A novel solid-phase synthesis of highly diverse guanidines: reactions of primary amines attached to the T2 linker

The reaction of primary amines with the T2 diazonium resin generates polymer-bound triazenes, which can in turn be acylated by the addition of isothiocyanate. The formed thioureas are readily transformed into the corresponding guanidines by the reaction with amines in the presence of mercury(II) oxide, tosyl chloride, or silver nitrate. This reaction sequence furnishes trisubstituted guanidines that are potentially useful pharmacophores.     

Taurine isothiocyanate: a versatile intermediate for the preparation of ureas, thioureas, and guanidines. Taurine-derived cyclodextrins

A versatile and expeditious synthesis of taurine-derived thioureas, ureas, and guanidines using taurine isothiocyanate as the key intermediate is reported. Thioureas were obtained by a one-pot two-step procedure starting from taurine by the isothiocyanation reaction with thiophosgene in aqueous THF, followed by coupling with aliphatic and aromatic amines. Desulfurization of thiourea derivatives with yellow mercury(II) oxide gave access to either taurine-containing ureas or guanidines in a one-pot three-step fashion. This methodology was successfully applied to the preparation of a cyclodextrin-derived thiourea and guanidine with a taurine residue in their structures.     

Combinatorial synthesis of heterocycles: solid-phase synthesis of 6-amino-2,4-dioxo-3,4-dihydro-1,3,5-triazine derivatives

A new solid-phase synthesis of trisubstituted 6-amino-2,4-dioxo-3,4-dihydro-1,3,5-triazines from a resin-bound amine component is described. The amine was readily converted to the corresponding polymer-bound S-methylthiopseudourea, which upon reaction with secondary amines gave the disubstituted guanidines. Cyclization of the polymer-bound guanidines with chlorocarbonylisocyanate afforded the triazinediones. The third point of diversity was introduced by the Mitsunobu reaction. The method is amenable for iterative combinatorial library generation.     

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.     

Solid-phase synthesis of urea and amide libraries using the T2 triazene linker

Starting from Merrifield resin, primary amines were immobilized in two steps by triazene linkage (T2-linker). While reaction with isocyanates gave rise to resin-bound urea derivatives, acylation by acid chlorides or anhydrides furnished amides bound to solid support via the nitrogen atom, therefore representing a novel backbone amide linker. Cleavage from the resin was conducted using dilute trimethylsilyl chloride or trifluoroacetic acid, respectively, to yield ureas and amines/amides in a library format (altogether 60 examples; manual synthesis: 17 ureas, 6 mono-alkylated ureas [including dihydroxylation and ozonolysis/Wittig reaction]; automated synthesis: 15 ureas, 15 amides) in high purities and good overall yields. The synthesis of a small library (4 x 4 member) was successfully conducted on a Bohdan Neptune synthesizer.     

CO2 deactivation of supported amines: does the nature of amine matter?

Adsorption of CO(2) was investigated on a series of primary, secondary, and tertiary monoamine-grafted pore-expanded mesoporous MCM-41 silicas, referred to as pMONO, sMONO, and tMONO, respectively. The pMONO adsorbent showed the highest CO(2) adsorption capacity, followed by sMONO, whereas tMONO exhibited hardly any CO(2) uptake. As for the stability in the presence of dry CO(2), we showed in a previous contribution [J. Am. Chem. Soc.2010, 132, 6312-6314] that amine-supported materials deactivate in the presence of dry CO(2) via the formation of urea linkages. Here, we showed that only primary amines suffered extensive loss in CO(2) uptake, whereas secondary and tertiary amines were stable even at temperature as high as 200 °C. The difference in the stability of primary vs secondary and tertiary amines was associated with the occurrence of isocyanate as intermediate species toward the formation of urea groups, since only primary amines can be precursors to isocyanate in the presence of CO(2). However, using a grafted propyldiethylenetriamine containing both primary and secondary amines, we demonstrated that while primary amines gave rise to isocyanate, the latter can react with either primary or secondary amines to generate di- and trisubstituted ureas, leading to deactivation of secondary amines as well.     

