Acid-catalyzed Decarboxylation Research Articles

An efficient approach for the synthesis and antimicrobial evaluation of some new benzocoumarins and related compounds

A convenient synthetic approach for pharmaceutically important benzocoumarin-based heterocyclic compounds has been studied. β-enaminonitrile has been used for the synthesis of a broad diversity of new benzocoumarins and related compounds over different reaction steps. Various synthetic approaches were used in this research for synthesis of heterocyclic systems such as acid-catalyzed hydrolysis, decarboxylation, deamination, ring opening and ring closure. The molecular structures of the newly synthesized derivatives were established by elemental analyses and spectral data (IR, 1H-NMR, and 13C-NMR). Some of the newly synthesized compounds were explored for their antimicrobial activities.

Product identification and the mechanisms involved in the transformation of cefazolin by birnessite (δ-MnO2)

Cefazolin, a widely used cephalosporin antibiotic in human therapy, was the target in this study. Manganese dioxide, which is abundant in soils and sediments, is one of the most important natural oxidants and catalysts. To better understand the fate of cephalosporin antibiotics in natural soils and sediments, the transformation of cefazolin with manganese dioxide (δ-MnO2) was investigated. Four major transformation products formed via the oxidation of thioether and olefin, hydrolysis and acid-catalyzed decarboxylation were identified, and plausible transformation pathways were proposed. The formation of transformation product species was found to be pH dependent due to the different oxidation abilities of δ-MnO2 under different pH conditions. The sulfoxide-type products formed in this study were previously reported to exhibit high genotoxicity. Therefore, the potential ecological risk of cefazolin transformation in natural sediments and soils is sufficient to merit concern.

How Acid-Catalyzed Decarboxylation of 2,4-Dimethoxybenzoic Acid Avoids Formation of Protonated CO2.

The decarboxylation of 2,4-dimethoxybenzoic acid (1) is accelerated in acidic solutions. The rate of reaction depends upon solution acidity in a manner that is consistent with the formation of the conjugate acid of 1 (RCO2H2(+)), with its higher energy ring-protonated tautomer allowing the requisite C-C bond cleavage. However, this would produce the conjugate acid of CO2, a species that would be too energetic to form. Considerations of mechanisms that fit the observed rate law were supplemented with DFT calculations. Those results indicate that the lowest energy pathway from the ring-protonated reactive intermediate involves early proton transfer from the carboxyl group to water along with C-C bond cleavage, producing 1,3-dimethoxybenzene and CO2 directly.

DFT investigation on the decarboxylation mechanism of ortho hydroxy benzoic acids with acid catalysis.

A density functional theory (DFT) study was performed to explore the mechanisms of the acid-catalyzed decarboxylation reaction of salicylic acids using the B3LYP method with 6-31++G(d,p) basis set in both gas phase and aqueous environment. The α-protonated cation of carboxylate acid was formed during the decarboxylation process in acidic conditions, and the presence of hydrogen ions promotes decarboxylation greatly by significantly decreasing the overall reaction energy barriers to 20.98kcalmol(-1) in gas phase and 20.93kcalmol(-1) in water, respectively. The hydrogen in the α-carbon came directly from the acid rather than from the carboxyl group in neutral state. Compared with the reaction in gas phase, water in aqueous state causes the reaction to occur more easily. Substituents of methyl group, chlorine and fluorine at the ortho-position to the carboxyl of salicylic acid could further lower the decarboxylation energy barriers and facilitate the reaction.

Carbon Kinetic Isotope Effects Reveal Variations in Reactivity of Intermediates in the Formation of Protonated Carbonic Acid

Kinetic evidence suggests that acid-catalyzed decarboxylation reactions of aromatic carboxylic acids can occur by a hydrolytic process that generates protonated carbonic acid (PCA) as the precursor of CO2. Measurements of reaction rates and carbon kinetic isotope effects (CKIE) for decarboxylation of isomeric sets of heterocyclic carboxylic acids in acidic solutions reveal that C-C cleavage to form PCA is rate-determining with significant variation in the magnitude of the observed CKIE (1.018-1.043). Larger values are associated with the more reactive member in each isomeric pair. This variation is consistent with stepwise mechanisms in which C-C cleavage is competitive with C-O cleavage, leading to reversion to the protonated reactant to varying degrees with an invariant intrinsic CKIE for C-C cleavage. Thus, the relative barriers to reversion and formation of PCA control the magnitude of the observed CKIE in a predictable manner that correlates with reactivity. Application of the proposed overall mechanism reveals that carboxylation reactions in acidic solutions will proceed by way of initial formation of PCA.

