Pivaloyl Chloride Research Articles

Synthesis of P-Modified DNA from Boranophosphate DNA as a Precursor via Acyl Phosphite Intermediates.

In this study, we successfully synthesized several kinds of P-modified nucleic acids from boranophosphate DNAs via an acyl phosphite intermediate in solution and on a solid support. In the solution-phase synthesis, phosphorothioate diester, phosphotriester, and phosphoramidate diester were synthesized in a one-pot reaction from boranophosphodiester via the conversion of an acyl phosphite as a key intermediate. In addition, doubly P-modified nucleic acid derivatives which were difficult to synthesize by the phosphoramidite and H-phosphonate methods were also obtained by the conversion reaction. In the solid-phase synthesis, a boranophosphate derivative was synthesized on a solid support using the H-boranophosphonate method. Then, an acyl phosphite intermediate was formed by treatment with pivaloyl chloride in pyridine, followed by appropriate transformations to obtain the P-modified derivatives such as phosphotriester and phosphorothioate diester. Notably, it was suggested that the conversion reaction of a boranophosphate to a phosphorothioate diester proceeded with retention of the stereochemistry of the phosphorous center. In addition, a phosphorothioate/phosphate chimeric dodecamer was successfully synthesized from a boranophosphate/phosphate chimeric dodecamer using the same strategy. Therefore, boranophosphate derivatives are versatile precursors for the synthesis of P-modified DNA, including chimeric derivatives.

Alternate end-game strategies towards Nirmatrelvir synthesis: Defining a continuous flow process for the preparation of an anti-COVID drug

Scalable alternate end-game strategies for the synthesis of the anti-COVID drug molecule Nirmatrelvir (1, PF-07321332) have been described. The first involves a direct synthesis of 1 via amidation of the carboxylic acid 7 (suitably activated as a mixed anhydride with either pivaloyl chloride or T3P) with the amino-nitrile 10·HCl. T3P was found to be a more practical choice since the reagent promoted efficient and concomitant dehydration of the amide impurity 9 (derived from the amino-amide contaminant 8·HCl invariably present in 10·HCl) to 1. This observation allowed for the development of the second strategy, namely a continuous flow synthesis of 1 from 9 mediated by T3P. Under optimized conditions, this conversion could be achieved within 30 min in flow as opposed to 12–16 h in a traditional batch process. The final API had quality attributes comparable to those obtained in conventional flask processes.

Total synthesis of chaiyaphumines A-D: A case study comparing macrolactonization and macrolactamization approaches

A comparison of macrolactonization and macrolactamization approaches to the synthesis of the pentadepsipeptide chaiyaphumines is outlined. Fmoc-based solid-phase synthesis approaches were used for the synthesis of the requisite precursors. Attempted solution-phase macrolactonization of a seco-acid precursor using Yamaguchi, pivaloyl chloride, or MNBA activation did not give cyclized products. The use of an MNBA / lanthanide(III) triflate mediated macrolactonization protocol led to an isomeric macrocycle. However, the use of a solution-phase macrolactamization approach using EDC·HCl / HOBt was achieved without detectable epimerization. This strategy was successfully applied to the total synthesis of the antimalarial compound chaiyaphumine A, as well as the natural products chaiyaphumine B, C, and D, by using a late-stage acylation of the threonine amino group. An X-ray crystal structure analysis of synthetic chaiyaphumine D reveals the presence of a type II’ beta turn and a type IV4 beta turn motif embedded in the 16-membered depsipeptide ring. This study illustrates potential challenge associated with macrolactonization approaches to depsipeptides compared to macrolactamization.

Kilogram synthesis of pinoxaden

AbstractAn optimized kilogram‐scale synthetic route for pinoxaden was successfully developed. The key intermediate dimethyl 2‐(2,6‐diethyl‐4‐methylphenyl)malonate (19) was prepared from 2,6‐diethyl‐4‐methylaniline through diazotization reaction, Suzuki cross‐coupling reaction, and alcoholysis reaction in 59% yield over three steps in 97.3% purity. 1,4,5‐Oxadiazepane dihydrobromide (11) was obtained from diethylene glycol through esterification, cyclization, deprotection, and salification in 64% yield over three steps. Pinoxaden was given by aminolysis of 19 with 11, followed by acylation by pivaloyl chloride in 64% yield over two steps in 99.9% purity. Purification methods for the intermediates and the final product were developed.

