Homoleptic Zincate‐Promoted Room‐Temperature Halogen–Metal Exchange of Bromopyridines

Homoleptic lithium tri‐ and tetraalkyl zincates were reacted with a set of bromopyridines. Efficient and chemoselective bromine–metal exchanges were realized at room temperature with a substoichiometric amount of nBu₄ZnLi₂?TMEDA reagent (1/3 equiv; TMEDA=N,N,N′,N′‐tetramethylethylenediamine). This reactivity contrasted with that of tBu₄ZnLi₂?TMEDA, which was inefficient below one equivalent. DFT calculations allowed us to rationalize the formation of N???Li stabilized polypyridyl zincates in the reaction. The one‐pot difunctionalization of dibromopyridines was also realized using the reagent stoichiometrically. The direct creation of C? Zn bonds in bromopyridines enabled us to perform efficient Negishi‐type cross‐couplings.     

New bifunctional organocatalysts based on (R,R)-cyclohexane-1,2-diamine for the asymmetric addition of nucleophiles to aldehydes

The amide and sulfamide derivatives of (1R,2R)-N,N-diethylcyclohexane-1,2-diamine can serve as organocatalysts for addition of Me₃SiCN and Et₂Zn to aldehydes.     

An efficient synthesis of 1-cyanoacetyl-5-halomethyl-4,5-dihydro-1H-pyrazoles in ionic liquid

The synthesis of eleven 1-cyanoacetyl-5-hydroxy-5-halomethyl-4,5-dihydro-1H-pyrazoles from the reaction of 4-alkoxy-3-alken-2-ones f(R ³C(O)C(R ²) = C(R ¹)OR, where R ³ = CF₃, CCl₃, CHCl₂, CO₂ Et; R ²/R ¹ = H/H, H/Me, H/Et, -(CH₂)₄-, Me/H, H/Pr, and R = Me, Et) with cyanoacetohydrazide is reported. The reaction was carried out in the ionic liquid ([bmim][BF₄]) and molecular solvents. The results showed that when the ionic liquid was used as reaction medium, the reaction time was drastically decreased and the yield was improved.     

Polymerization of acrolein and methyl vinyl ketone induced by amine–water and pyridine–phenol systems

It was reported that acrolein (AL) in tetrahydrofuran (THF) polymerizes at temperatures below 0°C in the presence of pyridine (Py) and water. To clarify this polymerization mechanism the polymerization of AL and methyl vinyl ketone (MVK) by an initiation system such as Py–water, triethylamine (Et₃N)–water, or Py–phenol(Ph) was carried out. The polymerization rate (R_p) of MVK in the Et₃N–water system was expressed by the same equation, R_p = k [Et₃N] [H₂O] [MVK]², used for AL in the Py–water system. Meanwhile, β-hydroxypropionaldehyde, β-phenoxypropionaldehyde, γ-ketobutanol, and β-phenoxy-1-methylpropionketone were obtained as the initial addition products. The polymer of AL obtained was composed of polymer units of vinyl and aldehyde polymerization, but the structure of MVK polymer obtained by the Py–water system was composed of only vinyl polymerization units. The polymerization of MVK by the Py–Ph system did not occur, however. These results were discussed in terms of the initiation and propagation mechanisms.     

Synthesis of Cannabinoid Model Compounds. Part 3. (6aR, 10aR)-N-ethyl-Δ8-tetrahydrocannabinol-18-amide, (6aR, 10aR, 17 RS)-N-ethyl-17-methyl-Δ8- tetrahydrocannabinol-18-amide and (6aR, 10aR)-17,18-didehydro-Δ8-tetrahydrocannabinol