Density functional theory study of the mechanism of the acid-catalyzed decarboxylation of pyrrole-2-carboxylic acid and mesitoic acid

The mechanisms of the acid-catalyzed decarboxylation of pyrrole-2-carboxylic acid and mesitoic acid have been investigated based on density functional theory calculations at the B3LYP/6-311G (d, p) level. A polarizable continuum model (PCM) has been established in order to evaluate the effects of solvents on these reactions. The results of the calculations indicate that the first step of the acid-catalyzed decarboxylation of the pyrrole-2-carboxylic acid has two possible pathways, that is, the proton of H3O+ attacks either the α-carbon atom or the carboxyl oxygen atom. The subsequent process of forming a four-membered ring transition state is the rate-determining step. The activation energies of acid-catalyzed decarboxylation of pyrrole-2-carboxylic acid proceeding via attack at the α-carbon atom and the carboxyl oxygen atom are determined to be 194.21 and 210.41 kJ/mol, respectively. The computational results show that both pathways are favored. However, for the reaction of mesitoic acid with H3O+, the reaction barrier for the former pathway is calculated to be 212.15 kJ/mol, whilst the latter pathway has a reaction barrier of 200.45 kJ/mol. Our computational results are consistent with the experimental observations of Mundle and Kluger.

Hydrolytic Decarboxylation of Carboxylic Acids and the Formation of Protonated Carbonic Acid

Acid-catalyzed decarboxylation reactions of carboxylic acids should avoid formation of protonated carbon dioxide, a very high energy species. A potential alternative route parallels ester hydrolysis, with addition of water to the carboxyl group followed by protonation of the unsaturated leaving group and formation of protonated carbonic acid, a species that had been predicted to be a viable reaction intermediate. The hydrolytic mechanism for the decarboxylation of pyrrole-2-carboxylic acid is consistent with observed (12)C/(13)C kinetic isotope effects (1.010 +/- 0.001 at H(0) = -0.01 and 1.043 +/- 0.001 at H(0) = -2.6), solvent kinetic isotope effects (k(H(2))(O)/k(D(2))(O) = 2 at H(0) = 0.9; k(H(2))(O)/k(D(2))(O) = 1 at H(0) = -2.9), and activation parameters [DeltaH() = 23.5 kcal.mol(-1) and DeltaS() = 5.5 cal.deg(-1).mol(-1) at H(0) = -2.9]. Thus, the specific route for a decarboxylation process is a consequence of the nature of the potential carbanion (or its conjugate acid), the acidity of the medium and avoidance of formation of protonated carbon dioxide.

Transient Kinetic Studies Support Refinements to the Chemical and Kinetic Mechanisms of Aminolevulinate Synthase

5-Aminolevulinate synthase catalyzes the pyridoxal 5'-phosphate-dependent condensation of glycine and succinyl-CoA to produce carbon dioxide, CoA, and 5-aminolevulinate, in a reaction cycle involving the mechanistically unusual successive cleavage of two amino acid substrate alpha-carbon bonds. Single and multiple turnover rapid scanning stopped-flow experiments have been conducted from pH 6.8-9.2 and 5-35 degrees C, and the results, interpreted within the framework of the recently solved crystal structures, allow refined characterization of the central kinetic and chemical steps of the reaction cycle. Quinonoid intermediate formation occurs with an apparent pK(a) of 7.7 +/- 0.1, which is assigned to His-207 acid-catalyzed decarboxylation of the alpha-amino-beta-ketoadipate intermediate to form an enol that is in rapid equilibrium with the 5-aminolevulinate-bound quinonoid species. Quinonoid intermediate decay occurs in two kinetic steps, the first of which is acid-catalyzed with a pK(a) of 8.1 +/- 0.1, and is assigned to protonation of the enol by Lys-313 to generate the product-bound external aldimine. The second step of quinonoid decay defines k(cat) and is relatively pH-independent and is assigned to opening of the active site loop to allow ALA dissociation. The data support important refinements to both the chemical and kinetic mechanisms and indicate that 5-aminolevulinate synthase operates under the stereoelectronic control predicted by Dunathan's hypothesis.

