Routes of functionalized guanidines. Synthesis of guanidino diesters

Abstract

Six general methods for the synthesis of acyclic and cyclic guanidines, of structures 1 and 2 and bearing a variety of substituents, are described. These guanidines may be symmetrical or unsymmetrical, and the substituents they bear provide the basis for further chemical manipulation. The acyclic guanidines are derived from single carbon intermediates, such as 3, 9, 13, and 14, and the appropriately substituted amine. The cyclic guanidines result from the functionalization of a 2-p-toluenesulfonamidopyrimidine which is subsequently hydrogenated. Use of the tosyl as B protecting group reduces the effects of the strongly alkaline guanidine moiety, and its facile removal is achieved with hydrogen fluoride. Detosylation of the tosyl-protected guanidino diester 12 resulted in formation of the imidazolin-4-one 51; this reaction proved to be general for the guanidines 1, 2 = 1, and 2, z = 1, 2. These imidazolinones underwent deuterium exchange for which a mechanism involving the formation of a mesoionic intermediate is proposed.

A Synthesis of (+)-Saxitoxin

“…The preparation of the desired nine-membered ring guanidine 1 follows from oxathiazinane 4 through a series of straightforward functional group transformations (Scheme ). Notable steps in this sequence include the assembly of pseudothiourea 6 using MeS(Cl)CNMbs, a reagent specifically formulated for this work . In addition, sequential reaction of oxathiazinane 6 with Cl 2 CNMbs and (Me 3 Si) 2 NH installs the first of two guanidines while serving to activate the heterocyclic ring for subsequent hydrolytic opening. , Collectively, the conversion of 4 to 8 covers 11 steps and provides a stereodefined acyclic intermediate bearing all of the required components for assembling the tricyclic framework of STX.…”

Syntheses of and structural assignments for some N-phosphono-2-iminoimidazolidines (cyclic guanidines)

“…Surprisingly, only one phosphorylated product could be detected and isolated, and it was identical to the sole product of the creatine kinase-catalyzed phosphorylation of l. 5 The natural abundance, proton-decoupled carbon-13 NMR spectrum of this product was examined. The chemical shift assignments are shown below (relative to dioxane): either 10 or 11 were hydrolyzed, Ar-(2-benzylaminoethyl)glycine dihydrochloride (12) was produced. In analogy to the synthesis of l,5 intermediate 12 was then converted to 7 by treatment with cyanogen bromide in aqueous solution.…”

“…A variety of conditions, described elsewhere,9 were used in unsuccessful attempts to phosphorylate 7. Scheme II shows a successful route to the unequivocal synthesis of l-carboxymethyl-2-(diphenoxyphosphinylimino) imidazolidine (13), the diphenyl ester of 3. The scheme was patterned after syntheses of other cyclic guanidines by Bosin et al 12 The use of the powerful methylating agent, methyl fluorosulfonate,13 was found to be necessary for the conversion of 14 to 15. Intermediate 17 was purified by the unusual procedure of chromatography over silica gel of its sodium salt, using methanol as eluent.…”

“…AT-(2-Benzylaminoethyl)glycine Dihydrochloride (12). This compound was obtained by hydrolysis of either l-benzyl-2-ketopiperazine (10) itself (method 1) or its IV-tosyl derivative 11 (method 2).…”

Guanidines from ‘toxic substances’ to compounds with multiple biological applications – Detailed outlook on synthetic procedures employed for the synthesis of guanidines

“…Microwave-assisted synthesis of highly functionalized guanidines on soluble polymer support © 2012 Elsevier Ltd. 51 Synthesis of novel functionalized guanidines and their different reactions have also been extensively carried out by many research groups, employing different approaches. Including the synthesis of dicarbethoxyguanidine, [103] nitroguanidine, [104] nitrotriarylguanidines, [105] N 1 -(6 -Methoxy-8-quinolylaminoalkyl-)guanidines, [106] 1-(Alky1amino)-guanidines, [107] N-alkyl-N'-carboalkoxy guanidines, [108] guanidino diesters, [109] N-guanidino-modified arginines, [110] radioabeled guanidines, [111] pyranosyl nucleosides with guanidine functionality, [112] phosphinyl guanidines, [113] guanidinium chlorides, [114] phase transfer catalyzed alkylation of guanidines, [115] N-triflyl guanidines, [116] cyclic guanidines, [117], [70] monocyclic guanidines, [118] bicyclic guanidines, [25], [119] tricyclic guanidines, [120] tetracyclic guanidines, [121] macrocyclic guanidines, [122] and polycyclic guanidines. [123] …”