Construction and Functionalization of Highly Strained N -Doped Zigzag Hydrocarbon Belts

Construction and Functionalization of Highly Strained <i>N</i> -Doped Zigzag Hydrocarbon Belts

Synthesis and Reaction of 2-Acetylamino-2’- Tellurocyanato-1,1’-Binaphthyl

2-Acetylamino-2’-tellurocyanato-1,1’-binaphthyl (1) was prepared from the reaction of potassium tellurocyanate with 2-acetylamino-[1,1’- binaphthalene]-2’-diazonium chloride. Treatment of 1 with hydrochloric acid gave bis(2-amino-1,1’-binaphthalene-2’-yl) ditelluride (2) in 65% yield. Reaction of 2 with phenylacetyl chloride and trimethylacetyl chloride gave bis(2-phenylacetylamino-1,1’-binaphthalene-2’-yl) ditelluride (3) and bis(2-trimethyl-acetylamino-1,1’-binaphthalene-2’-yl) ditelluride (4), respectively. (2-Acetylamino-1,1’-binaphthyl-2’-yl)tellurium tribromide (5) was prepared by reaction of 1 with bromine. Partial reduction of 5 gave the corresponding tellurenyl bromide (6) which in turn reacted with KCN to afford compound 1 in good yield. Alkaline hydrolysis of 1 or reduction of 5 and 6 with hydrazine hydrate in boiling ethanol gave bis (2-acetylamino-1,1’-binaphthalene-2’-yl) ditelluride (7) in good yield. All these new compounds were characterized by elemental analyses, IR, 1H and 13C NMR and mass spectrometry.

Lithiation and silylation of 7-amino-3-tert-butyl-4-oxopyrazolo[5,1-c][1,2,4]triazines

The treatment of 7-amino-8-bromo-3-tert-butylpyrazolo[5,1-c][1,2,4]triazin-4(6H)-one with an excess of NaH in THF and AlkLi (Alk = Bun, But) at -97 °C produced disodium (8-lithio-3-tert-butyl-4-oxopyrazolo[5,1-c][1,2,4]triazin-1-id-7-yl)amide unstable under ambient conditions. The chemical properties of the newly synthesized compound were studied. The electrophilic attack occurs at the N(1), C(7)—N, or C(8) ring positions depending on the nature of the electrophilic agent (PhCHO, ButCOCl, TMSBr). The treatment of the N(1)-Boc-protected derivative with BuLi resulted in the C(8)-metalation accompanied by the addition of alkyl at the carbonyl groups or at the N(2) atom. The low-temperature reaction with pivaloyl chloride was studied using deuterium labeling of the amino group, which confirmed the hydrogen atom transfer from the C(7)—NH group to the C(8) position of the heterocycle. The structures of the synthesized compounds were established by IR spectroscopy, 1H, 2H, 13C, and 2D 1H—29Si HMBC NMR spectroscopy, high-resolution mass spectrometry, and single-crystal X-ray dif raction.

Regioselective and stereocontrolled syntheses of protected L-glycosides from L-arabinofuranosides

Synthesis of novel mono- and di-O-protected l-arabinofuranoside derivatives was described via regioselective base-catalyzed acylations of methyl α- and β-l-arabinofuranosides with acyl chlorides. A new method for selective 3(2)-O-acylation of 5-O-silyl (trityl) l-arabinofuranosides was investigated based upon generation of organoboron compounds using l-Selectride and subsequent reaction of salt carbohydrate species with pivaloyl or 4-chlorobenzoyl chloride as the electrophile. Syntheses of methyl 2,3-anhydro-l-furanosides were accomplished from selectively protected methyl l-arabinofuranosides. 2(3)-Deoxy-l-pentofuranosides, including 2-deoxy-l-ribofuranoside, and their 5-O-blocked derivatives were prepared by stereoselective reductions of 2,3-anhydro-l-furanosides with l-Selectride.

Interface Reinforcement of Pulp Fiber Based ABS Composite with Hydrogen Bonding Initiated Interlinked Structure via Alkaline Oxidation and tert-Butyl Grafting on Cellulose.

