Scope and limitations of montmorillonite K 10 catalysed opening of epoxide rings by amines

Montmorillonite K 10 efficiently catalyses the opening of epoxide rings by amines in high yields with excellent regio- and diastereo-selectivities under solvent-free conditions at room temperature affording an improved process for synthesis of 2-amino alcohols. Reaction of cyclohexene oxide with aryl/alkyl amines leads to the formation of trans-2-aryl/alkylaminocyclohexanols. For unsymmetrical epoxides, the regioselectivity is controlled by the electronic and steric factors associated with the epoxide and the amine. Selective nucleophilic attack at the benzylic carbon of styrene oxide takes place with aromatic amines, whereas, aliphatic amines exhibit preferential nucleophilic attack at the terminal carbon. Aniline reacts selectively at the less hindered carbon of other unsymmetrical epoxides. The difference in the internal strain energy of the epoxide ring in cycloalkene oxides and alkene oxides led to selective nucleophilic opening of cyclohexene oxide by aniline in the presence of styrene oxide. Due to the chelation effect, selective activation of the epoxide ring in 3-phenoxy propylene oxide takes place in the presence of styrene oxide leading to preferential cleavage of the epoxide ring in 3-phenoxy propylene oxide by aniline.     

ZrCl4 as a new and efficient catalyst for the opening of epoxide rings by amines

Zirconium(IV) chloride catalyses the nucleophilic opening of epoxide rings by amines leading to the efficient synthesis of β-amino alcohols. The reaction works well with aromatic and aliphatic amines in short times at room temperature in the absence of solvent. Exclusive trans stereoselectivity is observed for cyclic epoxides. Aromatic amines exhibit excellent regioselectivity for preferential nucleophilic attack at the sterically less hindered position during the reaction with unsymmetrical epoxides. However, in case of styrene oxide, selective formation of the benzylic amine was observed during the reactions with aromatic amines.     

Sulfamic acid catalyzed ring opening of epoxides with amines under solvent-free conditions

Sulfamic acid (SA) catalyses the nucleophilic opening of epoxide rings by amines leading to the efficient synthesis of ß-amino alcohols. The reaction works well with aromatic and aliphatic amines in short reaction times and in the absence of solvent. Exclusive trans stereoselectivity is observed for the ring opening of cyclohexene oxide. This method exhibits excellent regioselectivity for preferential nucleophilic attack at the less hindered position during the reaction with unsymmetrical epoxides.     

An efficient synthesis of 2-amino alcohols by silica gel catalysed opening of epoxide rings by amines

Silica gel (60-120 mesh) efficiently catalyses the opening of epoxide rings by amines at rt under solvent-free conditions providing an easy method for the synthesis of 2-amino alcohols. Aromatic and aliphatic amines react with cyclohexene oxide with exclusive formation of the trans-2-aryl/alkylaminocyclohexanols in high yields. A complementary regioselectivity is exhibited by aromatic and aliphatic amines during the reaction with styrene oxide. The epoxide ring of non-styrenoidal unsymmetrical alkene oxide undergoes selective nucleophilic attack at the sterically less hindered carbon by aniline.     

Zinc tetrafluoroborate hydrate as a mild catalyst for epoxide ring opening with amines: scope and limitations of metal tetrafluoroborates and applications in the synthesis of antihypertensive drugs (RS)/(R)/(S)-metoprolols

The scope and limitations of metal tetrafluoroborates have been studied for epoxide ring-opening reaction with amines, and Zn(BF(4))(2)·xH(2)O has been found to be a mild and efficient catalyst affording high yields under solvent-free conditions at rt with excellent chemo-, regio-, and stereoselectivities. The catalytic efficiency followed the order Zn(BF(4))(2)·xH(2)O ? Cu(BF(4))(2)·xH(2)O > Co(BF(4))(2)·6H(2)O ? Fe(BF(4))(2)·6H(2)O > LiBF(4) for reactions with cyclohexene oxide and Zn(BF(4))(2)·xH(2)O ? Co(BF(4))(2)·6H(2)O ? Fe(BF(4))(2)·6H(2)O > Cu(BF(4))(2)·xH(2)O for stilbene oxide, but AgBF(4) was ineffective. For reaction of styrene oxide with aniline, the metal tetrafluoroborates exhibited comparable regioselectivity (1:99-7:93) with preferential reaction at the benzylic carbon of the epoxide ring. A reversal of regioselectivity (91:1-69:31) in favor of the reaction at the terminal carbon of the epoxide ring was observed for reaction with morpholine. The regioselectivity was dependent on the electronic and steric factors of the epoxide and the pK(a) of the amine and independent of amine nucleophilicity. The role of the metal tetrafluoroborates is envisaged as "electrophile nucleophile dual activation" through cooperativity of coordination, charge-charge interaction, and hydrogen-bond formation that rationalizes the catalytic efficiency, substrate reactivity, and regioselectivity. The methodology was used for synthesis of cardiovascular drug metoprolol as racemic and enriched enantiomeric forms.     

Y(NO3)3·6H2O catalyzed regioselective ring opening of epoxides with aliphatic, aromatic, and heteroaromatic amines

Yttrium nitrate hexahydrate [Y(NO₃)₃·6H₂O] was found to be an efficient catalyst for selective ring opening of epoxides with aliphatic, aromatic, and heteroaromatic amines at room temperature under solvent-free conditions. The system tolerated a variety of hindered and functionalized epoxides/amines and afforded the desired β-amino alcohols at low catalyst concentration.     

Theoretical study of the full reaction mechanism of human soluble epoxide hydrolase

The complete reaction mechanism of soluble epoxide hydrolase (sEH) has been investigated by using the B3LYP density functional theory method. Epoxide hydrolases catalyze the conversion of epoxides to their corresponding vicinal diols. In our theoretical study, the sEH active site is represented by quantum-chemical models that are based on the X-ray crystal structure of human soluble epoxide hydrolase. The trans-substituted epoxide (1S,2S)-beta-methylstyrene oxide has been used as a substrate in the theoretical investigation of the sEH reaction mechanism. Both the alkylation and the hydrolytic half-reactions have been studied in detail. We present the energetics of the reaction mechanism as well as the optimized intermediates and transition-state structures. Full potential energy curves for the reactions involving nucleophilic attack at either the benzylic or the homo-benzylic carbon atom of (1S,2S)-beta-methylstyrene oxide have been computed. The regioselectivity of epoxide opening has been addressed for the two substrates (1S,2S)-beta-methylstyrene oxide and (S)-styrene oxide.     

Copper(II) tetrafluoroborate-catalyzed ring-opening of epoxides by amines

Copper(II) tetrafluoroborate catalyzes efficiently the selective opening of epoxides by amines leading to the synthesis of β-amino alcohols. The reaction works well with aromatic and aliphatic amines in high yields under solvent-free conditions.     

Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF2H by a Preorganization Strategy

Unlike the facile synthesis of β‐monofluoromethyl alcohols by nucleophilic monofluoromethylation of epoxides, the synthesis of β‐difluoromethyl alcohols by nucleophilic difluoromethylation of epoxides still remains a challenge. Herein, studies on tackling this problem with PhSO(NTBS)CF₂H ( 2 ; TBS=tert‐butyldimethylsilyl) are reported. The preorganization of 2 and epoxides with BF₃ ? Et₂O was found to be crucial for the reaction. The reaction shows excellent regioselectivity and has a broad substrate scope. The facile transformation of the ring‐opened products to β‐difluoromethyl, γ‐difluoromethyl, and β‐difluoromethylenyl alcohols demonstrates the synthetic utility of the reaction.     

Reactivity of mu-hydroxodizinc(II) centers in enzymatic catalysis through model studies

The stable dinuclear complex [Zn2(BPAM)(mu-OH)(mu-O2PPh2)](ClO4)2, where BPAN = 2,7-bis[2-(2-pyridylethyl)-aminomethyl]-1,8-naphthyridine, was chosen as a model to investigate the reactivity of (mu-hydroxo)dizinc(II) centers in metallohydrolases. Two reactions, the hydrolysis of phosphodiesters and the hydrolysis of beta-lactams, were studied. These two processes are catalyzed in vivo by zinc(II)-containing enzymes: P1 nucleases and beta-lactamases, respectively. The former catalyzes the hydrolysis of single-stranded DNA and RNA. beta-Lactamases, expressed in many types of pathogenic bacteria, are responsible for the hydrolytic degradation of beta-lactam antibiotic drugs. In the first step of phosphodiester hydrolysis promoted by the dinuclear model complex, the substrate replaces the bridging diphenylphosphinate. The bridging hydroxide serves as a general base to deprotonate water, which acts as a nucleophile in the ensuing hydrolysis. The dinuclear model complex is only 1.8 times more reactive in hydrolyzing phosphodiesters than a mononuclear analogue, Zn(bpta)(OTf)2, where bpta = N,N-bis(2-pyridylmethyl)-tert-butylamine. Hydrolysis of nitrocefin, a beta-lactam antibiotic analogue, catalyzed by [Zn2(BPAN)(mu-OH)(mu-O2PPh2)](ClO4)2 involves monodentate coordination of the substrate via its carboxylate group, followed by nucleophilic attack of the zinc(II)-bound terminal hydroxide at the beta-lactam carbonyl carbon atom. Collapse of the tetrahedral intermediate results in product formation. Mononuclear complexes Zn(cyclen)-(NO3)2 and Zn(bpta)(NO3)2, where cyclen = 1,4,7,10-tetraazacyclododecane, are as reactive in the beta-lactam hydrolysis as the dinuclear complex. Kinetic and mechanistic studies of the phosphodiester and beta-lactam hydrolyses indicate that the bridging hydroxide in [Zn2(BPAN)(mu-OH)(mu-O2PPh2)](ClO4)2 is not very reactive, despite its low pKa value. This low reactivity presumably arises from the two factors. First, the briding hydroxide and coordinated substrate in [Zn2(BPAN)(mu-OH)(substrate)]2+ are not aligned properly to favor nucleophilic attack. Second, the nucleophilicity of the bridging hydroxide is diminished because it is simultaneously bound to the two zinc(II) ions.     

Unusual regioselectivity in the opening of epoxides by carboxylic acid enediolates

Addition of carboxylic acid dianions appears to be a potential alternative to the use of aluminium enolates for nucleophilic ring opening of epoxides. These conditions require the use of a sub-stoichiometric amount of amine (10% mol) for dianion generation and the previous activation of the epoxide with LiCl. Yields are good, with high regioselectivity, but the use of styrene oxide led, unexpectedly, to a mixture resulting from the attack on both the primary and secondary carbon atoms. Generally, a low diastereoselectivity is seen on attack at the primary center, however only one diastereoisomer was obtained from attack to the secondary carbon of the styrene oxide.     

2-Amino homopropargyl alcohols from the highly regioselective Ag2CO3-catalyzed nucleophilic openings of alkynyl epoxides by amines

The nucleophilic ring opening of propargyl epoxides by amines based on a silver catalyst is presented. The reaction takes place under mild conditions and features a high regioselectivity to provide an effective method for the synthesis of 2-amino homopropargyl alcohols in moderate to high yields.     

The aminolysis and esterification of unsymmetrical epoxides

The reactions of 1,2-epoxypropane (I) and 2-methyl-2,3-epoxypentane (II) with various primary and secondary amines and with hexahydrophthalic anhydride in the presence of hydroxylic catalysts have been studied. The direction of ring opening of the epoxides on reaction with the amines is unaltered by the presence of phenol as catalyst, and involves attack at the least substituted carbon atom of the epoxide ring. The structures of the piperidino adducts (viz. IV and V) derived from the phenol-catalysed reaction of piperidine with I and II, respectively, were proved by unambiguous syntheses of IV and V by the interaction of the corresponding chlorhydrin with piperidine. With hexahydrophthalic anhydride in the presence of water, I gave a low molecular weight polymeric ester whereas II afforded mainly a diadduct derived from the reaction of two molecules of II with one molecule of the anhydride. Reaction mechanisms are discussed briefly.     

A facile and efficient synthesis of β-amino alcohols using 2,2,2-trifluoroethanol as a metal-free and reusable medium

Trifluoroethanol was used as a reusable catalyst and medium for the ring opening of epoxides using aliphatic and aromatic amines as nucleophile under mild conditions to give the corresponding β-amino alcohols in high yields and regioselectivity.     

Rhodium-catalyzed ring opening of vinyl epoxides with alcohols and aromatic amines

[Rh(CO)(2)Cl](2) is an effective catalyst for the ring opening of vinyl epoxides with alcohols and aromatic amines under neutral conditions at room temperature. The reaction occurs with excellent diastereo- and regioselectivity (>20:1) giving the trans-1,2-amino alcohols or alkoxy alcohols for a wide range of substrates. The regio- and stereochemistry of these reactions is complementary to that typically obtained with palladium-catalyzed ring openings of vinyl epoxides.     

Ruthenium(III) Chloride–Catalyzed Ring Opening of Epoxides with Aromatic Amines

Ruthenium(III) chloride catalyzes the nucleophilic opening of epoxides by anilines, leading to the efficient synthesis of β‐amino alcohols. High regioselectivity can be considered as a noteworthy advantage of this method.     

Control of metal-directed self-assembly by metal-amine interactions

The complexation of a tweezers ligand with zinc perchlorate in the absence and presence of amines in methanol solution was explored. L(2)Zn(2)(ClO(4))(4) was a thermodynamic product of the reaction in the absence of an amine. The complex was shown to interact with aliphatic amines resulting in the formation of a Zn-N(amine) bond. If metal-ligand complexation was carried out in the presence of an amine the formation of a trinuclear zinc complex L(3)Zn(3)(6+) was observed. Moreover the transformation of complex L(2)Zn(2)(4+) to L(3)Zn(3)(6+) occurred, when the former was subjected to an amine in the amount, which is sufficient to coordinate more than one amino group on each zinc atom. Complexes ligand-zinc-amine were shown to be kinetically stable, and the method of their preparation was crucial to the purity of the final complexes. L(3)Zn(3)(6+) was favored under kinetic control: reagent concentration 10(-5)M, slow addition of zinc perchlorate to the mixture of an amine and the ligand. Under thermodynamic control (fast mixing of reagents, concentration 10(-2)-10(-3) M) formation of a mixture of complexes was observed. All pure complexes and their mixtures were characterized using UV-Vis, ROESY, PFGSE NMR and ESI-MS techniques. On the basis of DFT calculations the mechanism of influence of an amine on self-assembly was suggested.     

Synthetic Utility of Epoxides for Chiral Functionalization of Isoxazoles

The lithio-anion of isoxazole 2 was found to ring open propylene oxide in good yields with complete regioselectivity. Vinylic and benzylic epoxides were utilized as key examples of electrophiles and found to produce a mixture of regioisomeric adducts. Additionally, the use of chiral epoxides was explored, and absolute configuration was determined by X-ray crystallography to prove that nucleophilic attack at the benzylic carbon of (R)-styrene oxide proceeds with 100% inversion at the benzylic carbon to afford the (S)-alcohol (4b).     

Zn(OAc)2/podand catalyzed ring opening of epoxides by aromatic amines under solvent-free conditions

A highly regioselective ring opening of epoxides with aromatic amines in the presence of a catalytic amount of Zn(OAc)₂ and a recently synthesized podand under solvent-free conditions is described. The yields of the amino alcohols are uniformly good and the recovered catalyst could be used in new attempts without any purification.