A synthesis of esters, amides, and sulfones bearing a 1-cyclopentenyl group at the α-position from cyclobutanones with one-carbon ring-expansion

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from cyclobutanones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters, lithium enolate of carboxylic acid N,N-dimethylamides, or lithium α-carbanion of alkyl phenyl sulfones gave adducts in high yields. The adducts were treated with isopropylmagnesium chloride or ethylmagnesium chloride in dry toluene to give esters, amides, and sulfones bearing a 1-cyclopentenyl group at the α-position in moderate to good yields with one-carbon ring-expansion via magnesium carbenoid 1,2-CC insertion reaction. The magnesium carbenoid 1,2-CC insertion reaction proved to be highly stereospecific. The reaction mechanism and origin of the specificity are described.     

Nuclear magnetic resonance studies of internal rotation. V—Rotational barriers of acetylenic amides

The rotational barriers about the C? N bond of the N,N-dimethylamides of propiolic, methylpropiolic and phenylpropiolic acids have been determined by the iterative total line shape nuclear magnetic resonance method.     

An effective synthesis of N,N-dimethylamides from carboxylic acids and a new route from N,N-dimethylamides to 1,2-diaryl-1,2-diketones

Carboxylic acids were heated at 150 °C in DMF in the presence of 1.25 equiv of thionyl chloride to give corresponding N,N-dimethylamides in good yields. Tandem chlorination and amidation reactions occurred in the one-pot procedure. Dicarboxylic acids needed prolonged reaction time to produce bisamides in good yields. Some benzamides were efficiently converted into corresponding 1,2-diaryl-1,2-diketones (benzils) under acyloin condensation conditions in the presence of 4,4′-di-tert-butylbiphenyl (DBB) in THF. Ultrasonic irradiation effectively accelerates the reaction, but it is not critical. However, the presence of DBB is fatal to the reaction. Although a few synthetic methods for benzils from benzoic acids have been reported so far, this method is one of the most convenient and highly reproducible procedures.     

Domino condensation/aza-Michael/O→N acyl migration of carbodiimides with activated α,β-unsaturated carboxylic acids to form hydantoins

Activated α,β-unsaturated carboxylic acids undergo an unexpected domino condensation/aza-Michael/O→N acyl migration with carbodiimides, producing N,N-disubstituted hydantoins in good yields. An array of structurally varied aspartic acid-derived hydantoins, including some fluorinated derivatives, have been synthesized by this method, whose scope and limits are discussed.     

A novel solid-phase synthesis of di- and trisubstituted N-acyl ureas

A novel, mild method for the synthesis of di- and trisubstituted N-acyl ureas on solid support is described. Addition of carboxylic acids to a resin-bound carbimidoyl chloride gave, initially, an O-acyl isourea which subsequently rearranged to the corresponding N-acyl urea. Trisubstituted N-acyl ureas were assembled on a Wang resin from a wide range of Fmoc amino acids, secondary amines and carboxylic acids. Acid mediated cleavage yielded the products in good yields and excellent purities. In addition, the regioselective synthesis of disubstituted N-acyl ureas is demonstrated with four examples.     

An expedient route for the reduction of carboxylic acids to alcohols employing 1-propanephosphonic acid cyclic anhydride as acid activator

A simple and efficient method for the synthesis of alcohols from the corresponding carboxylic acids is described. Activation of carboxylic acid with 1-propanephosphonic acid cyclic anhydride (T3P) and subsequent reduction using NaBH₄ yield the alcohol in excellent yields with good purity. Reduction of several alkyl/aryl carboxylic acids and N^α-protected amino acids/peptide acids as well as N^β-protected amino acids was successfully carried out to obtain corresponding alcohols in good yields. All the products were fully characterized by ¹H NMR and mass spectral analyses. The procedure is mild, simple and the isolation of the products is easy.     