Interface optimization in preparing natural fiber based biocomposite becomes a key factor that determines overall properties, especially mechanical performance. The solution for upgrading interfacial adhesion stemmed from polar fiber and nonpolar polymer remains unclear. Here, a kind of pulp fiber/acrylonitrile-butadiene-styrene (ABS) composite with content ratio of 1:1 was fabricated by functionalizing the cellulose fiber to coordinate interaction between fiber and ABS. With addition of 5 wt % polyacrylamide (PAM) there existed an interlinked three-element structure in composite. Three types of treatment to cellulose fiber, including alkali immersion, pivaloyl chloride grafting for 10 h and 20 h were conducted. Pulp fiber that was treated with alkali for one hour, followed by pivaloyl chloride reaction for ten hours, proved to be effective for interfacial adhesion. X-ray Photoelectron Spectroscopy (XPS) analysis reveals 21.9% of carbonyl and 12.1% of ester function in this fiber, which corresponds to oxidation and grafting. For its composite SEM picture displays that most of cellulose fiber are rooted in ABS and evident traces of tearing or fracture can be observed after tension test. DMA test indicates that this modified pulp fiber/ABS composite exhibits great compatibility, because of combined loss modulus peak ranging from 80 °C to 100 °C. Moreover, the well miscible composite has a tensile strength of 58.1 MPa and elastic modulus of 2515 MPa, increasing by nearly 50% and 60% from those of pure ABS, respectively.

Development of a Practical Synthesis of a Pyrimidine Derivative with Fungicidal Activity

A scalable synthesis of a pyrimidine fungicide lead was developed. The pyrimidine head, 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol, was prepared by metal–halogen exchange of 2-iodo-5-bromopyridine with i-PrMgCl followed by treatment with pivaloyl chloride (PivCl) in the presence of CuCN·2LiCl and subsequent addition of 5-lithiopyrimidine. The boronic acid tail, (4-(1-cyanocyclobutyl)-2-fluorophenyl)boronic acid, was prepared via treatment of 1-(4-bromo-3-fluorophenyl)cyclobutane-1-carbonitrile with i-PrMgCl and trimethylborate. The o-fluoro Grignard reagent formed during this reaction sequence was analyzed by two-drop calorimetry and accelerating rate calorimetry, which revealed minimal safety concerns for scale-up. Finally, the boronic acid tail was coupled with the pyrimidine head in the presence of catalytic palladium acetate [Pd(OAc)2]/triphenylphosphine (PPh3) to deliver the final product in >95% yield after crystallization.

Pivaloyl chloride as a new derivatization agent for parabens and its application in simultaneous derivatization and air-assisted liquid–liquid microextraction of the analytes in hygiene and personal care products

An air-assisted liquid–liquid microextraction method using of an extraction solvent (less dense than water) has been proposed for simultaneous derivatization and extraction of some p-hydroxybenzoic acid esters (parabens) in different samples before their determination with gas chromatography-flame ionization detection. The analytes are derivatized by a fast reaction occurring between parabens and pivaloyl chloride (as a derivatization agent) and extracted into toluene (as an extraction solvent) under mild conditions in a test tube. After performing the microextraction procedure, a home-made device (an inverse funnel having a capillary tube) is placed into the tube. A thin film of the extractant accumulated on the surface of the aqueous phase is transferred into the capillary part of the device. A fraction of the organic phase is removed by a microsyringe and injected into the separation system for analysis. Under optimum conditions, detection and quantification limits were between 0.60 and 1.0; and 1.7 and 3.1 ng mL−1 in solution; and 6.0 × 10−6 and 1.0 × 10−5; and 1.7 × 10−5 and 3.1 × 10−5 g kg−1 in solid, respectively. The enhancement and enrichment factors were obtained in the ranges of 492–650 and 380–410, respectively. Relative standard deviations were less than 6% (n = 6) for intra- and less than 9% (n = 4) for inter-day precisions calculated at a concentration of 50 ng mL−1 of each analyte. The calibration graphs were linear with coefficients of determination ≥ 0.994. Finally, the selected parabens were successfully analyzed in various hygiene and personal care products by the proposed method.

Uranyl Functionalization Mediated by Redox-Active Ligands: Generation of O-C Bonds via Acylation.

A series of uranyl compounds with the redox-active iminoquinone ligand have been synthesized, and their electronic structures elucidated using multinuclear NMR, EPR, electronic absorption spectroscopies, SQUID magnetometry, and X-ray crystallography. Characterization and analysis of the iminoquinone (iq0) complex, (dippiq)UO2(OTf)2THF (1-iq), the iminosemiquinone (isq1-) complex, (dippisq)2UO2THF (2-isq), and the amidophenolate (ap2-) complex, [(dippap)2UO2THF][K(18-crown-6)(THF)2]2(3-ap crown) show that reduction events are ligand-based, with the uranium center remaining in the hexavalent state. Reactivity of 2-isq with B-chlorocatecholborane or pivaloyl chloride leads to U-Ouranyl bond scission and reduction of U(VI) to U(IV) concomitant with ligand oxidation along with organic byproducts. 18O isotopic labeling experiments along with IR spectroscopy, mass spectrometry, and multinuclear NMR spectroscopy confirm that the organic byproducts contain oxygen atoms which originate from U-Ouranyl bond activation.

