Synthesis of Pd complexes bearing an enantiomerically resolved seven-membered N-heterocyclic carbene ligand and initial studies of their use in asymmetric Wacker-type oxidative cyclization reactions

The development of enantiomerically resolved, axially-chiral seven-membered N-heterocyclic carbene (⁷NHC) ligands for palladium is described. These ⁷NHC ligands are derived from enatiomerically pure 2,2′-diamino-6,6′-dimethylbiphenyl, which is transformed via a synthetic sequence consisting of ortho-arylation, N-alkylation, and cyclization to afford seven-membered-ring amidinium salts. Synthesis of the seven-membered amidinium salts benefits from microwave irradiation, and in-situ metalation of the amidinium salts yields ⁷NHC-Pd^II complexes. The chiral ⁷NHC-Pd complexes were examined as chiral catalysts under aerobic conditions in two intramolecular oxidative amination reactions of alkenes. In one case, enantioselectivities up to 63% ee were obtained, while the other substrate underwent cyclization to afford essentially racemic products. The catalytic data compare favorably to results obtained with a Pd^II catalyst bearing a chiral five-membered-ring NHC ligand and, thereby, highlight the potential significance of this new class of chiral NHC ligands.     

Unusually weak binding interactions in tetrazole-amidine complexes

[reaction: see text] Tetrazoles frequently replace carboxylic acids in pharmaceutical drugs. However, while the binding modes of tetrazolate and carboxylate anions in amidinium complexes turns out to be similar, the association constant of the former is 2-3 orders of magnitude smaller in DMSO. Crystal structures revealed that the N...H-N hydrogen bonds in amidinium tetrazolates are bent (162 degrees and 169 degrees ) and noticeably longer (N...N 2.96 A) than corresponding hydrogen bonds in both amidinium carboxylates and ammonium tetrazolates.     

Catalysis of a Diels-Alder Reaction by Amidinium Ions

Amidines and guanidines are important functional groups in molecular recognition and host-guest chemistry. Here it is shown that lipophilic amidinium ions catalyze a cycloaddition reaction representing the key step of the Quinkert-Dane estrone synthesis. Hydrogen-bond-mediated association with the organic cation leads to an electrophilic activation of the dienophile and to enhanced rates of the Diels-Alder reaction. The observed effects are similar to those expected from mild Lewis acids. In competition experiments, amidinium catalysis favors the reaction of the less electron deficient dienophile.     

A novel three-component one-pot pyrimidine synthesis based upon a coupling-isomerization sequence

[reaction: see text] 2,4,6-Tri(hetero)aryl-substituted pyrimidines can be readily synthesized in a three-component one-pot process based upon a coupling-isomerization sequence of an electron-poor (hetero)aryl halide and a terminal propargyl alcohol subsequently followed by a cyclocondensation with amidinium salts.     

A chiral molecular recognition approach to the formation of optically active quaternary centres in aza-Henry reactions

An approach to asymmetric catalysis based on chiral molecular recognition by the combination of chiral Lewis acids and chiral organocatalysis for the formation of optically active quarternary centers in the aza-Henry reaction is presented; this procedure leads to products with up to 98% ee and a diastereomeric ratio of 14 : 1 in excellent yields with catalyst loadings of 5 mol%.     

Highly diastereoselective approach toward (+/-)-tetraponerine T6 and analogues via the double cycloisomerization-reduction of bis-alkynylpyrimidines

A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomerization-reduction of bis-alkynylpyrimidines 3a-m, has been developed. The requisite bis-alkynylpyrimidines 3a-m were readily prepared via regioselective sequential Sonogashira coupling reactions of dibromopyrimidines 1. Bis-alkynylpyrimidines 3a-m were converted into the 5-6-5 tricyclic heteroaromatic cores 4a-m via the Cu(I)-assisted double cycloisomerization reaction. The reaction proceeded stepwise, which was confirmed by the isolation of the mono-pyrrolization intermediate 5. The structure of 5 was assigned by 2D NMR and by independent synthesis. Cycloisomerization of 5 under standard conditions afforded tricyclic 4g in 89% yield. The PtO2-catalyzed hydrogenation of bis-pyrrolopyrimidines 4d, 4g, and 4i in acidic media afforded stable amidinium derivatives, 11a, 11b, and 11c. Further reduction of the latter with LiAlH4 allowed for the highly diastereoselective total synthesis of (+/-)-tetraponerine T6 and its analogues.     

