Lower rim substituted p-tert-butyl calix[4]arene; Part 14. Synthesis, structures and binding studies of calix[4]arene thioamides

A number of p-tert-butylcalix[4]arene thioamides were synthesized and characterized by ¹H-NMR and elemental analysis. Compounds 1–5 are O-substituted derivatives with –CH₂–C(=S)–N–X groups, where NX = morpholidyl, NEt₂, NHC₂H₄Ph, NHCH₂Ph and NHEt, respectively. The X-ray structures of the ligands 1, 3, 5 and of the complex 3·Pb(ClO₄)₂, (compound 6), are presented and their slightly distorted cone conformation is established. The influence of the nature of the thioamide functions (secondary or tertiary) on the extractability of some selected metal cations was investigated. Whereas all these calixarenes show the highest extraction level for Ag⁺, tertiary thioamides are more efficient extractants for Pb²⁺ than secondary thioamides.     

Synthesis of 5,6-dihydro-4H-1,3-thiazine containing peptide mimics from N-(3-hydroxypropyl)thioamides and epimerization studies

The first synthesis of 1,3-thiazine fused peptide mimics is described from N-(3-hydroxypropyl)thioamides under MsCl/NEt₃ conditions. The method is amenable to oligopeptidomimics with polar and apolar side chains. Substantial epimerization occurs at chiral C(2) exo methines in non-Pro fused mimics even under neutral conditions. ¹H NMR and crystal structure analyses indicate that the Thi analogues primarily associate with each other through intermolecular hydrogen bonds, involving the nitrogen of 1,3-thiazine and the N–H of the fused residue, which may be the basis for enamination–racemization process in these peptide mimics.     

Hetero-Diels–Alder reactions of perfluoroalkyl thioamides with electron-rich 1,3-dienes: synthesis of new 2-aminosubstituted-3,6-dihydro-2H-thiopyrans and related compounds

Hetero-Diels–Alder reactions of perfluoroalkyl thioamides with electron-rich 1,3-dienes such as 2,3-dimethylbutadiene, isoprene or penta-1,3-diene gave a simple and efficient access to new 2-aminosubstituted-3,6-dihydro-2H-thiopyrans. Three different procedures were used depending on the nature of the polyfluoroalkyl chains (R_F=CF₃, (CF₂)_nCF₃, (CF₂)₄H) and on the nitrogen substituents of the thioamides (R¹, R²=H, p-Tol, morpholino, Ac). Moreover, cycloadditions of silyloxydienes (1- or 2-trimethylsilyloxy-1,3-butadiene and Danishefsky's diene) with N-acyl,N-tolyl trifluoromethylthioamides afforded in almost all cases the corresponding 3,6-dihydro-2H-thiopyrans or 3-oxo-tetrahydrothiopyrans. For non-symmetrical 1,3-dienes, the regio- and stereochemistry of the reactions were studied (especially using X-ray diffraction analysis) indicating a strong similarity with those reported for fluorinated thiocarboxyl derivatives. Finally, two silylated 3,6-dihydro-2H-thiopyrans underwent an unexpected base-induced ring contraction to give new 1,3-thiazolidin-4-ones.     

Axially chiral thioamides of acrylic acid: correlated and uncorrelated internal rotations

In acrylic thioamides (Scheme. 1), two intramolecular motions are possible: thiocarbonyl–nitrogen (C–N) and alkenyl–carbonyl (C–C) rotations. Since the two mobile molecular fragments can interact by steric and by resonance effects, we intended to demonstrate the existence of correlated in addition to the above uncorrelated motions. For each of the three thioamides chosen, at least two of the four stereoisomers were enriched by crystallization and by liquid chromatography on nonracemic sorbents. Thereby axial chirality of acrylic thioamides was proven for the first time. Thermal equilibrations were monitored quantitatively by time-dependent ¹H NMR spectroscopy in the presence of a nonracemic additive, a method which, to our knowledge, has not previously been described. These kinetic results were evaluated by a simulation program with reference to uncorrelated and correlated rotations (Fig. 4, Fig. 5, Fig. 6). We have shown that all of these motions occur in thioamide 14. The enantiomers of thioamide 13 do not interconvert directly. However, indirect, two-step enantiomerizations in 13 have been proven one of the two steps consisting of correlated rotations. The latter are, therefore, possible in acrylic thioamides, a class of compounds which differ considerably from the molecules for which correlated motions were hitherto known.     

Tributylphosphine, excellent organocatalyst for conjugate additions of non-nucleophilic N-containing compounds

Conjugate additions of non-nucleophilic N-containing compounds such as amides, thioamides, sulfonamides, and electron-poor anilines with different Michael acceptors can be promoted through the use of tributylphosphine. The range of useful pK_a's of nucleophiles has been established (pK_a<25) and new insights into the mechanism proposed.     

