Chiral organobases: Properties and applications in asymmetric catalysis

Chiral organobases are efficient catalysts used in asymmetric reactions. This review provided a summary of chiral organobases in the aspects of their properties and applications.     

Über die Reaktionen von monosubstituierten Guanidinen mit α,β-ungesättigten Ketonen

Action of methyl-, benzyl- and phenylguanidine on mesityloxide yields the 2-R ³-imino-4,4,6-trimethyl-1,2,3,4-tetrahydropyrimidines resp. 2-R³-aminopyrimidines8 b, c ande, cyclohexylidenacetone reacts with benzylguanidine to give the 2-benzylimino-4-methyl-1,3-diazaspiro[5.5]undeca-4-en resp. the benzylaminodiazaspiroundecadien (8 d). The isomeric 1- and 3-R³-pyrimidinimines (resp.-amines)9 b-e and10 b-e are not formed in the reaction. The structures were proved by spectroscopical and chemical methods.

Herrn Prof. Dr.G. Zigeuner zum 60. Geburtstag gewidmet.     

An efficient one-pot synthesis of functionally diverse 2-aminothiazoles from isothiocyanates,amidines/guanidines and halomethylenes

An efficient one-pot method for the synthesis of 2-aminothiazoles using simple starting materials like isothiocyanates, amidines/guanidines and various halomethylenes is reported. The synthesis of 2-aminothiazoles involves reactions such as nucleophilic addition, S-alkylation and intramolecular nucleophilic substitution in which amines departs as the leaving group.     

First iron-catalyzed guanylation of amines: a simple and highly efficient protocol to guanidines

The first iron-catalyzed guanylation of amines is reported. Commercially available Fe(OAc)₂ acts as an excellent catalyst for the addition of amines to carbodiimides. The reaction is broadly applicable to a variety of primary, secondary, and heterocyclic amines, and tolerates a wide range of functionalities allowing the easy preparation of a large family of guanidines. The low price and low toxicity of the commercially available iron catalyst make this methodology highly attractive.     

Eco-friendly methods of synthesis and preliminary biological evaluation of sulfonamide derivatives of cyclic arylguanidines

The chemotype of arylsulfonamide derivatives of cyclic arylguanidines is a source of molecules with valuable biological activities, including antimicrobial and antitumor properties. The methods of the synthesis presented in the literature are characterized with low selectivity and high environmental nuisance. In this publication, we present a developed alternative and earlier undescribed pathway C, for the synthesis of arylsulfonamide derivatives of cyclic arylguanidines (N-(1H-arylimidazol-2-yl)arylsulfonamides and N-(1,4-dihydroquinazolin-2-yl)arylsulfonamides), including reaction between 2-(methylsulfanyl)-benzimidazole or 2-(methylsulfanyl)-3,4-dihydroquinazoline with arylsulfonamides. We also optimized previously reported methods; A (reaction of 2-aminobenzimidazole or 2-amino-3,4-dihydroquinazoline with arylsulfonyl chlorides) and B (reaction of dimethyl-(arylsulfonyl)carbonodithioimidate with aryldiamines). The conducted research allowed achieving two independent ecological and quick methods of obtaining the desired products. We used ecological methods of ultrasound-assisted or microwave synthesis, solvent-free reactions and a “green” reaction environment. In both pathways, it has proven advantageous to use H₂O as the solvent and K₂CO₃ (1 or 3 equivalent) as the basic agent. In the sonochemical variant, the efficiency reached B: 37–89 %, C: 90 % in 60 min (P = 80 W and f = 40 kHz), while in the microwave synthesis it was B: 38–74 %, C: 63–85 % in 0.5–4 min (P = 50 W). Path A led to a complementary substitution product (i.e. 1-(arylsulfonyl)-1H-benzimidazol-2-amine or 1-(arylsulfonyl)-1,4-dihydroquinazolin-2-amine). We obtained a small group of compounds that were tested for cytotoxicity. The 10f (N-(1,4-dihydroquinazolin-2-yl)naphthalene-1-sulfonamide) showed cytotoxic activity towards human astrocytoma cell line 1321 N1. The calculated IC₅₀ value was 8.22 µM at 24 h timepoint (doxorubicin suppressed 1321 N1 cell viability with IC₅₀ of 1.1 µM). The viability of the cells exposed to 10f for 24 h dropped to 48.0 % compared to vehicle control, while the cells treated with doxorubicin experienced decline to 47.5 %. We assessed its potential usefulness in pharmacotherapy in the ADMET study, confirming its ability to cross the blood–brain barrier (Pe = 5.0 ± 1.5 × 10^-6 cm/s) and the safety of its potential use in terms of DDI and hepatotoxicity.     