The novel cannabinoids (6aR, 10aR)-N-ethyl-Δ⁸-tetrahydrocannabinol-18-amide (15) and (6aR, 10aR, 17 RS)-N-ethyl-17-methyl-Δ⁸- tetrahydrocannabinol-18-amide (16) , designed as cannabinoid affinity ligands, were synthesized from the corresponding acids 11 and 12 via the N-hydroxysuccinimide esters. Amide 16 was tested in the rat and was generalized to Δ⁹-tetrahydrocannabinol, being 5 times less potent than the training drug. An improved synthesis of (6aR, 10aR)-17,18-didehydro-Δ⁸-tetrahydrocannabinol (23) is reported. As model reaction for the preparation of a tritiated Δ⁸-tetrahydrocannabinol, compound 23 was selectively deuterated at C(17) and C(18) in benzene/Et₃N using [(C₆H₅)₃P]₃RuCl₂ as catalyst.     

An efficient synthesis of 1-cyanoacetyl-5-halomethyl-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazoles in ionic liquid

The synthesis of eleven 1-cyanoacetyl-5-hydroxy-5-halomethyl-4,5-dihydro-1H-pyrazoles from the reaction of 4-alkoxy-3-alken-2-ones f(R ³C(O)C(R ²) = C(R ¹)OR, where R ³ = CF₃, CCl₃, CHCl₂, CO₂ Et; R ²/R ¹ = H/H, H/Me, H/Et, -(CH₂)₄-, Me/H, H/Pr, and R = Me, Et) with cyanoacetohydrazide is reported. The reaction was carried out in the ionic liquid ([bmim][BF₄]) and molecular solvents. The results showed that when the ionic liquid was used as reaction medium, the reaction time was drastically decreased and the yield was improved. Correspondence: Marcos A. P. Martins, Núcleo de Química de Heterociclos – NUQUIMHE, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.     

Structural Investigation of New Lithium Amidinates and Guanidinates

A series of potentially useful lithium amidinates and guanidinates were prepared and fully characterized. Treatment of N,N′‐diisopropylcarbodiimide with phenyllithium in diethyl ether afforded the lithium amidinate [PhC(NiPr)₂Li(OEt₂)]₂ ( 1 ). Similar treatment of N,N′‐diorganocarbodiimides R′–N=C=N–R′ [R′ = iPr, cyclohexyl (Cy)] with secondary lithium amides LiNR₂ [R₂ = Et₂, iPr₂, (CH₂)₄] followed by crystallization from THF or 1,4‐dioxane gave the lithium guanidinates [R₂NC(NR′)₂Li(S)]₂ [ 2 : R = Et, R′ = iPr, S = THF; 3 : R₂ = (CH₂)₄, R′ = iPr, S = THF; 4 : R = R′ = iPr, S = ½ 1,4‐dioxane; 5 : R₂ = (CH₂)₄, R′ = Cy, S = 1,4‐dioxane] as crystalline solids. Reaction of N‐lithioaziridine with the corresponding carbodiimides afforded solvent‐deficient [{C₂H₄NC(NiPr₂)₂}₂Li₂(THF)]₂ ( 6 ), and [C₂H₄NC(NEt)(NtBu)Li(THF)]₂ ( 7 ). Crystal structure determination revealed the presence of common ladder‐type dimeric structures for 1 – 5 . Compound 6 exists as a dimer of two ladder‐type dimers in the crystal, and 7 exhibits an unusual dimeric structure comprising an eight‐membered C₂N₄Li₂ ring.     

Synthesis of Binam‐P Derived C2‐Symmetric bis‐Iminophosphonamide Ligands. Molecular Structure of [(R)‐Binam(Ph2PN(H)tBu)2]

The Staudinger reaction of organic azides tBuN₃, 1‐Ad‐N₃, and DippN₃ (Dipp = 2,6‐diisopropylphenyl) with (R)‐N,N′‐bis(diphenylphosphanyl)‐2,2′‐diamino‐1,1′‐binaphthyl [(R)‐Binam‐P], obtained by an optimized procedure from (R)‐(+)‐Binam, Ph₂PCl, and Et₃N in DCM, leads to preparation of a series of new C₂‐symmetric bis‐iminophosphonamide ligands [(R)‐Binam(Ph₂PN(H)R)₂] [R = tBu ( 1 ), Ad ( 2 ), and Dipp ( 3 )]. The molecular structure of 1· 2DMSO was confirmed by X‐ray structure analysis.     

