Bicyclic Guanidine Research Articles

Determinative role of ring size and substituents in highly selective synthesis of functionalized bicyclic guanidine and tetra substituted thiophene derivatives based on salt adducts afforded by cyclic thioureas and ketene dithioacetal

The condensation of organic salt adducts generated by cyclic thioureas and 2-di(methylsulfanyl)methylenemalononitrile with dialkyl acetylenedicarboxylates selectively leads to either tetrasubstituted thiophenes (2 examples) or hitherto unreported bicyclic guanidine (13 examples) derivatives, with controlling factors being ring size, the substituent on the S-methylisothiourea and the bulk of the substituent on the dialkyl acetylenedicarboxylates. Green solvents, short reaction time; easy purification, high yield and selectivity, are key feature of this protocol in the condensation step. The performances of the reactions in the presence of free-base and a catalyst at room temperature is unprecedented in the synthesis of thiophene frameworks and functionalized bicyclic guanidine scaffolds.

Photoinduced Cross-Linking of Dynamic Poly(disulfide) Films via Thiol Oxidative Coupling.

Initially developed as an elastomer with an excellent record of barrier and chemical resistance properties, poly(disulfide) has experienced a revival linked to the dynamic nature of the S-S covalent bond. A novel photobase-catalyzed oxidative polymerization of multifunctional thiols to poly(disulfide) network is reported. Based solely on air oxidation, the single-step process is triggered by the photodecarboxylation of a xanthone acetic acid liberating a strong bicyclic guanidine base. Starting with a 1 μm thick film based on trithiol poly(ethylene oxide) oligomer, the UV-mediated oxidation of thiols to disulfides occurs in a matter of minutes both selectively, i.e., without overoxidation, and quantitatively as assessed by a range of spectroscopic techniques. Thiolate formation and film thickness determine the reaction rates and yield. Spatial control of the photopolymerization serves to generate robust micropatterns, while the reductive cleavage of S-S bridges allows the recycling of 40% of the initial thiol groups.

De Novo Asymmetric Synthesis of (+)-Monanchorin.

A de novo asymmetric total synthesis of the guanidine alkaloid natural product (+)-monanchorin has been achieved in nine steps from the commodity chemicals furan and caproic acid. The asymmetry of the route was introduced by a Noyori reduction of an acylfuran. In addition, this route relies upon an Achmatowicz rearrangement, a diastereoselective palladium catalyzed glycosylation, reductive amination, and an acid catalyzed bicyclic guanidine mixed acetal formation.

Diboranyl Phosphonium Cations: Synthesis and Chemical Properties

AbstractHydride abstraction from the diborane [HB(hpp)]2 (hpp = 1,3,4,6,7,8‐hexahydro‐2H‐pyrimido[1,2‐a]pyrimidinate) followed by base stabilization led to the first (highly water sensitive) diboranyl phosphonium cations of the general formulas [HB(hpp)2BPR3]+ and [HB(hpp)2BPHR2]+. The B–P bond strength could be varied over a relatively large range by choice of the substituents R on the phosphine. The cation [HB(hpp)2BPCy3]+ (Cy = cyclohexyl) was structurally characterized. The PCy3 base of this cation could be substituted by a stronger base (a carbene or a bicyclic guanidine). In solution, [HB(hpp)2BPCy3]+ very slowly decomposes, and [HB(hpp)3BH]+ was identified as one of the decomposition products.

Unconventional Bifunctional Lewis-Brønsted Acid Activation Mode in Bicyclic Guanidine-Catalyzed Conjugate Addition Reactions.

DFT calculations have demonstrated that the unconventional bifunctional Brønsted-Lewis acid activation mode is generally applicable to a range of nucleophilic conjugate additions catalyzed by bicyclic guanidine catalysts. It competes readily with the conventional bifunctional Brønsted acid mode of activation. The optimal pro-nucleophiles for this unconventional bifunctional activation are acidic substrates with low pKa, while the best electrophiles are flexible 1,4-diamide and 1,4-diester conjugated systems.

A Metal‐Free Synthesis of N‐Aryl Carbamates under Ambient Conditions

AbstractThe first chemo‐ and site‐selective process for the formation of N‐aryl‐carbamates from cyclic organic carbonates and aromatic amines is reported. The reactions proceed smoothly under extremely mild reaction conditions using TBD (triazabicyclodecene) as an effective and cheap organocatalyst, thus providing a sustainable and new methodology for the formation of a wide variety of useful N‐aryl carbamate synthons in good to excellent yields. Computational investigations have been performed and show the underlying reason for the observed unique reactivity as related to an effective proton‐relay mechanism mediated by the bicyclic guanidine base.

A Metal-Free Synthesis of N-Aryl Carbamates under Ambient Conditions.