O,O-Diethyl dithiophosphoric acid mediated direct synthesis of thioamides from aldehydes and ketones

A general and convenient method for a one-pot conversion of aldehydes and ketones into thioamides has been developed. The protocol involves oximation of aldehydes and ketones followed by deoxygenative thioamidation of oximes with O,O-diethyl dithiophosphoric acid which acts as an acid as well a source of sulfur. The method is operationally simple, high yielding, and also applicable to the conversion of amides and nitriles into the corresponding thioamides.     

Correlation between the reactivity and spectroscopic properties of N‐substituted secondary thioamides. New intramolecular N···H+···N binding approach and proton complexes based on thioamide ligation

On the basis of a comparison of chemical shifts and wavenumbers of several secondary thioamides and amides having monocationic substituents attached to thiocarbamoyl or carbamoyl groups by a polymethylene chain, new intramolecular unconventional N···H⁺···N hydrogen bonding effects were discovered. It is argued that the CH₂—N rotation is hindered and two ⁺H···NHCH₃ non‐equivalent protons occur in a proton spectrum of hydrochloride 1a (at 10.68 and 2.77 ppm, respectively) instead of two ⁺NH₂CH₃ protons. Presumably, the above steric factors inhibit the acidic hydrolysis of 1a (stabilized by strong intramolecular N···H⁺···N hydrogen bonds) to an amide and prevent intramolecular cyclization of 2a (stabilized by strong intramolecular neutral–neutral N···HN hydrogen bonds) to a cyclic amidine. Postulation of additional dihydrogen bond formation is helpful in understanding the spectroscopic differences of 4 and 5 . The above new bonding is also compared with intramolecular N···H—N⁺ hydrogen bonds in primary amine salts 7 and 8 . In contrast to 3 , a cooperative hydrogen bonded system is observed in 9 and 10 . The weak hydrogen bonds in 7 – 10 facilitate the hydrolysis and cyclization reactions of secondary thioamides. The spectroscopic data for secondary (thio)amides are especially useful for characterizing the electronic situation at the (thio)carbamoyl nitrogen atoms and they are perfectly correlated with the reactivity. Examples of chelation of protons by thioamides ( 11 and 12 ), which contain strongly electron‐donating pyrimidine groups, are presented to show the contribution of dihydrogen bonding in the protonation reaction similar to 1 and 4 . Copyright © 2003 John Wiley & Sons, Ltd.     

Etude par RMN du mecanisme des reactions de transcomplexation entre les sels de chloroiminium (reactifs de vilsmeier) et les amides ou thioamides. Appl

Previous studies have established the existence of an acid-base equilibrium between the Vilsmeier complex (Me₂NCHCl)⁺ B^? and dimethylformamide. It is shown that the behaviour of chloroiminium salts as Lewis acids towards amides or thioamides is a general phenomenon. When the acids and bases are differently substituted, the reaction may have synthetic applications.     

Remarkable Shape‐Sustaining,Load‐Bearing,and Self‐Healing Properties Displayed by a Supramolecular Gel Derived from a Bis‐pyridyl‐bis‐amide of L‐Phenyl Alanine

A series of bis‐amides decorated with pyridyl and phenyl moieties derived from L ‐amino acids having an innocent side chain (L ‐alanine and L ‐phenyl alanine) were synthesized as potential low‐molecular‐weight gelators (LMWGs). Both protic and aprotic solvents were found to be gelled by most of the bis‐amides with moderate to excellent gelation efficiency (minimum gelator concentration=0.32–4.0 wt. % and gel–sol dissociation temperature T_gel=52–110 °C). The gels were characterized by rheology, DSC, SEM, TEM, and temperature‐variable ¹H NMR measurements. pH‐dependent gelation studies revealed that the pyridyl moieties took part in gelation. Structure–property correlation was attempted using single‐crystal X‐ray and powder X‐ray diffraction data. Remarkably, one of the bis‐pyridyl bis‐amide gelators, namely 3,3‐Phe (3‐pyridyl bis‐amide of L ‐phenylalanine) displayed outstanding shape‐sustaining, load‐bearing, and self‐healing properties.     

New Methods of Synthesis of Phosphoryl and Thiophosphoryl Halides from Organylchlorophosphonium Hexachlorophosphorates

A new method of synthesis of phosphonic and thiophosphonic chlorides is offered, based on treatment of acyclic and cyclic organylchlorophosphonium hexachlorophosphorates with dimethylformamide, dimethylacetamide, or dimethylthioacetamide. The method involves no formation of phosphoryl chloride and thiophosphoryl chloride, which facilitates isolation of the target products. The reactions of alkenylchlorophosphonium hexachlorophosphorates with amides and thioamides results in incorporation of the PCl₆ ^- anion into an insoluble chloroiminium salt which is easily separated by filtration. Removal of the solvent leaves almost pure phosphonic or thiophosphonic chlorides.     