Herstellung enantiomerenreiner Derivate von 3-Amino- und 3-Mercaptobuttersäure durch SN2-Ringöffnung des β-Lactons und eines 1,3-Dixoanons aus der 3-Hydroxybuttersä ure

Preparation of Enantiomerically Pure Derivatives of 3-Amino- and 3-Mercaptobutanoic Acid by S_N2 Ring Opening of the β-Lactone and a 1,3-Dioxanone Derived from 3-Hydroxybutanoic Acid From (S)-4-methyloxetan-2-one ( 1 ), the β-butyrolactone readily available from the biopolymer ( R )-polyhydroxybutyrate (PHB) and various C, N, O and S nucleophiles, the following compounds are prepared:(s)-2-hydroxy-4-octanone ( 3 ), (R)-3-aminobutanoic acid ( 7 ) and its N-benzyl derivative 5 , (R)-3-azidobutanoic acid ( 6 ) (R)-3-mercaptobutanoic acid ( 10 ), (R)-3-(phenylthio)butanoic acid ( 8 ) and its sulfoxide 9 . The (6R)-2,6-dimethyl-2-ethoxy-1,3-dioxan-4-one ( 4 ) from (R)-3-hydroxybutanoic acid undergoes S^N2 ring opening with benzylamine to give the N-benzyl derivative (ent- 5 ) of (S)-3-aminobutanoic acid in 30?40% yield.     

N-Benzyl Derivatives of Leucine Esters

Leucine methyl and ethyl esters reacted with 3-bromobenzaldehyde and 4-chlorobenzaldehyde in anhydrous methanol in the presence of magnesium sulfate to afford the coresponding Schiff bases of the general formula (CH3)2CHCH2CH(COOR¹)N=CHR² [R¹ = CH3, C2H5, R²= 3-BrC6H4, 4-ClC6H4]. Their reduction with sodium tetrahydridoborate yielded N-benzyl derivatives (CH3)2CHCH2CH(COOR¹)NHCH2R², which were converted into N-acyl-N-benzyl derivatives (CH3)2CHCH2CH(COOR¹)N(COR³)CH2R²[R³= CH₃, C₆H₅].     

Helical poly(phenylacetylene)s containing schiff‐base and amino groups: Synthesis,secondary structures,and responsiveness to benzoic acid

Novel acetylenic monomers containing Schiff‐base and amino groups, (S)‐N‐(4‐ethynylbenzylidene)‐1‐phenylethanamine ( 1a ), (R)‐N‐(4‐ethynylbenzylidene)‐1‐phenylethanamine ( 1b ), N‐(4‐ethynylbenzylidene)‐1‐phenylethanamine ( 1c ), (R)‐N‐(4‐ethynylbenzyl)‐1‐phenylethanamine ( 1d ), and (R)‐N‐(4‐ethynylbenzyl)‐1‐phenylethanamine ( 1e ) were synthesized and polymerized with [(nbd)RhCl]₂/Et₃N catalyst to afford the corresponding polymers 2a ‐ e with moderate molecular weights (M_n = 9000–60,000) in high yields (85–97%). All the polymers were soluble in common organic solvents including toluene, CHCl₃, CH₂Cl₂, THF, and DMF. Large optical rotations and strong CD signals demonstrated that 2a , 2b , 2d , and 2e take helical structures with a predominantly one‐handed screw sense. The effects of solvents and temperature revealed that these polymers took dynamic helical structure based on the steric effect of side groups. The CD patterns of 2d and 2e containing free amino moieties were completely inverted by the addition of benzoic acid. Upon further addition of NaOH, the CD pattern returned to the original one, indicating the reversible conformational change of these polymers according to pH. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 5248–5256     