Design of sulfides with a locked conformation as promoters of catalytic and asymmetric sulfonium ylide epoxidation

[reaction: see text] A new generation of 2,5-dimethylthiolanes with a locked conformation was developed to promote the asymmetric addition of chiral sulfonium ylides to aldehydes. The novel chiral sulfur derivative 4 succeeded the synthesis of trans-stilbene oxide derivatives with enantiomeric ratios ranging from 95:5 to 98:2. This user-friendly organocatalytic process proved to be efficient with 20-10% of sulfide 4 in 1 or 2 days of reaction. An insight into the ylide intermediate conformation is given on the basis of a computational ab initio study.     

Structurally homologous beta- and meso-alkynyl amidinium porphyrins

Alkynylamidinium groups have been introduced at the beta and meso positions of a nickel(II) porphyrin (PNi(II)) framework. The modification permits the distance between the amidinium-amidine acid-base group and porphyrin to be increased while effectively maintaining pi conjugation between the porphyrin macrocycle and the acid-base functionality. Use of an ethynyl spacer as a linker (i) extends the amidinium functionality away from the sterically bulky mesityl groups of the porphyrin, allowing it to be nearly planar with respect to the porphyrin ring, and (ii) draws the pi-orbital character of the porphyrin out toward the amidinium functionality, thereby engendering sensitivity of the electronic properties of the porphyrin macrocycle to the protonation state of the amidinium. The barrier for rotation of the amidinium group, as calculated by time-dependent density functional theory (TDDFT), is approximately 8.5 kT (5 kcal/mol) for both porphyrins. Analysis of UV-visible absorption profiles for the beta- and meso-alkynylamidinium PNi(II) upon deprotonation enables accurate determination of the amidinium acidity constants for the ground state (pK(a)(beta) = 7.03 +/- 0.1, pK(a)(meso) = 7.74 +/- 0.1 in CH(3)CN) and excited state (pK(a)*(beta) = 6.89 +/- 0.1, pK(a)*(meso) = 8.37 +/- 0.1 in CH(3)CN) porphyrins. Whereas pK(a)* < pK(a) for the beta-alkynylamidinium porphyrin, pK(a)* > pK(a) for the meso-alkynylamidinium porphyrin, indicating that beta-alkynylamidinium PNi(II) is a photoacid and meso-alkynylamidinium PNi(II) is a photobase. These divergent behaviors are supported by analysis of the frontier molecular orbitals of the homologous pair with TDDFT.     

Competitive reactions of coordinated carbon monoxide and methyl isocyanide with amines

The relative reactivities of CO and CNR ligands with CH₃NH₂ were investigated in complexes which contained both ligands. Like (C₅H₅Fe(CO)₃⁺; the (C₅H₅)Fe(CO)₂(CNCH₃)⁺ complex reacts with CH₃NH₂ to give the carbamoyl complex (C₅)Fe(CO)(CNCH₃)(CONHCH₃); this is a readily reversible reaction. In contrast, (C₅H₅)Fe(CO)(CNCH₃)₂⁺ reacts with CH₃NH₂ to give the amidinium or carbene complex, (C₅H₅)Fe(CO)(CNCH₃)[C(NHCH₃)₂]⁺]. In a slow reaction, (C₅H₅)Fe(PPh₃)(CO)(CNCH₃)⁺ forms the amidinium complex, (C₅H₅)Fe(PPh₃)(CO)[C(NHCH₃)₂]⁺. Factors that affect the site of CH₃NH₂ reaction are discussed. The complexes have been characterized by IR and NMR spectroscopy; a variable temperature NMR study of (C₅H₅)Fe(CO)(CNCH₃)[C(NHCH₃)₂]⁺ indicates restricted rotation around the CN bonds of the amidinium ligand.     

Electronic Spectra and Protonation of 1,4-Di(arylamino)anthraquinones and Their Monodimethylformamidinium Salts in Acid Solutions

Electronic spectra of arylaminoanthraquinones and their amidinium salts in acids were studied, and experimental data on electrophilic substitution of diarylaminoanthraquinone amidinium salts in acetic and sulfuric acids of various concentrations were considered.     