The utilization of ball milling in synthesis of aryl guanidines through guanidinylation and N-Boc-deprotection sequence

Solid state ball milling was used in guanidinylation reactions of aromatic amines with N,N′-Di-Boc-1H-pyrazole-1-carboxamidine reagent. Reaction conditions are advantageous, and in general reactions proceed in significantly shorter reaction times and in higher yields than under the conventional solution conditions. Mechanochemical conditions were also successfully applied to the cleavage of N-Boc protecting group.     

Targeting nitric oxide synthase with Tc/Re-tricarbonyl complexes containing pendant guanidino or isothiourea moieties

The visualization of inducible nitric oxide synthase (iNOS) in vivo with specific radioactive probes could provide a valuable insight into the diseases associated with upregulation of this enzyme. Aiming at that goal, we have synthesized a novel family of conjugates bearing a pyrazolyl-diamine chelating unit for stabilization of the fac-[M(CO)₃]⁺ core (M = ^99mTc, Re) and pendant guanidino (L¹ = guanidine, L² = N-hydroxyguanidine, L³ = N-methylguanidine, L⁴ = N-nitroguanidine) or S-methylisothiourea (L⁵) moieties for iNOS recognition. L¹-L⁵ reacted with fac-[M(CO)₃(H₂O)]⁺, yielding complexes of the type fac-[M(CO)₃(k³-L)]⁺ (M = Re/^99mTc; 1/1a, L = L¹; 2/2a, L = L²; 3/3a, L = L³; 4/4a, L = L⁴; 5/5a, L = L⁵), which were fully characterized by the usual analytical methods in chemistry and radiochemistry, including X-ray diffraction analysis in the case of 1. The rhenium complexes 1-5 were prepared as “cold” surrogates of the ^99mTc(I) complexes. Enzymatic assays with murine purified iNOS demonstrated that L¹, L², 1 and 2 are poor NO-producing substrates. These assays have also shown that metallation of L⁴ and L⁵ (K_i > 1000 μM) gave complexes with increased inhibitory potency (4, K_i = 257 μM; 5, K_i = 183 μM). The organometallic rhenium complexes permeate through LPS-treated RAW 264.7 macrophage cell membranes, interacting specifically with the target enzyme, as confirmed by the partial suppression of NO biosynthesis (ca. 20% in the case of 4 and 5) in this cell model. The analog ^99mTc(I)-complexes 1a-5a are stable in vitro, being also able to cross cell membranes, as demonstrated by internalization studies in the same cell model with compound 4a (4h, 37 °C; 33.8% internalization). Despite not being as effective as the α-amino-acid-containing metal-complexes previously described by our group, the results reported herein have shown that similar ^99mTc(I)/Re(I) organometallic complexes with pendant amidinic moieties may hold potential for targeting iNOS expression in vivo.     

Novel triazinium-imidothioate zwitterions: intermediates in the reaction of [1,3,4]thiadiazolo[2,3-d][1,2,4]triazolo[1,5-a][1,3,5]triazinium cations with amines

Starting with bis([1,3,4]thiadiazolo)[1,3,5]triazinium halides 1, a novel class of heterocyclic compounds, the [1,3,4]thiadiazolo[2,3-d][1,2,4]triazolo[1,5-a][1,3,5]triazinium halides 5 were prepared. The reaction between 5 and primary or secondary amines 6 yielded highly substituted guanidines 8 and fused tricyclic bis([1,2,4]triazolo)[1,5-a:1′,5′-d][1,3,5]triazinium halides 9. The formation of the reactive triazinium-imidothioate zwitterions 7, which is controlled by the influence of negative hyperconjugation, was proven by NMR data and the X-ray structure of 7c. The subsequent ring-closure/ring-opening steps can be understood in terms of an S_N(ANRORC) process accompanied by intramolecular proton-transfer reactions. The zwitterions 7 were reacted with EtI forming cationic derivatives 10 or hydrolyzed at pH 6-7 to give novel heterocyclic ethanethioamides 11.     

Reaction of β-alkoxyvinyl α-ketoesters with acyclic NCN binucleophiles – Scalable approach to novel functionalized pyrimidines

Two protocols for synthesis of series of low-molecular-weight di- and tri-substituted pyrimidines bearing a functional group at the 4th position, which rely on a base-mediated condensation of amidines or guanidines with β-alkoxyvinyl α-keto esters, have been developed. This approach allowed for multigram preparation of novel pyrimidine-4-carboxylates in 21–90% yield. The synthetic utility of these compounds was demonstrated by some standard functional group transformations providing promising building blocks for organic synthesis and drug discovery.     

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.