Syntheses,Structures, and Biological Activity of NiII,PdII, and PtII Complexes with New Tetradentate Benzamidine Ligands

N‐(Dialkylthiocarbamoyl)benzimidoyl chlorides react with o‐(salicylidenimine)benzylamine with formation of a novel class of tetradentate benzamidine ligands (H₂L^Et and H₂L^Morph), which readily react with Ni(CH₃COO)₂, [PdCl₂(CH₃CN)₂], and [PtCl₂(PPh₃)₂] under formation of complexes of the composition [M(L^R)] [M = Ni ( 4 ), Pd ( 5 ), Pt ( 6 )]. In all complexes, H₂L^R is doubly deprotonated and bonded to the metal ion via its N₂OS donor set and establishes a distorted square‐planar coordination sphere. The antiproliferative effects of the compounds on MCF‐7 and Hep‐G2 cells were studied. The complexes of H₂L^Morph are generally more active than those of H₂L^Et. While H₂L^Et and its complexes exhibit stronger effects on the Hep‐G2 line, the corresponding compounds of H₂L^Morph show almost equal effects on the two cell lines. In each series of compounds, the cytotoxicity increases in the order H₂L^R << 4 < 5 < 6 .     

Nitridorhenium(V) Complexes with 1,3‐Dialkyl‐4,5‐dimethylimidazole‐2‐ylidenes

The nitridorhenium(V) complexes [ReNCl₂(PR₂Ph)₃] (R = Me, Et) react with the N‐heterocyclic carbenes (NHC) 1,3‐diethyl‐4,5‐dimethylimidazole‐5‐ylidene (L^Et) or 1,3,4,5‐tetramethylimidazole‐2‐ylidene (L^Me) in absolutely dry THF under complete replacement of the equatorial coordination sphere. The resulting [ReNCl(L^R)₄]⁺ complexes (L^R = L^Me, L^Et) are moderately stable as solids and in solution, but decompose in hot methanol under formation of [ReO₂(L^R)₄]⁺ complexes. With 1,3‐diisopropyl‐4,5‐dimethylimidazole‐5‐ylidene (L^i‐Pr), the loss of the nitrido ligand and the formation of a dioxo species is more rapid and no nitridorhenium intermediate could be isolated. The Re‐C bond lengths in [ReNCl(L^Et)₄]Cl of approximately 2.195Å are relatively long and indicate mainly σ‐bonding in the electron‐deficient d² system under study. The hydrolysis of the nitrido complexes proceeds via the formation of [ReO₃N]^2? anions as could be verified by the isolation and structural characterization of the intermediates [{ReN(PMe₂Ph)₃}{ReO₃N}]₂ and [{ReN(OH₂)(L^Et)₂}₂O][ReO₃N].     

Stereoselective Conversion of Campholene- to Necrodane-Type Monoterpenes. Novel Access to (−)-(R,R)- and (R,S)-α-Necrodol and the Enantiomeric γ-Necrodols

Naturally occurring (?)-(R,R)-α-necrodol ((?)- 1 ) and its C(4)-epimer (?)- 2 are obtained in 84 and 44% yields, respectively, by lithium ethylenediamide (LEDA) treatment of the corresponding β-necrodols (?)- 3 and (?)- 4 (Scheme 1, Table), both readily available from (?)-campholenyl acetate ((?)- i ) by an efficient stereoselective synthesis. The thermodynamically preferred (?)-(R)-γ-necrodol ((?)- 5 ) becomes the major product (≥ 80% yield) after either prolonged treatment with LEDA or exposure of α- and β-necrodols to BF₃·Et₂O. In an alternative route, (+)- 5 is prepared starting from (+)-campholenal ((+)- ii ) via Pd-catalysed decarbonylation to (?)-(S)-1,4,5,5-tetramethylcyclopent-l-ene ((?)- 6 ) and subsequent application of an acid-catalysed CH₂O-addition/rearrangement sequence (Scheme 2).     