The first chemo- and site-selective process for the formation of N-aryl-carbamates from cyclic organic carbonates and aromatic amines is reported. The reactions proceed smoothly under extremely mild reaction conditions using TBD (triazabicyclodecene) as an effective and cheap organocatalyst, thus providing a sustainable and new methodology for the formation of a wide variety of useful N-aryl carbamate synthons in good to excellent yields. Computational investigations have been performed and show the underlying reason for the observed unique reactivity as related to an effective proton-relay mechanism mediated by the bicyclic guanidine base.

Soluble paramagnetic Ru26+ paddlewheels with alkyl-substituted bicyclic guanidinates

Syntheses are reported for two diruthenium compounds having the formula Ru2(TRhpp)4Cl2, where R=Me (1) and Et (2) and TRhpp is the anion of a tetraalkyl-substituted bicyclic guanidinate. The Ru26+ core of 1 is enclosed by four tetramethyl-substituted bicyclic guanidinates and two chlorine atoms positioned along the Ru–Ru axis. Each compound possesses two unpaired electrons at ambient temperature consistent with a formal bond order of three and a σ2π4δ2π∗2 (Q8π∗2) electronic configuration. The compounds are EPR-silent as determined by examination of frozen dichloromethane solutions at 77K using an X-band spectrometer. There is a short Ru–Ru distance of 2.2896(15)Å.

Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization Intramolecular-Diels-Alder Reaction: The First Catalytic Enantioselective Total Synthesis of (+)-alpha-Yohimbine.

Hydroisoquinoline derivatives were prepared in moderate to good enantioselectivities via a bicyclic guanidine-catalyzed tandem isomerization intramolecular-Diels-Alder (IMDA) reaction of alkynes. With this synthetic method, the first enantioselective synthesis of (+)-alpha-yohimbine was completed in 9 steps from the IMDA products.

Mechanistic insights into bicyclic guanidine-catalyzed reactions from microscopic and macroscopic perspectives.

Chiral bicyclic guanidine can act as an efficient chiral Brønsted base catalyst in enantioselective reactions, delivering good yields with high enantioselectivities. There is interest in understanding the detailed mechanisms of these guanidine-catalyzed reactions. Herein, we performed a detailed kinetic study of three different types of chiral bicyclic guanidine-catalyzed reactions, determining the bifunctionality of our guanidine catalyst. Although these three reactions share a similar catalytic cycle, their intrinsic kinetic behaviors are significantly different from each other because of the difference in the rate-determining step. The calculated theoretical rate expression for each reaction, as a result of the mechanism elucidated with density functional theory calculations, agrees well with the respective experimentally observed rate equation.

ChemInform Abstract: Synthetic Strategies for Preparing Bicyclic Guanidines

AbstractReview: 98 refs.

Optimization of methods for the generation of carbodiimides for zwitterionic 1,3-diaza-Claisen rearrangements

Strained, tertiary, allylic, amine 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene reacts with in situ generated carbodiimides in a 1,3-diaza-Claisen rearrangement to afford structurally interesting bicyclic guanidines. Use of more electron deficient carbodiimides makes these rearrangements more facile; however, there are not sufficient methods for the synthesis of highly electron deficient carbodiimides. Herein reported is the exploration of the synthesis of such carbodiimides from parent ureas and isothioureas and their use in 1,3-diaza-Claisen rearrangements.

Intramolecular aminochalcogenation and diamination of alkenes employing N-iodosuccinimide

A NIS-mediated intramolecular diamination and aminosulfuration of alkenes with N-alkyl or N-aryl thioureas is reported. A chiral cyclic thiourea was also synthesized by the methodology. The protocol is also proven to be efficient in the intramolecular diamination and/or aminooxygenation of alkenes with N-alkyl or N-aryl ureas and ones with N-carbamate sulfamides. The resulting bicyclic thiourea could be further transformed into bicyclic guanidine.

Synthetic Strategies for Preparing Bicyclic Guanidines

AbstractDifferent synthetic approaches leading to compounds containing bicyclic guanidine scaffolds are summarised. Because of the diversity within this group of target molecules and the wide range of individually reported synthetic routes, this review is divided into three subsections according to the key intermediate used to obtain the bicyclic structure. The first section is dedicated to strategies in which monocyclic guanidine derivatives are used as the key intermediates. The second section presents direct syntheses of bicyclic guanidines from acyclic or non‐guanidine starting materials. The last part of the text addresses the synthesis of target compounds through the use of polymer‐supported chemistry. The applicability of each synthetic approach for the preparation of target molecules with certain x+y combinations of individual cycles is specified.

Synthesis of bicyclic guanidines via cascade hydroamination/Michael additions of mono-N-acryloylpropargylguanidines.

A cascade silver(I)-catalyzed hydroamination/Michael addition sequence has been developed to deliver highly substituted bicyclic guanidines. This transformation gives rise to geometrically and constitutionally stable ene–guanidines and generates a remote stereocenter with moderate to high diastereoselectivity.