Nucleic Acid Related Compounds. 136. Synthesis of 2-Amino- and 2,6-Diaminopurine Derivatives via Inverse-Electron-Demand Diels-Alder Reactions

Thermal inverse-electron-demand Diels-Alder reactions of 5-aminoimidazoles and 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine (2) with spontaneous retro-Diels-Alder loss of ethyl cyanoformate and elimination of ammonia give 2,6-bis(ethoxycarbonyl)purines. A report that selective alkaline hydrolysis followed by acid-catalyzed decarboxylation gave 6-(ethoxycarbonyl)purine products was not in harmony with known reactions in purine chemistry. Our reinvestigation has shown that the 6-(ethoxycarbonyl) group undergoes preferential base-promoted hydrolysis, as expected, but regioselectivity for attack of hydroxide at the carbonyl group at C6 is not high (relative to hydrolysis of both C2 and C6 esters). The structure of 9-benzyl-2-(ethoxycarbonyl)purine was determined by X-ray crystallography and confirmed by Curtius rearrangement of the azidocarbonyl analogue to give 2-amino-6-benzylpurine. Acid-catalyzed decarboxylation of the 2,6-dicarboxylate formed during hydrolysis gave 9-benzylpurine, and Curtius rearrangement of 2,6-bis(azidocarbonyl)-9-benzylpurine gave 2,6-diamino-9-benzylpurine. Attempted applications of inverse-electron-demand Diels-Alder reactions of 2 with nucleoside derivatives were problematic.

Investigation of the enzymatic and nonenzymatic cope rearrangement of carbaprephenate to carbachorismate.

The dimethyl esters of carbaprephenate and 4-epi-carbaprephenate were prepared by modification of published procedures. In methanol these compounds are converted quantitatively to isomeric 6-hydroxytricyclo[3.3.1.0(2,7)]non-3-en-1,3-dimethyl esters via a two-step sequence involving an initial Cope rearrangement, followed by intramolecular Diels-Alder reaction of the dimethyl carbachorismate or 4-epi-carbachorismate intermediates. Carbaprephenate and its epimer were obtained by alkaline hydrolysis of the corresponding dimethyl esters. These compounds, in contrast to their ester precursors, undergo spontaneous acid-catalyzed decarboxylation in aqueous solution. Only at high pH does the Cope rearrangement compete with decarboxylation. At pH 12 and 90 degrees C, carbaprephenate slowly rearranges to carbachorismate, which rapidly loses water to give 3-(2-carboxyallyl)benzoic acid as the major product. A small amount of the intramolecular Diels-Alder adduct derived from carbachorismate is also observed by NMR as a minor product. Carbaprephenate is not a substrate for the enzyme chorismate mutase from Bacillus subtilis (BsCM), nor does carbaprephenate inhibit the normal chorismate mutase activity of this enzyme, even when present in 200-fold excess over chorismate. Its low affinity for the enzyme-active site is presumably a consequence of placing a methylene group rather than an oxygen atom proximal to the essential cationic residue Arg90. Nevertheless, BsCM variants that lack this cation (R90G and R90A) do not accelerate the Cope rearrangement of carbaprephenate either, and a catalytic antibody 1F7, which exhibits modest chorismate mutase activity, is similarly inactive. Poor substrate binding and the relatively high barrier for the Cope compared to the Claisen rearrangement presumably account for the lack of detectable catalysis. Acceleration of this sigmatropic rearrangement apparently requires more than an active site that is complementary in shape to the reactive substrate conformer.

Approaches to the synthesis of some tyrosine-derived marine sponge metabolites: synthesis of verongamine and purealidin N.