Efficient synthesis of ureas by direct palladium-catalyzed oxidative carbonylation of amines

A general synthesis of symmetrically disubstituted ureas and trisubstituted ureas by direct Pd-catalyzed oxidative carbonylation of primary amines or of a mixture of a primary and a secondary amine, respectively, with unprecedented catalytic efficiencies for this kind of process, is reported. Reactions are carried out at 90-100 degrees C in DME as the solvent in the presence of PdI(2) in conjunction with an excess of KI as the catalytic system and under 20 atm of a 4:1 mixture of CO and air. In some cases, working in the presence of an excess of CO(2) (40 atm) in addition to CO and air (60 atm total) had a beneficial effect on substrate reactivity and product yield. Cyclic five-membered and six-membered ureas were easily formed from primary diamines. The methodology has been successfully applied to the synthesis of pharmacologically active ureas, such as those deriving from alpha-amino esters or urea NPY5RA-972, a potent antagonist of the neuropeptide Y5 receptor.     

α-Haloalkyl Haloformates and Related Compounds 3.1 A Facile Synthesis of Symmetrical and Unsymmetrical Ureas via Chloromethyl Carbamates

Chloromethyl carbamates were prepared by the reaction of chloromethyl chloroformates with amines and found to produce mono-, symmetrically or unsymmetrically di-and trisubstituted ureas including their N-hydroxy and N-alkoxy derivatives in moderate to good yield.     

Efficient synthetic protocol for substituted guanidines via copper(I)-mediated intermolecular amination of isothiourea derivatives

Amination of S-methyl-N,N′-bis-Boc-isothiourea with either primary or sterically hindered secondary amines promoted by copper(I) chloride and K₂CO₃ gave N,N′-bis-Boc protected guanidines in good to excellent yields under mild reaction conditions.     

‘One-flask’ transformation of isocyanates and isothiocyanates to guanidines hydrochloride by using sodium bis(trimethylsilyl)amide

A ‘one-flask’ synthesis of guanidines was developed by reacting isocyanates and isothiocyanates with sodium bis(trimethylsilyl)amide followed by addition of primary or secondary amines with a catalytic amount of AlCl₃. The desired guanidines were obtained in good yields and the reaction was applicable to aliphatic and aromatic substrates. A plausible mechanism was proposed through the generation of cyanamide anion from isocyanates or isothiocyanates with sodium bis(trimethylsilyl)amide. Addition of amines and catalytic amount of AlCl₃ smoothly converted the cyanamides to the desired guanidines.     

N-arylation of primary and secondary aliphatic amines on solid supports

A general and mild method for the N-arylation of primary and secondary aliphatic amines is reported. Copper acetate, triethylamine mediated C/N cross-coupling reaction of arylboronic acids at room temperature to solid-supported primary and secondary amines gave good to excellent yields of the desired N-arylated products.     

The Preparation of 1,2,3‐Trisubstituted Guanidines

An operationally straightforward and efficient benzotriazole‐based method for the guanylation of diverse amines by use of the new reagent classes (bis‐benzotriazol‐1‐yl‐methylene)amines 13a – 13f and benzotriazole‐1‐carboxamidines 17a – 17i is described. The preparation is described for a variety of both acyclic and cyclic 1,2,3‐trisubstituted guanidines in high yields.     

Reaktionen von 5-diazourazilen mit primären aminen zu 1,2,3-triazolcarbonsäurederivaten

The reaction of 5-diazouracils with saturated primary amines affords [(1-alkyl-1,2,3-triazol-4-yl) carbonyl]ureas. The primary formation of a non-isolable 6-amine-adduct 2 is followed by 1,6-ring opening of the pyrimidone and ring closure to the triazole derivative.     