Isocyanide based multicomponent reactions of oxazolidines and related systems

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxyethylamino acid amide products are obtained both via a three- or four-component approach from N-alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethylamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated using an ¹⁸O labelling experiment. The carboxylic acid component can be replaced by a range of other acidic nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-aminotetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicomponent reaction products.     

Alkylation reactions of benzothiazoles with N,N-dimethylamides catalyzed by the two-component system under visible light

Eosin Y/K₂S₂O₈ catalyzed C2-alkylation reactions of benzothiazoles with N,N-dimethylamides under visible light have been developed. The reactions completed smoothly in the presence of Eosin Y as the photocatalyst and K₂S₂O₈ as the oxidant under solvent-free conditions in open air. This green and simple method provides an alternative route for the synthesis of C2-alkylation of benzothiazoles and tolerates a number of functional groups to afford moderate to excellent yields.     

Evaluation of a series of prolylamidepyridines as the chiral derivatization reagents for enantioseparation of carboxylic acids by LC–ESI–MS/MS and the application to human saliva

Mass spectrometry has become a popular analytical tool because of its high sensitivity and specificity. The use of a chiral derivatization reagent for the mass spectrometry (MS) detection seems to be efficient for the enantiomeric separation of racemates. However, the number of chiral reagents for the liquid chromatography (LC)–MS/MS analysis is very limited. According to these observations, we are currently in the process of developing novel labeling reagents for chiral molecules in MS/MS analysis. The derivatization reagent that is effective for enhancing not only the electrospray ionization–MS/MS sensitivity but also the reversed-phase LC resolution of carboxylic acid enantiomers should have a highly proton-affinitive moiety and an asymmetric structure near the reactive functional group. Furthermore, the resulting derivative has to provide a characteristic product ion suitable for the selected reaction monitoring. Based upon these considerations, a series of prolylamidepyridines ((S)-N-pyrrolidine-2-carboxylic acid N-(pyridine-2-yl)amide (PCP2), (S)-N-pyrrolidine-2-carboxylic acid N-(pyridine-3-yl)amide, and (S)-N-pyrrolidine-2-carboxylic acid N-(pyridine-4-yl)amide) was synthesized as ideal labeling reagents for the enantioseparation of chiral carboxylic acids and evaluated in terms of separation efficiency and detection sensitivity by ultra-performance LC (UPLC)–MS/MS. Among the synthesized reagents, PCP2 was the most efficient chiral derivatization reagent for the enantioseparation of carboxylic acid. The Rs values and the detection limits of the derivatives of non-steroidal anti-inflammatory drugs, which were selected as the representative carboxylic acids, were in the range of 2.52–6.07 and 49–260 amol, respectively. The sensitive detection of biological carboxylic acids (detection limits, 32–520 amol) was also carried out by the proposed method using PCP2 and UPLC–MS/MS. The PCP2 was applied to the determination of carboxylic acids in human saliva. Several biological carboxylic acids, such as lactic acid (LA), 3-hydroxybutylic acid, maric acid, succinic acid, α-ketoglutalic acid, and citric acid, were clearly identified in the saliva of healthy persons and diabetic patients. Furthermore, the ratio of d-LA in diabetic patients was higher than that in normal subjects. Judging from these results, PCP2 seems to be a useful chiral derivatization reagent for the determination not only of chiral, but also achiral, carboxylic acids in real samples.

Indium- and zinc-mediated Barbier-type allylations of an N,N-(dimethylsulfamoyl)-protected aldimine and subsequent deprotection

Barbier-type Zn and In-mediated allylations of an N,N-(dimethylsulfamoyl)-protected aldimine with different allyl bromides were investigated for the preparation of N-homoallylic sulfamides. The desired N,N-(dimethylsulfamoyl)-protected products were obtained in moderate to high yields in THF as the optimal solvent. Their further derivatization was demonstrated by a facile preparation of a functionalized dehydropiperidine by an allylation/olefin metathesis reaction sequence. A high yielding deprotection of the N,N-dimethylsulfamoyl group was likewise demonstrated.     