Syntheses and Structures of a Class of Bridged Bis(Amidinate)s and Derivatives

A series of different types of ‘bridge’ linked bis(amidinate)s have been prepared. Reactions of a variety of linked diamines with pivaloyl chloride yielded the corresponding diamides in very high yields. Conversion of the diamides to the diimine chloride is achieved with PCl5 in CH2Cl2. Reactions of the diimine chloride with aniline or t-butyl amine yielded the bis(amidinate)s in good yields, while reaction with pyrrolyl sodium or 2,5-dimethyl pyrrolyl potassium afforded the corresponding derivatives. Their structures were characterised by NMR and HRMS, and some products were further characterised by X-ray crystal structure analysis. It was found that the locations of the hydrogen atoms within the two amidine fragments vary. The structures showed that in the phenylene-linked bis(amidinate)s, the hydrogen atoms were attached to different nitrogen atoms in the amidine groups, and in the cyclohexylene-linked bis(amidinate)s or their derivatives, the C=N of the amidine groups were conjugated with the aromatic rings.

Regio- and stereoselective syntheses of l-pentose derivatives from l-arabinose

Novel l-arabinose, l-ribose, 2-deoxy-l-ribose and 2-fluoro-2-deoxy-l-arabinose derivatives were synthesized from readily available l-arabinose. Different synthetic routes to methyl 3,5-di-O-acylated-l-arabino(ribo)furanosides as valued intermediates for the preparation of C-2 functionalized l-pentoses were investigated via regioselective transformations of 1,2-di-O-acetyl-3,5-di-O-pivaloyl-l-arabinofuranose, and selective acylation of methyl l-arabinofuranoside with 4-chlorobenzoyl or pivaloyl chloride. Short three-five-step syntheses of methyl 2-deoxy-α-l-ribofuranoside, its 3,5-di-O-acyl derivatives, valuable precursors for preparation of antiviral 2′-deoxy-l-nucleosides, were accomplished via simple and efficient reduction of methyl 2-O-mesyl-l-arabinofuranoside with L-Selectride or tandem reaction involving a complex hydride 2-deoxygenation/acylation of intermediate 2-deoxysugar. A new synthesis of 2′-deoxy-2′-fluoro-β-l-arabinofuranosyl thymine (l-FMAU) was performed using a mild fluorination of protected l-ribofuranoside and a novel sequence of conversions for the preparation of 2-deoxy-2-fluoro-l-arabinofuranoside derivatives.

Syntheses of Amino-Substituted Iridabenzofurans and Subsequent Selective N-Functionalisation.

The first examples of amino-substituted fused-ring metallabenzenes, the cationic iridabenzofuran [Ir(C7 H4 O{NH2 -2}{OMe-7})(CO)(PPh3 )2 ][O3 SCF3 ] (5) and neutral analogue Ir(C7 H4 {NH2 -2}{OMe-7})Cl(PPh3 )2 (6), can be prepared by reduction of the corresponding nitro-substituted iridabenzofurans with zinc and concentrated hydrochloric acid. N-functionalised derivatives of 5 and 6 are formed through alkylation, sulfonylation or acylation. Thus, consecutive treatments with methyl triflate and base gives the corresponding trimethylammonium-substituted iridabenzofurans while sulfonamide derivatives are formed with p-toluenesulfonyl chloride. N-Acylation of 5 or 6 with acid chlorides, however, selectively form either amide or imide products depending on the charge on the metal and the steric size of the acid chloride. Cationic 5 gives amide substituted products regardless of the conditions whereas neutral 6 rapidly undergoes di-N-acylation with excess benzoyl chloride under mild conditions to give the imide-substituted product Ir(C7 H4 O{N[C(O)Ph]2 -2}{OMe-7})Cl(PPh3 )2 (13). Selective mono-acylation of 6 can be achieved with one equivalent of benzoyl chloride or with excess of the sterically congested pivaloyl chloride.