An ionic liquid as reaction medium for the synthesis of halo-containing β-enaminones at room temperature

A series of twenty halomethylated β-enaminones [RC(O)CH=C(R ¹)NR ³ R ⁴, where R = CF₃,CCl₃, CHCl₂; R ¹ = H, Me, Ph; R ³ = H, Me, Bu, Et; R ⁴ = Me, Et, Bu, allyl, tert-amyl, CH₂CH₂OH, Bn, Ph] were synthesized using the ionic liquid [bmim]BF₄ at room temperature. It is demonstrated that this ionic liquid is a reaction medium suitable for the amination of β-alkoxyvinyl halomethyl ketones. The advantages of this method are the absence of solvents, short reaction times, and good yields. Correspondence: Marcos A. P. Martins, Núcleo de Química de Heterociclos – NUQUIMHE, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.     

Double stereoselective coordination of chiral N,S ligands: Synthesis,coordination chemistry and utilization in Pd‐catalyzed allylic alkylation

A series of chiral pentane‐2,4‐diyl‐based thioether‐amine ligands [ 4 and 5 ; (R,S)‐ and (S,S)‐R¹SCH(CH₃)CH₂CH(CH₃)NHR², respectively, where 4a R¹ = iPr, R² = Ph; 4b R¹ = tBu, R² = Ph; 4c R¹ = 1‐Ad, R² = Ph; 5a R¹ = iPr, R² = Ph; 5b R¹ = tBu, R² = Ph; 5c R¹ = 1‐Ad, R² = Ph; 5d R¹ = iPr, R² = 4‐MeOC₆H₄; 5e R¹ = iPr, R² = 4‐MeC₆H₄; 5f R¹ = iPr, R² = 3,5‐Me₂C₆H₃] with stereogenic S‐ and N‐donor atoms has been prepared starting from cyclic sulfates via optically pure γ‐aminoalcohol or 2,4‐dimethylazetidine intermediates. The synthesis of the novel diastereomerically related ligand sets 4 and 5 was accomplished starting from the same source of chirality. The modular ligand structure and the novel synthetic strategies developed for their synthesis allowed the easy modification of the ligands’ (i) S‐ and (ii) N‐substituents, as well as (iii) the relative stereochemistry within the ligand backbone. Six‐membered [Pd(N,S)Cl₂]‐type chelate complexes of the diastereomerically related ligands 4a and 5a were synthesized and characterized by X‐ray crystallography in the solid phase, by density functional theory calculations and in solution by NMR spectroscopy. The coordination of 5a resulted in the formation of a single chair conformation by the stereospecific locking of both stereolabile (N and S) donor atoms. In contrast, compound 4a forms rapidly equilibrating palladium species due to the fast inversion of the sulfur donor. Ligands with stereochemically fixed donor atoms provided robust and efficient catalytic systems that can be effectively applied in alkylene carbonates as green reaction media. Remarkably, the phosphine‐free catalysts are air‐stable, and at room temperature in the presence of moisture gave excellent ee’s (up to 93%) in asymmetric allylation processes thanks to the double stereoselective coordination.     