The oxidation of tyrosine ethyl ester (7) with Na(2)WO(4)/H(2)O(2) in ethanol, dimethyldioxirane in acetone, or methyltrioxorhenium/H(2)O(2) in EtOH gave the corresponding tyrosine oxime (8) in high yield. Controlled bromination of the aromatic ring gave the monobromo oxime (9), the dibromo oxime (10), or the spiroisoxazoline (11) depending upon reaction conditions. Synthesis of the known metabolite verongamine (15) was achieved by oxidation of O-methyl bromotyrosine methyl ester and amidation of the resulting oxime ester (14) with histamine. The mono- and di-bromotyrosine oxime derivatives (9 and 10) were further transformed into the naturally occurring nitriles (16 and 17) by base hydrolysis of the ester and acid-catalyzed decarboxylation. Wadsworth-Emmons olefination of the dibromobenzaldehyde (20b) with phosphonate (18) gave the pyruvate silylenolether (21b). Deprotection and in situ oxime formation gave the oxime ester (23b). Attempted purification of the pyruvate ester resulted in a homoaldol condensation yielding butenolide (22). Amidation of the oxime ester (23b) with histamine, followed by deprotection of the MOM ether gave the first synthesis of purealidin N (28). Oxidative spirocyclization of the phenolic oxime ester (23d) with a polymer-bound iodosyl diacetate gave the spiroisoxazoline (24) and represents a formal synthesis of aerothionin (26a), homoaerothionin (26b), and aerophobin-1 (25).

The kinetics of the acid-catalysed decarboxylation of cis-[Co([15]aneN 4)CO 3]+ ([15]aneN 4=1,4,8,12-tetra-azapentadecane)

The decarboxylation of [Co( [15]aneN 4)CO 3] + in nitric acid solutions has been studied in detail over a temperature range at I=1.0 mol dm −3. The reaction is biphasic, the initial reaction is the carbonato ring opening step, which is followed by very rapid decarboxylation of the monodentate carbonato intermediate. The second step is the isomerisation of cis-[Co( [15]aneN 4)CO 3] + to the trans-isomer. At constant hydrogen ion concentration, values of k obs for the carbonato ring opening reaction are given by k obs= k o+ k H[H +], where k o relates to the spontaneous water hydrolysis and k H to the acid-catalysed process. The temperature dependence of k H gives ΔH †=71±2 J K −1 mol −1 and ΔS † 298= −66±6 J K −1 mol −1. The solvent deuterium isotope effect for the acid-catalysed decarboxylation k D2 O\\ kH2 O is 2.35, which is consistent with a rapid pre-equilibrium protonation of the carbonato ring, followed by rate-determining ring opening. The mechanisms of these reactions are considered in detail. At 25°C, the rate constant for the isomerisation reaction is 4.9×10 −6 s −1 and is independent of the acidity in the range [H +]=0.05 to 0.5 mol dm −3 at I=1.0 mol dm −3.

The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D 5W or D 5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH<2.0) prior to administration of ranitidine and increased gastric pH (pH>6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 μM) with only 4/30 levels detectable after D 5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D 5W pretreatment ( P<0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH.

2,2-Dimethylsuccinic acid derivatives in isoprenoid synthesis: a 2,2-dimethylvinyl anion equivalent in the synthesis of ar-atlantone, ar-turmerone, and prenylated aromatic compounds

The anion of methyl 2,2-dimethylsuccinate was alkylated with benzylic bromides to give the corresponding 3-substituted-2,2-dimethylsuccinates. Hydrolysis to the dicarboxylic acids, followed by bisdecarboxylation with lead tetraacetate, afforded 1-aryl-3-methyl-2-butenes, which are model prenylated aromatic compounds. Acylation of methyl 2,2-dimethylsuccinate with E-3-(4′-methylphenyl) crotonyl chloride gave the substituted succinate 9. Hydrolysis of the ester groups and acid-catalyzed decarboxylation of the resulting β-ketoacid produced the keto acid 10, which was decarboxylated by the Kochi method, furnishing ar-atlantone. Hydrogenation of 10 yielded 12, which on similar decarboxylation afforded ar-turmerone.