Stereoselective 4-benzyloxybut-2-enylation of aldehydes via an allyl-transfer reaction using a chiral allyl donor

[reaction: see text] A direct and highly stereoselective (E)-4-benzyloxybut-2-enylation of aldehydes was successfully carried out to give 5-benzyloxyhomoallylic alcohol (11) via an allyl-transfer reaction using a chiral allyl donor (10). The chiral allyl donor (10) was prepared by catalytic Sharpless asymmetric epoxidation of 3-methylbut-2-en-1-ol, followed by a stereospecific vinyl Grignard reaction of the epoxide in the presence of CuBr and selective benzylation of the primary alcohol of diol.     

Functional mimicry of carboxypeptidase A by a combination of transition state stabilization and a defined orientation of catalytic moieties in molecularly imprinted polymers

An artificial model for the natural enzyme carboxypeptidase A has been constructed by molecular imprinting in synthetic polymers. The tetrahedral transition state analogues (TSAs 4 and 5) for the carbonate hydrolysis have been designed as templates to allow incorporation of the main catalytic elements, an amidinium group and a Zn(2+) or Cu(2+) center, in a defined orientation in the transition state imprinted active site. The complexation of the functional monomer and the template in presence of Cu(2+) through stoichiometric noncovalent interaction was established on the basis of (1)H NMR studies and potentiometric titration. The Cu(2+) center was introduced into the imprinted cavity during polymerization or by substitution of Zn(2+) in Zn(2+) imprinted polymers. The direct introduction displayed obvious advantages in promoting catalytic efficiency. With substrates exhibiting a very similar structure to the template, an extraordinarily high enhancement of the rate of catalyzed to uncatalyzed reaction (k(cat)/k(uncat)) of 10(5)-fold was observed. If two amidinium moieties are introduced in proximity to one Cu(2+) center in the imprinted cavity by complexation of the functional monomer 3 with the template 5, the imprinted catalysts exhibited even higher activities and efficiencies for the carbonate hydrolysis with k(cat)/k(uncat) as high as 410,000. These are by far the highest values obtained for molecularly imprinted catalysts, and they are also considerably higher compared to catalytic antibodies. Our kinetic studies and competitive inhibition experiments with the TSA template showed a clear indication of a very efficient imprinting procedure. In addition, this demonstrates the important role of the transition state stabilization during the catalysis of this reaction.     

Remote Sensitized Photoisomerization via Through‐Bond Triplet–Triplet Energy Transfer Mediated by a Salt Bridge in a Supramolecular Dyad

A supramolecular dyad, BP‐(amidinium‐carboxylate)‐NBD is constructed, in which benzophenone (BP) and norbornadiene (NBD) are connected via an amidinium‐carboxylate salt bridge. The photophysical and photochemical properties of the assembled BP‐(amidinium‐carboxylate)‐NBD dyad are examined. The phosphorescence of the BP chromophore is efficiently quenched by the NBD group in BP‐(amidinium‐carboxylate)‐NBD via the salt bridge. Time‐resolved spectroscopy measurements indicate that the lifetime of the BP triplet state in BP‐(amidinium‐carboxylate)‐NBD is shortened due to the quenching by the NBD group. Selective excitation of the BP chromophore results in isomerization of the NBD group to quadricyclane (QC). All of these observations suggest that the triplet–triplet energy transfer occurs efficiently in the BP‐(amidinium‐carboxylate)‐NBD salt bridge system. The triplet–triplet energy transfer process proceeds with efficiencies of approximately 0.87, 0.98 and the rate constants 1.8×10³ s^?1, and 1.3×10⁷ s^?1 at 77 K and room temperature, respectively. The mechanism for the triplet–triplet energy transfer is proposed to proceed via a “through‐bond” electron exchange process, and the non‐covalent bonds amidinium‐carboxylate salt bridge can mediate the triplet–triplet energy transfer process effectively for photochemical conversion.     