The Aggregation Behavior of Butyllithium in Diethyl Ether in the Presence of LiBr,LiClO4, and Phenyllithium: A Deuterium‐Induced Secondary 6Li‐NMR Isotope‐Effect Study

The aggregation of BuLi (LiR) in diethyl ether (Et₂O) in the presence of LiBr was studied by ⁶Li‐ and ¹³C‐NMR spectroscopy. For a 1.0 : 0.8 mixture of both species, the clusters (LiR)₄, Li₄R₃Br, Li₄R₂Br₂, Li₄RBr₃, and/or Li₂RBr in the ratio 7 : 81 : 12 with Li₄RBr₃ and/or Li₂RBr<1 were detected with the isotopic fingerprint method that is based on secondary deuterium (D)‐induced isotope shifts for δ(Li). The raising content of bromide ions causes increased shielding for δ(Li). As in the case of a 1 : 1 MeLi/LiBr mixture in Et₂O, cluster Li₄R₃Br is the most stable one. In the presence of N,N,N′,N′‐tetramethylethylenediamine (TMEDA), only a mixed dimer was found. For LiClO₄, no inclusion of the ClO$\rm{{_{4}^{-}}}$ ion could be detected. A mixture BuLi/PhLi 1 : 1 in Et₂O in the presence of TMEDA showed only dimers with the mixed dimer as the most stable cluster. Chemical exchange of Li between the two homodimers was detected by EXSY spectroscopy. This implies an exchange mechanism with a fluxional tetramer as intermediate.     

6,6′‐Di­methoxy‐2,2′‐[(1R,2R)‐cyclo­hexane‐1,2‐diyl­bis­(nitrilo­methyl­idyne)]­diphenol: three C—H⃛O hydrogen bonds generate a three‐dimensional framework

Molecules of the title compound, alternatively called (R,R)‐N,N′‐bis(3‐methoxysalicylidene)‐trans‐cyclohexane‐1,2‐diamine, C₂₂H₂₆N₂O₄, contain two intramolecular O—H⃛N hydrogen bonds and adopt a conformation with approximate twofold rotational symmetry. The mol­ecules are linked by three C—H⃛O hydrogen bonds [H⃛O = 2.45–2.55 Å, C⃛O = 3.329 (2)–3.398 (2) Å and C—H⃛O = 142–172°] into a continuous framework.     

Electrogenerated acetonitrile anion induced selective N-alkylation of bifunctional compounds

The simple galvanostatic reduction of a solution of MeCN-0.1 M Et₄NPF₆ leads to the formation of acetonitrile anion, whose counter-ion is the Et₄N⁺ cation, which leaves the anion ‘naked’. This enhances the reactivity of acetonitrile anion, which reveals to be selective in the N-monoalkylation of bifunctional compounds (cycloserine, β-amino alcohols, 2-substituted anilines) obtaining high yields. N,N-bis-alkylation has never been observed, indicating that the electrochemical methodology is highly regioselective.     

Synthesis and Reactivity of Organometallic Intermediates Relevant to Cobalt-Catalyzed Hydroformylation

Intermediates relevant to cobalt-catalyzed alkene hydroformylation have been isolated and evaluated in fundamental organometallic transformations relevant to aldehyde formation. The 18-electron (R,R)-(^iPrDuPhos)Co(CO)₂H has been structurally characterized, and it promotes exclusive hydrogenation of styrene in the presence of 50 bar of H₂/CO gas (1:1) at 100 °C. Deuterium-labeling studies established reversible 2,1-insertion of styrene into the Co−D bond of (R,R)-(^iPrDuPhos)Co(CO)₂D. Whereas rapid β-hydrogen elimination from cobalt alkyls occurred under an N₂ atmosphere, alkylation of (R,R)-(^iPrDuPhos)Co(CO)₂Cl in the presence of CO enabled the interception of (R,R)-(^iPrDuPhos)Co(CO)₂C(O)CH₂CH₂Ph, which upon hydrogenolysis under 4 atm H₂ produced the corresponding aldehyde and cobalt hydride, demonstrating the feasibility of elementary steps in hydroformylation. Both the hydride and chloride derivatives, (X=H⁻, Cl⁻), underwent exchange with free ¹³CO. Under reduced pressure, (R,R)-(^iPrDuPhos)Co(CO)₂Cl underwent CO dissociation to form (R,R)-(^iPrDuPhos)Co(CO)Cl.