Improved preparation of the clathrate host compound tri-o-thymotide and related trisalicylide derivatives

In order to improve the relatively low yield (ca. 35%) previously observed in the synthesis of tri-o-thymotide (TOT, 1) from o-thymotic acid (2)d, the cyclodehydration was studied using a variety of conditions. The low yield is due to the formation of di-o-thymotide (DOT, 3), previously reported, and at least three other products (4-6), which apparently result from the acid-catalyzed decarboxylation of 2 and subsequent condensation with thymol (7). Using pyridine as a solvent, side-product formation is inhibited. Under appropriate conditions, namely, neat POCl 3 at 50°C, the yield of 1 is 93%. Other salicylic acid derivatives also give high yields of the corresponding «trimers» under these conditions, thus providing a general, improved preparation of a family of potential clathrate host substances

Carbon Dioxide: A Reagent for the Simutaneous Protection of Nucleophilic Centers and the Activation of Alternative Locations to Electrophlic Attack. 16. A Novel Synthetic Method for the Side-Chain Functionalization of N-Methyl-o-toluidine and for the Preparation of 2-Substitiuted N-Methylindoles

N-Methyl-o-toluidine is readily converted into a range of side-chain functionalized derivatives in a one-pot sequence, using carbon dioxide for N-protection. The intermediate lithium carbamate is further lithiated by butyllithium at the side-chain methyl group, and then reacted with an electrophile; the product undergoes acid-catalyzed decarboxylation during work-up. 2-Substituted N-methylindoles are produced when carboxylate esters are used as electrophiles. The yields are good, and no ring-substituted products are detected

Carbon dioxide: A reagent for the protection of nucleophilic centers and the simultaneous activation of alternative locations to electrophilic attack: 15. A synthetic method for the α-substitution of N-phenylbenzylamine

N-Phenylbenzylamine has been converted into a variety of α-substituted derivatives in one-pot sequences,using carbon dioxide both for N-protection and a-carbon activation,and then subsequent lithiation at the a-carbon atom by either tert-or n-butyllithium.The resulting lithium carbamate reacts with electrophiles,followed smooth acid-catalyzed decarboxylation under mild condition to give α-substituted N-phenylbenzylamines in good yields.

A theoretical study on the mechanism of the thermal and the acid-catalyzed decarboxylation of 2-oxetanones (.beta.-lactones)

A theoretical study on the mechanism of the thermal and the acid-catalyzed decarboxylation of 2-oxetanones (.beta.-lactones)

Detection of non-typical porphyrin isomers in human urines by ion-pair reversed-phase high-performance liquid chromatography

An improved ion-pair reversed-phase high-performance liquid chromatographic system has been developed for the separation of uroporphyrin isomers I, II and III, whereas the isomers III and IV could not be resolved. Application of this method to the analysis of urines from porphyric patients indicated the presence of small amounts of the non-typical uroporphyrin isomer II. The questionable presence of the isomer IV was confirmed by acid-catalyzed decarboxylation to the corresponding coproporphyrin isomers, which were completely separated by a modified ion-pair method at elevated column temperatures. These procedures enabled the detection of small fractions of the atypical isomers II (1–3%) and IV (8–15%) besides the normal isomers I and III in urines of patients suffering from attacks of acute intermittent porphyria. Because such urines contain large amounts of porphobilinogen, the non-enzymatic self-condensation of porphobilinogen to uroporphyrinogens was studied under mild reaction conditions. In these experiments quite similar isomeric compositions were observed as compared to those in urines of patients with acute intermittent porphyria. Thus the non-typical uroporphyrin isomers II and IV present in human urines originate from a simple non-enzymatic condensation of porphobilinogen.

Carbon dioxide: A reagent for the protection of nucleophilic centres and the simultaneous activation of electrophilic attack: Part II. A new synthetic method for the 1-substitution of 1,2.3,4-tetrahydroisoquinolines

Tetrahydroisoquinoline was converted into several 1-substituted derivatives by using carbon dioxide both for N-protection and to give an intermediate carbanion stabilizing group. t-Butyllithium was used as a lithating agent at the alphacarbon atom of the secondary amino group. The resulting 1-substituted 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acids underwent smooth acid-catalysed decarboxylation under mild conditions.