Solid-phase synthesis of substituted guanidines using a novel acid labile linker

A novel acid labile linker for solid-phase synthesis of substituted guanidines has been developed. Its synthetic utility is exemplified by high-yielding pyrazole displacement with structurally and electronically diverse sets of aliphatic and aromatic amines. The final cleavage is achieved by treatment with 95:5 trifluoroacetic acid/water for 1 h. The corresponding guanidines were obtained in high purity (80-95%) and good isolated yields (50-95%). The scope and limitations of this linker were further demonstrated by the solid-phase synthesis of an 880-member library of individual trisubstituted arylguanidines employing pyrazole displacement with a set of 11 anilines and two subsequent Mitsunobu N-alkylations with sets of 10 and 8 alcohols, respectively.     

Facile direct synthesis of unsymmetrical ureas from N-Alloc-, N-Cbz-, and N-Boc-protected amines using DABAL-Me3

A practical synthetic method for the direct synthesis of unsymmetrically substituted ureas from N-Alloc-, N-Cbz-, and N-Boc-protected amines is described. In this study, efficient direct conversion of the Alloc-, Cbz-, and Boc-carbamate compounds to ureas was achieved in the presence of DABAL-Me₃, an air stable and easily handled reagent. Using this reaction method, both protected aromatic and aliphatic amines were successfully transformed into various trisubstituted and tetrasubstituted ureas with high yields without side product. Our findings offer promising guidelines for direct preparation of useful ureas from N-Alloc-, N-Cbz-, and N-Boc-carbamates.     

The reaction of isocyanide—mercuric chloride complexes with amines. Preparation of guanidines

Isocyanide—mercuric chloride complexes react readily with an excess of primary and secondary amines to give guanidines and metallic mercury in high yields through a redox decomposition reaction. In the presence of triethylamine, isocyanide—mercuric chloride complexes react with an equimolar amount of a primary amine to give a carbodiimide and metallic mercury. An intermediate organomercuric compound was isolated in the reaction of the isocyanide—mercuric chloride complex with pyrrolidone.     

A general method for the solid-phase synthesis of unsymmetrical tri- and tetrasubstituted ureas

A general method for the preparation of unsymmetrical di, tri-, and tetrasubstituted ureas on polymer supports is presented. Polymer-bound primary and secondary amines react with imidazolium salts (urea donors), which are generated from the reaction of N,N'-carbonyldiimidazole (CDI) with primary and secondary amines followed by alkylation with MeI to give tri- and tetrasubstituted ureas in excellent yields (76-98%) and purities (80-99%).     

A simple one-pot synthesis of triflyl guanidines: access to highly substituted electron-poor guanidines

Unsymmetrical di- and trisubstituted triflyl guanidines are accessed through a simple, one-pot protocol from the corresponding isothiocyanate and amine. Furthermore, in the presence of base, trisubstituted triflyl guanidines are alkylated to obtain tetrasubstituted triflyl guanidines in high yields and complete regioselectivity.     

Synthesis of Trisubstituted Ureas by a Multistep Sequence Utilizing Recyclable Magnetic Reagents and Scavengers

Unprecedented magnetic borohydride exchange (mBER), magnetic Wang aldehyde (mWang) and magnetic amine resins were prepared from highly magnetic polymer‐coated cobalt or iron nanoparticles. Microwave irradiation was used to obtain excellent degrees of functionalization (>95 %) and loadings (up to 3.0 mmol g^?1) in short reaction times of 15 min or less. A small library of ureas and thioureas was synthesized by the exclusive application of these magnetic resins. As a first step, a reductive amination of aromatic and aliphatic aldehydes was carried out with mBER. The excess of primary amine needed to complete the reaction was subsequently scavenged selectively by mWang. Simple magnetic decantation from the resins resulted in secondary amines in good to excellent yields and purities. The used magnetic resins were efficiently regenerated and reused for the next run. In a second step, the secondary amines were converted to trisubstituted (thio)ureas in excellent yields and purities by stirring with an excess of iso(thio)cyanate, which was scavenged by addition of the magnetic amine resin after completion of the reaction. The whole reaction sequence is carried out without any purification apart from magnetic decantation; moreover, conventional magnetic stirring can be used as opposed to the vortexing required for polystyrene resins.     

Structure based library approach to photosynthesis inhibitors:Combinatorial synthesis of hydrouracil library

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