N-triazinylammonium tetrafluoroborates. A new generation of efficient coupling reagents useful for peptide synthesis

A new generation of triazine-based coupling reagents (TBCRs), designed according to the concept of "superactive esters", was obtained by treatment of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium (DMTMM) chloride with lithium or silver tetrafluoroborate. The structure of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate was confirmed by X-ray diffraction. Activation of carboxylic acids by using this reagent proceeds via triazine "superactive ester". The coupling reagent was successfully used for the synthesis of Z-, Boc-, and Fmoc-protected dipeptides derived from natural and unnatural sterically hindered amino acids and for fragment condensation, in 80-100% yield and with high enantiomeric purity. The manual SPPS of the ACP(65-74) peptide fragment (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH) proceeded significantly faster than with TBTU or HATU, as well as the automated SPPS of the same fragment gave a purer product than by using TBTU or PyBOP. The reagent was also demonstrated to be efficient in on-resin head-to-tail cyclization of constrained cyclopeptides, in SPPS synthesis of Aib peptides, and in the synthesis of esters from appropriate acids, alcohols, and phenols. The high efficiency and versatility of this new generation of TBCRs confirm, for the first time, the usefulness of the concept of "superactive esters" in rational design of the structure of coupling reagents.     

Microwave-assisted synthesis utilizing supported reagents: a rapid and efficient acylation procedure

[reaction: see text] The application of microwave heating to a polymer-assisted solution-phase (PASP) synthesis technique has been utilized to develop a rapid and efficient protocol for the solution-phase synthesis of amides from either amine or carboxylic acid cores.     

Recyclable hypervalent iodine(III) reagent iodosodilactone as an efficient coupling reagent for direct esterification, amidation, and peptide coupling

A hypervalent iodine(III) reagent plays a novel role as an efficient coupling reagent to promote the direct condensation between carboxylic acids and alcohols or amines to provide esters, macrocyclic lactones, amides, as well as peptides without racemization. The regeneration of iodosodilactone (1) can also be readily achieved. The intermediate acyloxyphosphonium ion C from the activation of a carboxylic acid is thought to be involved in the present esterification reaction.     

Facile and efficient synthesis of 4-azidotetrafluoroaniline: a new photoaffinity reagent

p-Azidotetrafluoroaniline (1) was synthesized in 65-73% yield by two different methods employing a stable carbamate intermediate. The first method trapped the intermediate isocyanate generated via a modified Curtius rearrangement with 2-methyl-2-propanol or 2-(trimethylsilyl)ethanol to form the stable carbamates 2d and 2e, respectively. Benzoic acid 2c was first converted to its acid chloride with PCl(5). Displacement of the chloride by NaN(3) in acetone/water formed the acyl azide. Thermal rearrangement followed by the addition of the appropriate alcohols provided the carbamates. The acid labile carbamate 2d was deprotected with HCl/AcOH to provide 1, while trifluoroacetic acid was required to deprotect 2e and afford 1. In the second path, 1 was synthesized in five steps from pentafluoronitrobenzene (3a) in 65% overall yield. Compound 3a was converted into 4-azidotetrafluoronitrobenzene (3b) with NaN(3) in 93% yield and was used without further purification to form 1, 4-diaminotetrafluorobenzene (3c) by Sn/HCl reduction in 85% yield. The mono-9-fluorenylmethoxycarbonyl (FMOC) derivative 3d was formed from 3c with FMOC-Cl and pyridine in EtOAc in 92% yield. Diazotization of 3d under anhydrous conditions with TFA/NaNO(2) and NaN(3) gave 3e in 87% yield. The aryl azide was formed with concurrent nitration of the 2-position of the fluorenyl system. The protecting group was removed with piperidine to afford 1 in 93% yield. Irradiation of 1 with 254 nm light in cyclohexane gave cyclohexylamine 11, diamine 3c, and azobenzene 12 as the primary products. The formation of C-H insertion product 11 indicates that 1 forms a singlet nitrene upon photolysis. Two heterobifunctional photoaffinity reagents iodoacetamide 9 and dansyl derivative 10 were prepared.     

P-Triazinylphosphonium chlorides as a new group of coupling reagents

Tertiary phosphines in reaction with 2-chloro-4,6-dialkoxy-1,3,5-triazines gave unstable quaternary P-triazinylphosphonium chlorides, which readily decomposed with a departure of the alkyl group of the triazine ring substituent. Stable quaternary P-triazinylphosphonium chlorides were obtained only in reaction of 2-chloro-4,6-diphenoxy-1,3,5-triazine. Both, stable quaternary P-triazinylphosphonium chlorides as well unstable analogues prepared in situ activated carboxylic acid yielding “superactive” triazine esters, useful as highly efficient reagents in peptide bond synthesis.      

Polymer-supported Mukaiyama reagent: a useful coupling reagent for the synthesis of esters and amides

Polymer-supported N-alkyl-2-chloro pyridinium triflate was synthesized in one step from Wang resin. This reagent proved to be a very effective coupling reagent for the synthesis of esters or amides from carboxylic acids and alcohols or amines (primary and secondary). [reaction: see text]     

A new reagent for the efficient synthesis of disulfides from alkyl halides

Benzyltriethylammonium tetracosathioheptamolybdate [(C₆H₅CH₂N(Et)₃)₆Mo₇S₂₄] has been found to be a superior sulfur transfer reagent for the conversion of alkyl halides to the corresponding disulfides in excellent yields under very mild reaction conditions.     

