thermal half-life for cis to trans isomerization is greater than 11 h.

Cyclohexadienone diazeniumdiolates from nitric oxide addition to phenolates.

Sterically hindered phenols react with nitric oxide under basic condititons to give either cyclohexadienone diazeniumdiolates or oximates. Phenols with 2,6-di-tert-butyl and 4-methyl (butylated hydroxy toluene, BHT), 4-ethyl, or 4-methoxy methylene substituents yield the corresponding 2,6-di-tert-butyl-2, 5-cyclohexadienone-4-alkyl-4-diazeniumdiolate salts (4-methyl 1a, 4-ethyl 3a, 4-methoxymethylene 5a). Phenols with 2,6-di-tert-butyl and 4-methylene (2,6-di-tert-butylphenol) substituents yield 4-methoxymethylenediazeniumdiolate (5a) together with 2, 6-di-tert-butyl benzoquinone oximate (6a), while phenols with 2, 6-di-tert-butyl and 4-methylenedimethylamino or hydrogen substituents yield exclusively 2,6-di-tert-butyl benzoquinone oximate (6a). Alkylation of the silver salts of 1a, or treating the O(2)-protonated diazeniumdiolate with diazomethane, both yield mixtures of O(1)- and O(2)-methylated isomers. All the compounds exhibit exothermic thermal decomposition except the quinuclidinium (1e, 3e, 5e) and triethylenediammonium (1f) salts which decompose endothermically. Three of the compounds namely "O(2)-protonated" (Z)-1-[4-(2, 6-di-tert-butyl-4-methyl-cyclohexadienonyl)]diazen-1-ium+ ++-1, 2-diolinic acid (1b), O(2)-methyl (Z)-1-[4-(2, 6-di-tert-butyl-4-methyl-cyclohexadienonyl)]diazen-1-ium+ ++-1,2-diolate (1c), and "O(2)-protonated" (Z)-1-[4-(2, 6-di-tert-butyl-4-methoxymethylenecyclohexadienonyl)]diazen- 1-ium-1, 2-diolinic acid (5b) were characterized by single-crystal X-ray diffraction studies. The diazeniumdiolate framework in all the structures is coplanar with considerable pi-bonding delocalized over the O-N-N-O framework.

Discovery of novel and potent retinoic acid receptor alpha agonists: syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives.

In the course of our studies on retinoic acid receptor (RAR) agonists, we have designed and synthesized a series of benzofuran and benzothiophene derivatives. Some of these compounds (1a,b,e,f,j) markedly inhibited LPS-induced B-lymphocyte proliferation and exerted RARalpha selectivity. One of them, 4-[5-(4,7-dimethylbenzofuran-2-yl)pyrrol-2-yl]benzoic acid (1b), when orally administered significantly inhibited mouse antibody production and delayed type hypersensitivity (DTH) responses from a dose of 0.1 mg/kg.