Synthesis of antimalarial amide analogues based on the plant serrulatane diterpenoid 3,7,8-trihydroxyserrulat-14-en-19-oic acid

A plant-derived natural product scaffold, 3,7,8-trihydroxyserrulat-14-en-19-oic acid (1) was isolated in high yield from the aerial parts of the endemic Australian desert plant Eremophila microtheca. This scaffold (1) was subsequently used in the generation of a series of new amide analogues via a one-pot mixed anhydride amidation using pivaloyl chloride. The structures of all analogues were characterized using MS, NMR, and UV data. The major serrulatane natural products (1–3), isolated from the plant extract, and all amide analogues (6–15) together with several pivaloylated derivatives of 3,7,8-trihydroxyserrulat-14-en-19-oic acid (16–18) were evaluated for their antimalarial activity against 3D7 (chloroquine sensitive) and Dd2 (chloroquine resistant) Plasmodium falciparum strains, and preliminary cytotoxicity data were also acquired using the human embryonic kidney cell line HEK293. The natural product scaffold (1) did not display any antimalarial activity at 10µM. Replacing the carboxylic acid of 1 with various amides resulted in moderate activity against the P. falciparum 3D7 strain with IC50 values ranging from 1.25 to 5.65µM.

A mixed anhydride approach to the preparation of sulfinate esters and allylic sulfones: Trimethylacetic p-toluenesulfinic anhydride

Abstract A reagent combination of toluenesulfinic acid and trimethylacetyl chloride affords a putative trimethylacetic p-toluenesulfinic anhydride. This reagent has been used to prepare a series of sulfinate esters from primary and secondary alcohols. In addition, the reagent was used to convert Baylis-Hillman substrates into allylic sulfones. Attempts to use the reagent to convert amines to sulfinamides were unsuccessful. In contrast, the use of 2-pyrrolidinone afforded N-p-toluenesulfinyl pyrrolidinone in 64% yield. The use of a chiral 4-benzyl-1,3-oxazolidinone or 4-benzyl-1,3-oxazolidine-2-thione led to the isolation of S-p-tolyl p-toluenethiosulfonate.

Enantioselective Cascade Reaction for Synthesis of Quinolinones through Synergistic Catalysis Using Cu-Pybox and Chiral Benzotetramisole as Catalysts.

In contrast to the well-studied asymmetric catalyzed synthesis of tetrahydroquinolines, the asymmetric methodologies toward 3,4-dihydroquinolin-2-ones are quite rare. Herein, the first asymmetric cascade reaction is reported between ethynyl benzoxazinanones and mixed-anhydrides generated from aryl acetic acids and pivaloyl chloride, based on synergistic catalysis. This allowed the formation of attractive 3,4-dihydroquinolin-2-ones bearing two vicinal chiral centers at C3 and C4 in high yields with excellent diastereo- and enantioselectivities. A plausible chiral induction model for this reaction was proposed. The utility of this methodology was exemplified by further elaboration of the cyclization products by removal of the N-protecting groups.

Transition-metal-free synthesis of 3-(1-pyrrolidinyl)quinolines and 3-(1-pyrrolidinyl)quinoline 1-oxides via a one-pot reaction of 3-(1-pyrrolidinyl)crotonates with nitrobenzenes.

A carbanion of tert-butyl 3-(1-pyrrolidinyl)crotonate adds to nitrobenzenes to form σH-adducts, which in the presence of pivaloyl chloride and triethylamine are converted into 3-(1-pyrrolidinyl)quinolines or 3-(1-pyrrolidinyl)quinoline 1-oxides depending on the nitrobenzene structure. This is the first methodology in which a quinoline ring is constructed from a substrate bearing a pyrrolidinyl ring. Starting from optically pure enamines, the method allows synthesis of the corresponding chiral products without racemisation.

Anti-inflammatory Activities and Gastric Ulcer-inducing Properties of Tetraacetylquercetin and Tetrapivaloylquercetin

Quercetin (3,3’4’,5,7-pentahydroxyflavone) has been reported to show anti-inflammatory activity. However, its low oral bioavailability limits the application of quercetin in therapy. Ester derivatives of quercetin have been reported to have higher bioavailability than quercetin. This research aimed to study the anti-inflammatory activities and gastric ulcer-inducing properties of tetraacetylquercetinas well as tetrapivaloylquercetin. Synthesis of tetra-acyl derivatives of quercetin was conducted using acetic anhydride or pivaloyl chloride in the presence of pyridine and the structure was confirmed by 1 H-NMR and 13 C-NMR spectroscopy as well as elemental analysis. At a dose of 20 mg/kg bw, oral administration of quercetin only showed 20% inhibition activity on carragenan induced rat paw edema, while tetraacetyl and tetrapivaloyl derivatives at equimolar dose showed 11-33% and 5-15% inhibition activity respectively. Contrary to the gastric ulcer healing-promoting action of quercetin, tetraacetylquercetin caused mild gastric ulcers. However, no gastric ulcer was observed after administration of tetrapivaloylquercetin. It was concluded that acylation enhances the anti-inflammatory activity of quercetin but causes mild gastric ulcers in the case of tetraacetylation.