Palladium-Catalyzed Cascade sp2 C−H Functionalization/Intramolecular Asymmetric Allylation: From Aryl Ureas and 1,3-Dienes to Chiral Indolines

A chiral Pd^II-catalyzed cascade sp² C−H functionalization/intramolecular asymmetric allylation reaction is reported. A new chiral sulfoxide–oxazoline (SOX) ligand bearing single chiral center on the sulfur was identified as the optimal ligand for the reaction, being efficient both in the C−H cleavage step and the stereocontrol of the allylation step. The broad scope of this method with respect to aryl ureas and 1,3-dienes enables the rapid construction of valuable chiral indoline derivatives with high yields and enantioselectivities (up to 99 % yield, up to 95:5 e.r.).     

Structure and Tautomerism of Cyclopentadiene Derivatives: IX. Synthesis and Structure of Substituted N-Cyclopentadienyl Amidinium Ylides

A procedure has been developed for the synthesis of N-cyclopentadienyl amidinium ylides of the general formula C₅(CO₂Me)₄[ArNC(Ar')NHAr]. According to the X-ray diffraction data, ¹H and ¹³C NMR spectroscopy, and MNDO quantum-chemical calculations, the title compounds have a zwitterionic structure with the positive charge localized over the amidine NÄCÄN triad, and the negative charge, over the cyclopentadiene fragment. The configuration of the amidine moiety is stabilized by additional interaction of the NH hydrogen atom with the negatively charged cyclopentadiene ring (-bonding). The ylides are chiral due to atropoisomerism arising from a high energy barrier (G 298 >25 kcal/mol) to rotation of the Ar' substituent about the ordinary CÄC bond in the amidinium fragment.     

(S)-(+)-N-acetylphenylglycineboronic acid: a chiral derivatizing agent for Ee determination of 1,2-diols

A new chiral derivatizing agent for ee determination of 1,2-diols via (1)H NMR is described. (S)-(+)-N-acetylphenylglycineboronic acid (1) is synthesized in enantiomerically pure form; its reaction with chiral diols quantitatively yields cyclic boronic esters 5a-g. The latter show a remarkably high diastereodifferentiation of proton NMR signals useful for de determination. [reaction: see text]     

One-step stereoselective synthesis and NMR chiral shift properties of a novel hexacoordinated phosphorus cation

[reaction: see text] Tropolone, binol, and PCl(5) react in CH(2)Cl(2) at reflux to generate in one step a novel C(2)-symmetric hexacoordinated phosphorus cation of configuration controlled by the binol ligand. It behaves as an efficient NMR chiral shift agent for chiral anionic phosphate and borate anions.     

Electrophilic substitution reactions of alkylated 2-aminoindole derivatives

Bromination, nitration, and acylation of 1-methyl-2-dimethylaminoindole under mild conditions proceed to give the 3-substituted reaction products. In acidic media, in which the parent indole exists in the form of an amidinium cation, substitution occurs in the 5-position of the benzene ring. Aminoindoles, which are capable of existing only in the iminoindoline or aminoindolenine forms, always give products derived from substitution at the para position relative to the nitrogen atom, regardless of the reaction conditions.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 946–951, July, 1985.     

Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide

In this paper, the organocatalytic asymmetric 1,4-Michael addition reaction of azadienes and α-thiocyanoindanones was investigated. A series of chiral benzofuran compounds containing thiocyano group and quaternary carbon center were synthesized in moderate yields with good enantioselectivities (up to 90:10 er) and high diastereoselectivities (up to >95:5 dr). This is the first case of 1,4-Michael addition reaction using α-thiocyanoindanones to obtain a series of chiral thiocyano compounds and further broaden the scope of application of azadiene substrates. In addition, a possible reaction mechanism is also described in the article.     

Organocatalytic asymmetric double Michael reaction of Nazarov reagents with alkylidene azlactones for the construction of spiro-fused cyclohexanone/5-oxazolone system

A bifunctional thiourea-tertiary amine-catalyzed enantioselective double Michael reaction of Nazarov reagents and alkylidene azlactones was realized. Using this protocol, a series of optically active spiro-fused cyclohexanone/5-oxazolone derivatives, bearing three consecutive chiral centers including one spiro quaternary chiral center, were obtained in good yields with good stereoselectivities (up to 93% yield, 99:1 dr, and 91% ee). The synthetic utility of the products for the formation of chiral cyclic quaternary amino-acid derivatives was also demonstrated.