Improved procedure for the preparation of deoxynucleoside phosphoramidites: Arylphosphoramidites as new convenient intermediates for oligodeoxynucleotide synthesis

A simplified procedure for the preparation of deoxynucleoside methyl- and arylphosphoramidites is described. Both types of phosphoramidites can be conveniently activated by N-methylaniline trifluoracetate for their use in oligodeoxynucleotide synthesis.     

Tetraethylammonium tetraselenotungstate: a new and efficient selenium transfer reagent for the chemoselective synthesis of functionalised diselenides

A variety of functionalised organodiselenides were prepared in excellent yields from the corresponding halides and activated alcohols on treatment with tetraethylammonium tetraselenotungstate 1 under very mild conditions.     

Silica triflate as an efficient reagent for the solvent-free synthesis of coumarins

Silica triflate,as a new silica-based reagent,can be used for the efficient synthesis of 4-substituted coumarins via a Pechmann reaction under solvent-free reaction conditions.All reactions were performed at 80℃in good to high yields.     

Organophosphorus and nitro-substituted sulfonate esters of 1-hydroxy-7-azabenzotriazole as highly efficient fast-acting peptide coupling reagents

Organophosphorus esters 9, 10, 14, and 15 prepared via reaction of diethyl- and diphenylphosphoryl chloride, di(o-tolyl)phosphinyl chloride, and 2,8-dimethylphenoxaphosphinyl chloride with HOAt are excellent coupling reagents for peptide synthesis which are generally superior to their uronium/guanidinium analogues and HOBt- or HODhbt-derived phosphate ester counterparts in minimizing loss of configuration during segment coupling. The phosphinyl analogues are more shelf-stable than the phosphoryl systems. The new reagents have been tested in segment couplings leading to two tripeptides (20, 21) and a hexapeptide 22. Outstanding utility is also shown for the solid-phase assembly of the ACP decapeptide. Similar results were obtained with the 2- and 4-nitro- and 2,4-dinitrophenylsulfonyl esters derived from HOAt.     

Highly efficient synthesis of peptides by rational utilization of novel coupling reagents

The efficiency of different peptide coupling reagents, including carbodiimides, HOBt or HOAt-derived uronium, phosphoni-um and immonium salts, halouronium, halophosphonium, 2-halopyridinium and 2-halothiazoliuim salts, was evaluated. The synthetic strategy for coded peptides andnonribosomal peptides was discussed with an emphasis on the rational selection of peptide coupling reagents.     

Hexachloroethane: a highly efficient reagent for the synthesis of chlorosilanes from hydrosilanes

A new and efficient chlorination protocol is presented for the preparation of chlorosilanes from hydrosilanes. A variety of chlorinating agents in combination with palladium(II) chloride as the catalyst are examined. Among them, hexachloroethane is found to be the best choice, furnishing the desired product in good to quantitative yields under mild conditions. Various hydrosilanes are used as starting materials to explore the scope of this reaction.     

PS-IIDQ: an efficient polymer-supported amide coupling reagent

Polystyrene-IIDQ is a polymer-supported coupling reagent that couples carboxylic acids to amines in good yields and high purity without the requirement of a pre-activation step. Importantly the order of addition of the amine, acid or coupling agent makes no difference to the efficiency of the coupling reaction and the reagent can be readily regenerated.     

PS-IIDQ: a supported coupling reagent for efficient and general amide bond formation

Polystyrene-IIDQ, a polymer-supported coupling reagent, was synthesized in three steps from Merrifield resin in 86% overall conversion. This reagent efficiently coupled carboxylic acids to amines in good yields and high purities, required no pre-activation step, and was tolerant of the order of reagent addition. PS-IIDQ was observed to be more efficient than polymer-supported carbodiimides (PS-EDC and PS-DCC) and gave higher yields than HATU for general amide bond formation, including the coupling of anilines and hindered substrates. When evaluated with five carboxylic acids and nine amines (including anilines and secondary amines) PS-IIDQ gave an average isolated yield of 73%.     

Polymer-supported distannanes: a new and efficient synthesis of highly effective reagents for iodine atom transfer cyclisations

Polymeric distannanes were synthesised by the cross-linking of polystyrene bound tin hydride functionalities using a palladium mediated dehydrogenative coupling. The polymers were characterised by spectroscopic methods (IR and ¹³C, ¹¹⁹Sn NMR) and elemental analysis and were successfully applied to two iodine atom transfer cyclisations, performing as well as solution based hexaalkylditin reagents and significantly better than previously reported polymer-supported ditin reagents.     

Novel proton acceptor immonium-type coupling reagents: application in solution and solid-phase peptide synthesis

A novel proton acceptor coupling reagent shows superiority to those described previously. The oxygen in the carbocation moiety confers more solubility to the reagent. Furthermore, it enhances coupling yields and decreases racemization, allowing the use of 1 equiv of base.     

A new and efficient one-pot procedure for the synthesis of 2-styrylquinolines

A one-pot combination of a modified Friedländer annulation and a Knoevenagel condensation provides 2-styrylquinolines in good to excellent yields. A variety of substrates are reacted in one-pot in the presence of 1-methylimidazolium trifluoroacetate ([Hmim]TFA).