N-Sulfonyl acetylketenimine as a highly reactive intermediate for synthesis of N-Aroylsulfonamides

A highly reactive intermediate N-sulfonyl acetylketenimine was generated from an ynone-participated CuAAC/ring-opening method. Its unique structure allowed it to react with aryl carboxylic acids to give N-aroylsulfonamides via a novel Mumm-type rearrangement.     

P′CP′-Pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines

The P′CP′-pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines with allyl(tributyl)stannane is investigated for the preparation of N-homoallylic sulfamides. The desired N,N-dimethylsulfamoyl-protected products are obtained in moderate to high yields in DMF under very mild conditions and a high yielding and convenient deprotection of the N,N-dimethylsulfamoyl group is also demonstrated.     

Photoacid generators (PAGs) based on N-acyl-N-phenylhydroxylamines for carboxylic and sulfonic acids

Simple and efficient photoacid generators (PAGs) for carboxylic and sulfonic acids based on N-acyl-N-phenylhydroxylamines have been demonstrated. Irradiation of o-carboxylates and thermally rearranged o-arenesulfonates of N-acyl-N-phenylhydroxylamines using UV light (≥254 nm) in aqueous methanolic solution resulted in efficient generation of carboxylic and sulfonic acids, respectively. The carboxylic acid generation ability of N-acyl-N-phenylhydroxylamines was found to be dependent on their N-acyl substituents. Further, polymer bearing o-arenesulfonates of N-acyl-N-phenylhydroxylamine was synthesized and demonstrated as PAG for sulfonic acids.     

TsNBr2 promoted decarboxylative bromination of α,β-unsaturated carboxylic acids

A rapid process for decarboxylative bromination of α,β-unsaturated carboxylic acids have been developed using N,N-dibromo-p-toluenesulfonamide (TsNBr₂). Treatment of cinnamic acids with TsNBr₂ in presence of potassium carbonate in acetonitrile produces corresponding β-bromostyrenes at room temperature. Exclusive formation of (E)-β-bromostyrenes was observed in a stereoselective manner within a very short period of time (5–15?min). This method was further extended for obtaining 1-bromoalkynes from corresponding propiolic acids. Instantaneous formation of bromoalkynes was observed when the reaction was carried out in presence of DBU as a base in acetonitrile at room temperature. A wide variety of cinnamic acids and propiolic acids could be converted to corresponding β-bromostyrenes and 1-bromoalkynes respectively under mild reaction condition with high to excellent yield.     

Hydroxylamines and sulfinamide as amine components in the Petasis boronic acid-Mannich reaction: synthesis of N-hydroxy or alkoxy-α-aminocarboxylicacids and N-(tert-butyl sulfinyl)-α-amino carboxylicacids

An efficient synthesis of N-hydroxy or alkoxy-α-aminocarboxylic acids and N-(tert-butyl sulfinyl)-α-amino carboxylic acids has been developed from N,O-alkyl or hydroxylamines and tert-butyl sulfinamide utilizing a Petasis boronic acid-Mannich reaction. The scope and limitations of this method have been examined.     

Unsymmetrisch substitutierte N,N-bisphosphinomethyl- und N-phosphinomethyl-N-thiomethyl-α-aminosäuren

Unsymmetrically substituted chiral N,N-bis(phosphinomethyl)-α-amino acid derivatives are formed by interaction of N-phosphinomethylamino acids with secondary phosphines and formaldehyde. Nucleophilic cleavage of N-phosphinomethyloxazolidine carboxylic acids with secondary phosphines is another method to obtain unsymmetrically substituted chiral biphosphine derivatives.     