Divergent regioselectivity in photoredox-catalyzed hydrofunctionalization reactions of unsaturated amides and thioamides

A direct method to construct 2-oxazolines and 2-thiazolines from corresponding allylic amides and thioamides is reported. The redox-neutral intramolecular hydrofunctionalization is enabled by a dual catalyst system comprised of 9-mesityl-N-methyl acridinium tetrafluoroborate and phenyl disulphide and exhibits complete selectivity for the anti-Markovnikov regioisomeric products. The cyclization of allylic thioamides is postulated to operate via a modified mechanism in which oxidation of the thioamide, rather than the alkene, is responsible for the observed reactivity.     

Some trimethylphosphineoxide complexes of lanthanide and indium tris-(bis-trimethylsilylamides)

The reactions of the 3-coordinated metal tris-(bis-trimethylsilylamides) M[N(SiMe₃)₂]₃ (ML₃; where M = La, Pr, Eu, Gd and In) with trimethylphosphineoxide Me₃PO(L′) have been studied. All of these metals gave 1:1 complexes ML₃(L′) which dissociated on heating in vacuo. The Pr and Eu complexes gave interesting pseudo-contact shifted ¹H NMR spectra which are qualitatively in accord with the expected molecular structure. Variable temperature NMR measurements proved the restricted rotation of the silylamide (L) ligands occurs around the M–N axes. Evidence is also presented for unstable 5-coordinated complexes ML₃(L′)₂. The gadolinium 1:1 complex gave a very broad NMR spectrum and its ESR spectrum is being investigated.     

A line width method for determining chemical exchange rates from NMR spectra

The applicability of W_½, the line-width at one-half height corrected for field inhomogeneity and couplings, for characterization of nuclear magnetic resonance line shapes generated by exchange averaging of chemical shifts has been investigated for the case P_A = P_B. The Gutowsky-Holm equation, simplified by the assumption of a large T₂º such that T${}_{\text{2}}^{\text{º?1}}$ = 0, was used to produce a family of curves relating W_½ corrected to the rate of exchange for various Δv_AB values. The rate of internal rotation about the C? N amide bond has been studied in neat N,N-dimethyl-formamide between 79·5 and 159° by the W_½ method and the results, E_a = 24·9 and 24·1 Kcal/mole at 60 and 100 MHz do not agree with those recently reported by Rabinovitz and Pines, E_a = 20·5 Kcal/mole obtained by the total line shape method. For neat N,N-dimethylacetamide and for solutions of DMA in dimethylsulfoxide-d₆, application of the W_½ method yielded E_a, ΔH? and ΔS? values which are in excellent agreement with those obtained by Neuman and Jonas for DMA-d^ε using a total line shape analysis. The thermodynamic parameters for neat N,N-dimethylcarbamoyl chloride obtained by the total line shape and W_½ methods are also in excellent agreement, 16·4 and 16·8 Kcal/mole for E_a and 15·8 and 16·2 Kcal/mole for ΔH?, respectively. The W_½ method was also used for the determination of the activation parameters for rotation about the carbon-nitrogen bond in the following thioamides: N,N-dimethylthiobenzamide, (E_a = 19.8 Kcal/mole), N,N-diethylthiobenzamide, (E_a = 20·4 Kcal/mole), N,N-dimethylphenylthio-acetamide (E_a = 21·4 Kcal/mole). The results obtained for these thioamides are compared with the corresponding amides. Specifically N,N-dimethylbenzamide and N,N-diethylbenzamide were studied using the W_½ method and activation energies for rotation about the carbon-nitrogen bond of 17·5 and 15·6 Kcal/mole, respectively, were found. The relative magnitudes of these parameters are discussed on the basis of molecular geometry of the thioamides. Attention is drawn to the fact that for structurally related amides and thioamides, the barrier heights for internal rotation are not greatly different.     

Conversion of Thioamides into Their Corresponding Oxygen Analogues Using Silver Carbonate Supported on Celite

Silver carbonate supported on celite (Ag₂CO₃/Celite) is used as a mild heterogeneous reagent for conversion of variety of thioamides into their corresponding amides in acetonitrile at room temperature.