ChemInform Abstract: Guanidine‐Catalyzed γ‐Selective Morita—Baylis—Hillman Reactions on α,γ‐Dialkyl‐allenoates: Access to Densely Substituted Heterocycles.

AbstractThe bicyclic guanidine MTBD is shown to be an efficient catalyst for the Morita—Baylis—Hillman reaction of allenoates (I) with aldehydes (II).

Preparation of Low Calorie Structured Lipids Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene(TBD)-functionalized Mesoporous SBA-15 Silica in a Heterogeneous Manner

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD, a strong bicyclic guanidine base) functionalized SBA-15 material has been found to be an efficient solid catalyst for the interesterification between tributyrin and methyl stearate in a solvent-free system for the production of low-calorie structured lipid (LCSL). The solid base catalyst was characterized by using small-angle X-ray scattering, Fourier transform infrared spectra, thermo gravimetric analysis, scanning electron microscopy, transmission electron microscopy, nitrogen adsorption-desorption, and elemental analysis techniques. The obtained LCSL was analyzed by reverse-phase high-performance liquid chromatography for triacylglycerol composition. The influence of various reaction parameters, such as the substrate ratio, reaction temperature, and reaction time, on the interesterification reaction was investigated systematically. More than 90% LCSL was obtained at 80 °C within 1 h when the methyl stearate/tributyrin molar ratio of 2:1 was employed. The obtained solid catalyst could be recovered easily and reused for several recycles with a negligible loss of activity. By using the solid base catalyst, an eco-friendly more benign process for the interesterification reaction in a heterogeneous manner was developed.

Insights into the Organocatalyzed Synthesis of Urethanes in Supercritical Carbon Dioxide: An In Situ FTIR Spectroscopic Kinetic Study

AbstractThe kinetics of urethane (carbamate) formation in supercritical CO2 (scCO2) has been studied by in situ FTIR spectroscopy by using the reaction between n‐butanol and toluene‐2,4‐diisocyanate as a model for the synthesis of polyurethanes. We have evaluated the efficiency of different organocatalysts for this transformation to eliminate the need for potentially toxic organotin compounds. Bicyclic guanidines and amidines (7‐methyl‐1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene) lead to a significant acceleration of the reaction rate, but we found that their activity in scCO2 is reduced compared to reactions in conventional media because of the formation of guanidinium or amidinium alkylcarbonate salts. In scCO2, these catalysts are also sensitive to the presence of water and can lead to the formation of allophanate or isocyanurate byproducts. On the other hand, we have shown that catalysis with amine N‐oxides (N‐methylmorpholine‐N‐oxide) is suited to the scCO2 medium.

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) as a Lewis Base

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD, 1) was first synthesized by McKay and Kreling in the laboratories of Monsanto Canada Limited in 1957.[1] This bicyclic guanidine possesses a remarkably high Brønsted basicity (pKa = 28 in MeCN)[2] and has found broad applications as an organic superbase.[3] Moreover, the nucleophilic properties of guanidines have also been studied.[4] Mayr and co-workers quantified the nucleophilicities for a series of guanidines,[5] and TBD was by far the most powerful nucleophile among the investigated structures. In fact, TBD was found to be an even stronger nucleophile than the well-known Lewis base 4-dimethylaminopyridine (DMAP). In order to highlight the synthetic utility and usefulness of TBD as a Lewis base, a short overview of recent applications is presented.

A Strong Metal-to-Metal Interaction in an Edge-Sharing Bioctahedral Compound that Leads to a Very Short Tungsten–Tungsten Double Bond

An ionic edge-sharing bioctahedral (ESBO) species has been prepared having a tetramethylated bicyclic guanidinate with two fused six-membered rings characterized by a fairly flat N-C(N)-N skeleton and abbreviated as TMhpp. The anion has two W(IV) atoms bridged by two oxo groups; the metal atoms are also spanned by two bridging guanidinate ligands, and each has two monodentate chlorine atoms. The complex formulated as (H2TMhpp)2[W(μ-O)(μ-TMhpp)Cl2]2 has the shortest W-W distance (2.3318(8) Å) of any species with a σ(2)π(2) electronic configuration. The anion and cations are connected by hydrogen bonds. To unambiguously ascertain the existence of the double-bonded W2(μ-O)2 entity, density functional theory calculations and natural bond orbital analyses were done on an analogous but hypothetical species with a W2(μ-OH)2 core having trivalent tungsten atoms and a possible σ(2)π(2)δ(2) electronic configuration. The calculations decidedly support the presence of tungsten-oxo instead of tungsten-hydroxo groups and thus the existence of the double-bonded W2(μ-O)2 core. The strong bonding interaction between metal atoms is a clear indication that under certain circumstances the two octahedra in ESBO species do not behave as the sum of two mononuclear compounds.