Synthesis of <Emphasis Type="Italic">N,N</Emphasis>-Diethylhydrazine and Its Reactions with Carboxylic Acids and Alkyl Halides

N,N-Diethylhydrazine was synthesized by a modified procedure via nitrosation of diethylamine, followed by reduction of the resulting N-nitrosodiethylamine with zinc amalgam in a hydrochloric acid medium. Reactions of N, N-diethylhydrazine with carboxylic acids and alkyl halides resulted in formation of the corresponding hydrazinium salts.     

Intramolecular easily polarizable hydrogen bonds with anilides of 1-piperidine carboxylic acids

IR spectra are plotted from anilides of 1-piperidine carboxylic acids C₅H₁₀N(CH₂)_n CONHC₆H₄R in CHCl₃ and CDCl₃ solutions. In the cases of n = 1 and n = 4, weak intramolecular (NH?N) hydrogen bonds are formed. An asymmetrical energy surface occurs and the proton is present at the N of the anilide group. In the cases of n = 2 and n = 3, intramolecular proton transfer hydrogen bonds of the types N_BH?N_P ? ^?N_B?H⁺N_p are formed. In contrast to the intramolecular OH? N ? O^?1 ? H⁺N bonds with 1-piperidine carboxylic acids, these bonds to not cause IR continua but two bands: one in the region 3250–3190 and one in the region 2500–2450 cm^?1. The fact that, instead of IR continua, bands are observed is explained by the following: (1) these hydrogen bonds are relatively long; (2) they show only a narrow distribution of bond length; (3) the electrical fields at these bonds are small, since they are strongly screened.     

Identification and determination of carboxylic acids in food samples using 2-(2-(anthracen-10-yl)-1H-phenanthro[9,10-d]imidazol-1-yl)ethyl 4-methylbenzenesulfonate (APIETS) as labeling reagent by HPLC with FLD and APCI/MS

A new labeling reagent for carboxylic acids, 2-(2-(anthracen-10-yl)-1H-phenanthro[9,10-d]imidazol-1-yl)ethyl 4-methylbenzenesulfonate (APIETS) has been designed and synthesized. It was used to label eight fatty acids (lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid and linolenic acid) and four hydroxy pentacyclic triterpene acids (oleanolic acid, ursolic acid, betulinic acid and maslinic acid), successfully. APIETS could easily and quickly label carboxylic acids in the presence of K₂CO₃ catalyst at 85 °C for 35 min in N,N-dimethylformamide solvent. The carboxylic acids derivatives were separated on a C₈ reversed-phase column with gradient elution and fluorescence detection at λ_ex/λ_em = 315/435 nm. Identification of these derivatives was carried out by online mass spectrometry with atmospheric pressure chemical ionization in positive ion mode. The detection limits obtained were 13.37-30.26 fmol (signal-to-noise ratio of 3). The proposed method has been applied to the quantification of carboxylic acids in sultana raisin (Thompson seedless), hawthorn flake (Crataegus pinnatifida Bge.), Lycium barbarum seed oil and Microula sikkimensis seed oil with recoveries over 95.3%. It has been demonstrated that APIETS is a prominent labeling reagent for determining carboxylic acids with high performance liquid chromatography.     

Synthesis of dipeptides from N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione activated α-amino acids

A simple two step procedure for the synthesis of a dipeptide from N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione (HO-ASUD) activated α-amino acids is described. In presence of DCC, N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione readily esterifies the carboxylic acid group of all the N-protected amino acids to yield crystalline N-hydroxy-3-aza spiro[5,5]undecane-2,4-dione activated carboxy ester. The N-hydroxy-3-aza spiro[5,5]undecane-2,4-dione activated carboxy esters of N-protected amino acids readily condensed with other amino acids and gave a dipeptide. This new method is effective for the DCC coupling of a variety of chiral amino acids without loss of enantiomeric purity. Synthesis of fifteen dipeptides including the hitherto unreported Fmoc-l-Orn(Boc)-Val-OMe, Fmoc-l-Cys(trt)-Gly-OEt and Boc-l-Tyr-Gly-OEt is presented.