     

13C n.m.r. spectra of some thiobenzamides. Correlation between 13C and 1H n.m.r. spectra and signal assignments of syn and anti CH2 groups

¹³C n.m.r. spectra of a series of N,N-disubstituted thioamides have been recorded and signal assignments were performed. Separate signals are observed for methylene groups fixed on the nitrogen atom. Since the carbon atom syn to the thiocarbonyl sulfur resonates at higher field than the anti carbon, the syn-anti assignment in ¹H n.m.r. is easily obtained by selective double irradiation. This method, which is rapid and reliable, affords a rather general solution to the interesting problem of resonance assignments in tertiary amides and thioamides (and in analogous molecules such as oximes and nitrosamines).     

Thionation of amides using a solid-supported P2S5 reagent under microwave irradiation

In this Letter, we describe an improved method for the thionation of amides. Using a solid-supported P₂S₅ reagent, heating under microwave irradiation furnished thioamides in good to excellent yields, with a significantly reduced reaction time compared with that achieved under conventional heating. Furthermore, a change of solvent from that described in the literature enabled a simplified work-up and purification of the products.     

Photochemistry of <Emphasis Type="Italic">N</Emphasis>-substituted salicylic acid amides

The products of photolysis of N-substituted salicylic acid amides, viz., 2-hydroxy-3-tert-butyl-5-ethylbenzoic acid N-(4-hydroxy-3,5-di-tert-butylphenyl)amide (1) and 2-hydroxybenzoic acid N-[3-(4-hydroxy-3,5-di-tert-butylphenyl)prop-1-yl]amide (2), in heptane were studied by optical spectroscopy and stationary and nanosecond laser photolysis (Nd: YAG laser, 355 nm). It was shown by the method of partial deuteration of amides 1 and 2 that they exist in both the unbound state and as complexes with intraand intermolecular hydrogen bond. Amides 1 and 2 are subjected to photolysis, which results in the formation of a triplet state and phenoxyl radicals RO? presumably due to the absorption of the second photon by the excited singlet state. The formation of radical products due to N–H bond ionization was not observed. The main channel of decay of the triplet state and radicals RO? is triplet–triplet annihilation and recombination (k _r ≈ 2.3?10⁸ L mol^–1 s^–1), respectively. The UV irradiation of compounds 1 and 2 leads to the excitation of the amide groups, and no formation of radical products due to N–H bond ionization was observed.     

Selective Benzylic and Allylic Alkylation of Protic Nucleophiles with Sulfonamides through Double Lewis Acid Catalyzed Cleavage of sp3 Carbon–Nitrogen Bonds

The acid‐catalyzed benzylic and allylic alkylation of protic nucleophiles is fundamentally important for the formation of carbon? carbon and carbon? heteroatom bonds, and it is a formidable challenge for benzylic and allylic amine derivatives to be used as the alkylating agents. Herein we report a highly efficient benzylic and allylic alkylation of protic carbon and sulfur nucleophiles with sulfonamides through double Lewis acid catalyzed cleavage of sp³ carbon–nitrogen bonds at room temperature. In the presence of a catalytic amount of inexpensive ZnCl₂‐TMSCl (TMSCl: chlorotrimethylsilane), 1,3‐diketones, β‐keto esters, β‐keto amides, malononitrile, aromatic compounds, thiols, and thioacetic acid can couple with a broad range of tosyl‐activated benzylic and allylic amines to give diversely functionalized products in good to excellent yields and with high regioselectivity. Furthermore, the cross‐coupling reaction of 1,3‐dicarbonyl compounds with benzylic propargylic amine derivatives has been successfully applied to the one‐step synthesis of polysubstituted furans and benzofurans.     

Synthesis and Use of 2H‐Azirin‐3‐amines as Dipeptide Synthons

The synthesis of the new 2H‐azirin‐3‐amines (‘3‐amino‐2H‐azirines') 11, 20, 28 , and 33 as dipeptide synthons is described. The reactions of the starting amides with Lawesson reagent gave the corresponding thioamides, and consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ led to the desired products. It is shown that these 2H‐azirin‐3‐amines can conveniently be used as building blocks of the dipeptides Aib‐(Me)Axx (Axx=alanine, valine), Aib‐Homoproline, and Iva‐Pro in the synthesis of several model peptides. However, some limitations apply for the synthesis of such 2H‐azirin‐3‐amines. The starting material for the azirine synthesis, the corresponding thioamides, cannot generally be synthesized, and the 2H‐azirin‐3‐amines could not be obtained in all cases from the thioamides prepared.     

The thermal dissociation of the [Co(NH3)6]Cl3 and [Co(NH3)6]Br3 complexes in vacuo

The thermal dissociation of the complexes, [Co(NH₃)₆]X₃(X^?=Cl, Br), was studied in vacuo using the techniques of thermogravimetry, evolved gas analysis and mass spectrometric analysis. It was found that the reaction stoichiometry was identical to that previously determined in air but that the type of intermediate compounds formed were different. The dissociation occurred by the reactions: