Stereoselective synthesis of γ-lactone fused cyclopentanoids

The stereoselective synthesis of γ-lactone fused cyclopentanoids applying chemoenzymatic methods is described. rac-2-Hydroxymethyl-1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-ene and rac-2-hydroxymethyl-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene were successfully resolved by Candida rugosa lipase (CRL), to afford enantiomerically enriched products with an ee of 94 and 97%, respectively. The enantiomerically enriched acetates were then subjected to ruthenium and/or cerium catalyzed oxidation to afford α-diketones and subsequent alkaline H₂O₂ mediated oxidative cleavage reaction of α-diketones, followed by CH₂N₂ esterification, gave enantiomerically enriched γ-lactone fused cyclopentanoids with known absolute configurations.     

An efficient and general method for resolving cyclopropene carboxylic acids

A general method is described for the resolution of cycloprop-2-ene carboxylic acids via diastereomeric N-acyloxazolidines prepared from enantiomerically pure oxazolidinones. Although a number of oxazolidinones were shown to resolve cyclopropene carboxylic acids, the oxazolidinones of S-phenylalaninol, S-phenylglycine and (1S,2R)-cis-1-amino-2-indanol are optimal in terms of resolving power and cost effectiveness. Separations were performed using simple flash chromatography, and because there is typically a large difference in R_f values it is possible to separate gram quantities of pure diastereomers in a single chromatogram. The cycloprop-2-ene carboxylic acids that can be resolved include those that are substituted at the 1-position by H, Ph, α-naphthyl, CO₂Me, CH₂OMOM, and trans-styryl; alkene substituents include Me, n-alkyl, Ph and tethered alkynes. Remarkably, 2-methyl-3-propylcycloprop-2-ene carboxylic acid can also be resolved with ease. The relative configurations of four diastereomerically pure oxazolidines were determined by X-ray crystallography. Reduction of the N-acyloxazolidinones with LiBH₄ give enantiomerically pure derivatives of 3-hydroxymethylcyclopropene that react with either MeMgCl or vinylMgCl and catalytic CuI to give enantiomerically pure products of syn-addition.     

Base and catalyst-free synthesis of nitrobenzodiazepines via a cascade N-nitroallylation-intramolecular aza-Michael addition involving o-phenylenediamines and nitroallylic acetates

A [4+3] annulation of o-phenylenediamines with primary nitroallylic acetates affords nitrobenzodiazepines (NBDZs) in good to excellent yield. The reaction which proceeds in MeOH at room temperature in the absence of any base or catalyst involves a cascade S_N2 N-nitroallylation-intramolecular aza-Michael addition sequence. In the case of mono-N-arylated o-phenylenediamines and o-aminobenzamides, the reaction stops at the S_N2 stage affording nitroallylic amines. On the other hand, reaction of o-aminobenzamides with secondary nitroallylic acetates delivers S_N2′ products. Formation of stable S_N2 and S_N2′ products provides insights into the reactivity of primary and secondary nitroallylic acetates and also the mechanism of formation of nitrobenzodiazepines.     

The average structures of 2,3-diazabicyclo[2.2.1]hept-2-ene and 2,3-diazabicyclo[2.2.2]oct-2-ene

The average molecular structures of 2,3-diazabicyclo[2.2.1]hept-2-ene and 2,3-diazabicyclo[2.2.2] oct-2-ene have been determined by electron diffraction in the gas phase. The structural parameters were obtained by applying a least squares analysis on the molecular scattering intensity functions. For 2,3-diazabicyclo[2.2.1]hept-2-ene, C_s symmetry was assumed in calculating the geometry of the molecule. The parameters thus determined are: N₃=N₂ = 1.221 Å, N₃- C₄ = 1.445 Å, C₄-C₅ = 1.538 Å, C-H_(ave.) = 1.112 Å, < C₁N₂N₃ = 116.3°, < N₃C₄C₅ = 105.2°, < C₁C₄C₅ = 71.5°, C₄-C₇ = 1.547 Å, C₅-C₆ = 1.530 Å, < C₁C₇C₄ = 108.0°. For 2,3-diazabicyclo[2.2.2]oct-2-ene, C_2vsymmetry was assumed. The geometrical parameters are: N₃ = N₂ = 1.243 Å, N₃-C₄ = 1.473 Å, C₄-C₅ = 1.550 Å, C₅-C₆ = 1.516 Å, C-H_(ave.) = 1.119 Å,< C₁N₂N₃ = 115.1°, < N₃C₄C₅ = 109.1°, < C₆C₁C₄ = 71.6°.     

Diastereo‐ and Regioselective Addition of Thioamide Dianions to Imines and Aziridines: Synthesis of N‐Thioacyl‐1,2‐diamines and N‐Thioacyl‐1,3‐diamines

Addition reactions of thioamide dianions that were derived from N‐arylmethyl thioamides to imines and aziridines were carried out. The reactions of imines gave the addition products of N‐thioacyl‐1,2‐diamines in a highly diastereoselective manner in good‐to‐excellent yields. The diastereomeric purity of these N‐thioacyl‐1,2‐diamines could be enriched by simple recrystallization. The reduction of N‐thioacyl‐1,2‐diamines with LiAlH₄ gave their corresponding 1,2‐diamines in moderate‐to‐good yields with retention of their stereochemistry. The oxidative‐desulfurization/cyclization of an N‐thioacyl‐1,2‐diamine in CuCl₂/O₂ and I₂/pyridine systems gave the cyclized product in moderate yield and the trans isomer was obtained as the sole product. On the other hand, a similar cyclization reaction with antiformin (aq. NaClO) as an oxidant gave the cis isomer as the major product. The reactions of N‐tosylaziridines gave the addition products of N‐thioacyl‐1,3‐diamines with low diastereoselectivity but high regioselectivity and in good‐to‐excellent yields. The use of AlMe₃ as an additive improved the efficiency and regioselectivity of the reaction. The stereochemistry of the obtained products was determined by X‐ray diffraction.     

Reactions of 1,1,1-trihalo-3-nitrobut-2-enes with enamines derived from cycloalkanones. Rearrangement of trifluoromethylated 1,2-oxazine N-oxide into 1-pyrroline N-oxides and stereochemistry of the products

1,2-Oxazine N-oxides derived from (E)-1,1,1-trifluoro-3-nitrobut-2-ene and cyclohexanone enamines underwent spontaneous rearrangement with ring contraction to give 1-pyrroline N-oxides. Reactions of (E)-1,1,1-trifluoro(trichloro)-3-nitrobut-2-enes with N-cyclopent-enylmorpholine resulted in a series of novel CX₃-containing nitroalkyl enamines and g-nitro ketones; the stereochemistry of the synthesized compounds were studied by NMR spectroscopy and X-ray diffraction.     

Synthesis of 2-methyl-N-(2,2,2-trichloroethylidene)- and 2-methyl-N-(2,2,2-trichloroethyl)benzenesulfonamides from N,N-dichloro-2-methylbenzenesulfonamide and trichloroethylene

The reaction of N,N-dichloro-2-methylbenzenesulfonamide with trichloroethylene gave a new representative of highly electrophilic N-sulfonyl polyhaloaldehyde imines, 2-methyl-N-(2,2,2-trichloroethylidene) benzenesulfonamide. High reactivity of the product was demonstrated in the addition of water and 2-methylbenzenesulfonamide and reactions with benzene, toluene, anisole, thiophene, and 2-chlorothiophene. N,N-Dichlorobenzenesulfonamides and N,N-dichlorotrifluoromethanesulfonamide failed to react with 1,1,3,3,4,4-hexachlorobut-1-ene and 1,1,2,3,4-pentachlorobuta-1,3-diene under the conditions ensuring formation of N-(2,2,2-trichloroethylidene)arenesulfonamides from N,N-dichloroarenesulfonamides and trichloroethylene.     

Rhodium-catalyzed hydroformylation of C6 alkenes and alkene mixtures - a comparative study in homogeneous and aqueous-biphasic media using PPh3, TPPTS and TPPMS ligands

The complexes RhH(CO)L₃, where L = PPh₃, P(m-C₆H₄SO₃Na)₃ (TPPTS), and (C₆H₅)₂P(m-C₆H₄SO₃Na) (TPPMS) were used as catalyst precursors for a comparative study of the catalytic hydroformylation of several C6 alkenes and alkene mixtures under moderate reaction conditions in homogeneous (PPh₃) and aqueous-biphasic (TPPTS, TPPMS) media. The biphasic systems are efficient for the hydroformylation of hex-1-ene, 2,3-dimethyl-1-butene, styrene, cyclohexene, and mixtures thereof, in water/n-heptane at 80 °C. The main problem associated with these catalysts is their tendency to promote alkene isomerization if the effective syngas concentration in the liquid phases is low, but this side-reaction can be suppressed by using higher CO/H₂ pressures (54 atm). The selectivity of both water-soluble catalysts for linear products of hex-1-ene and for branched products of styrene is modest in comparison with the homogeneous system, which may limit their utility for classical oxo uses, but this is not a disadvantage for other interesting applications related to the hydroformylation of alkene mixtures and particularly to naphtha upgrading where linear and branched products are equally useful. The catalysts can be recycled without significant loss of activity and are resistant to the presence of benzothiophene in the mixture.     

New N,N-diamine ligands derived from (−)-menthol and their application in the asymmetric transfer hydrogenation

Natural (?)-menthol was applied to construction of mono-N-tosylated-1,2-diamine derivatives. The O-tosylation and elimination of the tosylate of the menthol intermediate led to trans-p-menth-2-ene. The unsaturated menth-2-ene was next transformed into a mixture of N-tosylaziridines, which upon reaction with sodium azide gave four isomeric azides. The reduction of the formed tosylazides on Pd/C gave new chiral mono-N-tosylated-1,2-diamines, which were used as ligands in the asymmetric transfer hydrogenation protocol on aromatic ketones and endocyclic imine.     

Conjugate addition of aromatic amines to ethenetricarboxylates

The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl₂ and ZnBr₂ at room temperature gave amine adducts in high yields. The products were converted to α-amino acid, dl-aspartic acid derivatives. Using Lewis acids such as Sc(OTf)₃ and Zn(OTf)₂ at higher temperature (40-80 °C), the reaction of ethenetricarboxylates and N-methylaniline gave an aromatic substitution product. A catalytic enantioselective conjugate addition using a chiral Lewis acid was also investigated. For example, the reaction of 1,1-diethyl 2-tert-butyl ethenetricarboxylate with N-methylaniline in the presence of chiral bisoxazoline-Cu(II) complex in THF at −20 °C for 17 h gave an amine adduct in 91% yield and 78% ee. On the other hand, the reaction with aniline and primary aniline derivatives gave adducts with almost no ee%.     

Polymerization of norbornene by palladium(II) complexes bearing ethylene-bridged bisindolinyl- or bis(1,2,3,4-tetrahydroquinolinyl) ligands

Novel moisture and air stable, cationic palladium(II) amine complexes (1–4) of the general type [Pd(N∩N)(X)₂](BF₄)₂, [N∩N=1,2-bis(N-indolinyl)ethane (BIE) 1, 3; 1,2-bis(N-1,2,3,4-tetrahydroquinolinyl)ethane (BTQE) 2, 4; X=NCCH₃, H₂O] were found to catalyze the polymerization reaction of bicyclo[2.2.1]hept-2-ene at room temperature. The amorphous polymer products consist of 2,3-linked norbornene units; no indications for ring opened species could be observed. The polymerization activity of the diaqua-complexes 3, 4 is superior compared to their acetonitrile analogues due to a facile activation by a Wacker-type reaction. The cationic Pd(II)-compounds are inactive towards homo- and copolymerization reactions of polar monomers, like acrylates or carbon monoxide. However, addition of methylacrylate resulted in polynorbornene products with increased molecular weight and narrow molecular weight distributions.     

Palladium(II)-catalyzed Suzuki–Miyaura reactions of arylboronic acid with aryl halide in water in the presence of 4-(benzylthio)-N,N,N-trimethybenzenammonium chloride

This work reported that Suzuki–Miyaura coupling reactions of arylboronic acid with aryl bromide or iodides were mediated by Pd(OAc)₂ and 4-(benzylthio)-N,N,N-trimethylbenzenammonium chloride in the presence of Na₂CO₃ in water under the mild conditions. The corresponding Suzuki–Miyaura coupling products were obtained in good to excellent yields.     

Stereoselective conjugate addition reactions of lithium amides to α,β-unsaturated chiral iron acyl complexes [(η-C5H5)Fe(CO)(PPh3)(COCHCHR)]

Conjugate addition of achiral lithium dimethylamide to the chiral iron cinnamoyl complexes (S,E)- and (S,Z)-[(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHPh)] proceeds with high diastereoselectivity, with this protocol being used to establish unambiguously the absolute configuration of Winterstein’s acid (3-N,N-dimethylamino-3-phenylpropanoic acid) as (R). The highly diastereoselective conjugate addition of lithium N-benzyl-N-trimethylsilylamide to a range of α,β-unsaturated iron acyl complexes, followed by in-situ elaboration of the derived enolate by either alkylation or aldol reactions is also demonstrated, facilitating the stereoselective synthesis of both cis- and trans-β-lactams. This methodology has been used to effect the formal asymmetric syntheses of (±)-olivanic acid and (±)-thienamycin. Addition of chiral lithium amides derived from primary and secondary amines to the iron crotonyl complex [(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHMe)] indicates that lithium N-α-methylbenzylamide shows low levels of enantiorecognition, while lithium N-3,4-dimethoxybenzyl-N-α-methylbenzylamide and lithium N-benzyl-N-α-methylbenzylamide show high levels of enantiodiscrimination. The high level of observed enantiorecognition was used to facilitate a kinetic resolution of (RS)-[(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHMe)] with homochiral lithium (R)-N-3,4-dimethoxybenzyl-N-α-methylbenzylamide. Further mechanistic studies show that conjugate additions of (RS)-lithium N-benzyl-N-α-methylbenzylamide to either the (RS)- or homochiral iron crotonyl complex show 2:1 stoicheiometry, while homochiral lithium N-benzyl-N-α-methylbenzylamide shows 1:1 stoicheiometry.     

<Emphasis Type="Italic">N</Emphasis>-β-Nitroxyethyl derivatives of 1,1’-[methylenebis(oxy)]bis(triaz-1-ene 2-oxides)

Synthetic procedures towards new N-β-hydroxyethyl- and N-β-bromoethylated 1,1’-[methyl enebis(oxy)]bis(triaz-1-ene 2-oxides) were developed. N-β-Nitroxyethyl[methylenebis(oxy)]- bis(triaz-1-ene 2-oxides) were first synthesized by nitration of N-β-hydroxyethyl derivatives and nucleophilic substitution of the bromine atom of N-β-bromoethyl derivatives. The first representative of a new class of energetic compounds, namely, (1-nitroxymethoxy)triaz-1-ene 2-oxide, was synthesized.     

Fluorination and chlorination of nitroalkyl groups

Heterocycles substituted with a nitromethyl (CH₂NO₂) or phenyl-nitromethyl (CHPhNO₂) group were prepared by reaction of a methyl- or phenylmethyl-substituted heterocycle, respectively, with lithium di-isopropylamide followed by quenching the intermediate carbanion with methyl nitrate. Conversion of CH₂NO₂ attached to an alkyl or aryl moiety into a dichloronitromethyl (CCl₂NO₂) group was achieved using N-chlorosuccinimide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane. Similarly, CH₂NO₂ attached to an alkyl or aryl group was converted into difluoronitromethyl (CF₂NO₂) using either 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™) or N-fluorobenzenesulfonimide with DBU as base and dichloromethane as solvent. Reaction of ω-nitroacetophenone with Selectfluor/DBU in dimethylformamide followed by acidification and distillation gave the parent difluoronitromethane in a useful ‘one-pot’ procedure.     

Nucleophilic addition to nitroacrylates: application towards the synthesis of 2,3-dehydroamino acids and 2,3-diamino acids

The addition of the N-pronucleophiles to 2- or 3-nitro-2-alkenoates in the presence of base provided Michael addition products. In the case of 3-nitro compounds, reaction occurred via the formation of α-adducts and the subsequent elimination of nitrous acid to produce olefins with high Z stereoselectivity. 3-Phthalimido-2-nitrocinnamate adduct 8a was converted into 2,3-diamino ester 11a.     

Copper-catalyzed one-pot N-alkenylation and N-alkylation of amides: an efficient synthesis of substituted 2,3-dihydropyrroles

A novel copper-catalyzed synthesis of substituted 2,3-dihydropyrroles via one-pot N-alkenylation and N-alkylation of amides with 1,4-diiodobut-1-ene derivatives has been developed. The reactions proceed in good to high yields using CuI as the catalyst, K₂CO₃ as the base, and rac-trans-N,N′-dimethylcyclohexane-1,2-diamine as the ligand.     

Reactivity of fluorinated sulfur-containing heterocycles towards nucleophilic and oxidizing reagents

The reaction of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene, 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene and 2,2-bis(trifluoromethyl)-3,6-dihydro-4,5-dimethyl-2H-thiopyran with i-C₃H₇MgCl leads to the formation of ring opening products as the result of nucleophilic attack of the Grignard reagent on the sulfur atom. According to DFT calculations the reactivity of the sulphur-containing substrate correlates with the strain energy of the heterocycle. The oxidation of 3-thia-4,4-bis(trifluoromethyl)tricyclo[5.2.1.0^2,5]non-7-ene by hydrogen peroxide in hexafluoro-iso-propanol solvent resulted in formation of the corresponding sulfoxide however, the reaction with m-chloroperoxybenzoic acid produced the product of exhaustive oxidation of sulfur and the double bond. In sharp contrast, the oxidation of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene and 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene by MCPBA (2d, 25 °C) proceeds with the preservation of the double bond, leading to the selective formation of the corresponding sulfones.     

N,N-Bis(halomethyldimethylsilyl)acetamides and their reactions

N,N-Bis(halomethyldimethydimethylsilyl)acetamides, MeCON(SiMe₂CH₂X)₂, (X = Cl, Br) were prepared by transsilylation of N,O-bis(trimethylsilyl)acetamide with halomethyldimethylchlorosilane. With water and methanol, instead of the expected SiN cleavage, nucleophilic substitution of halogen took place and the products were 1-acetyl-2,2,6,6-tetramethyldisilamorpholine and N,N-bismethoxymethyldimethylsilyl)acetamide respectively. These compounds were shown by IR and ¹H NMR spectra to have the N,N-disilylacetamide structure. Thermodynamic, kinetic constants of hindered rotation around the CN bond in these compounds were determined from their temperature-variable ¹H NMR spectra. The main products of thermolysis of the silylamides are α,ω-dichloropolydimethylsiloxanes and polydimethylcyclosiloxanes.     

Double nucleophilic reaction of amines to the imidazole nucleus and selective synthesis of 5-aminoimidazoles

Reaction of 2-(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole with an excess of N,N-dimethylamine at room temperature gave an abnormal adduct, trans-4,5-bis(dimethylamino)-1-methyl-2,2-dimethylpropyl-2-imidazoline, which was derived from a serial, double nucleophilic addition into the imidazole nucleus in 74% yield together with a normal S_N product, 1-methyl-2-(1-dimethylamino-2,2-dimethylpropyl)-1H-imidazole in 15% yield. The former was easily converted to 1-methyl-5-(dimethylamino)-2-(2,2-dimethylpropyl)-1H-imidazole by only reflux in toluene in 90% yield. The scope, mechanism and limitation of these reactions are discussed.