Presence Of Excess Base Research Articles

Hauser-Kraus Annulation Initiated Multi-Cascade Reactions for Facile Access to Functionalized and Fused Oxazepines, Carbazoles and Phenanthridinediones.

The Hauser-Kraus (H-K) annulation of N-unsubstituted 3-olefinic oxindoles with 3-nucleophilic phthalides triggers a cascade of ring expansion and ring contraction reactions through several regioselective steps in one pot. While oxazepines were isolated in the presence of stoichiometric amounts of base at room temperature, carbazoles and phenanthridinediones were the products in the presence of excess base and microwave irradiation. Mechanistic studies guided by stepwise reactions and control experiments revealed that the isolable oxazepine intermediate, formed via ring expansion of the H-K adduct, is the key precursor to carbazole and phenanthridinedione via decarboxylative regioselective cyclizations.

Stereoselective Conjugate Addition-Enamination of α-Linear N-tert-Butanesulfinyl Ketimines with Nitroolefins

Abstract N-Sulfinyl metalloenamines, generated by deprotonating α-linear N-tert-butanesulfinyl ketimines, reacted with nitroalkenes via stereoselective conjugate addition to give Michael adducts with opposite stereochemistry to that obtained using α-branched sulfinylketimines. In the presence of excess base (2.5 equiv t-BuOK), the adducts derived from α-linear ketimines were further stereoselectively deprotonated to afford the corresponding kinetically favorable N-sulfinyl (Z)-enamine derivatives in good yields with good stereoselectivities. A reaction model was proposed to rationalize the observed stereochemistry.

Tin(IV) and Antimony(V) Complexes Bearing Catecholate Ligands Connected to Ferrocene – Syntheses, Molecular Structures, and Electrochemical Properties

The ferrocenyl‐containing 3,5‐di‐tert‐butylcatechol Fc‐L‐CatH2 (2) was synthesized by the condensation of the precursor 6‐(hydrazonomethyl)‐3,5‐di‐tert‐butylcatechol 6‐(H2N–N=CH)CatH2 (1) with ferrocenecarboxaldehyde (L = –CH=N–N=CH–, Cat = 3,5‐di‐tert‐butylcatecholate, Fc = ferrocene). The exchange reaction between catechol 2 and Ph3SbBr2 in the presence of a base (Et3N) in toluene leads to the formation of the triphenylantimony(V) catecholate (Fc‐L‐Cat)SbPh3 (3) as the main product and the ionic bromotriphenylantimony(V) catecholate (Fc‐LH‐Cat)SbPh3Br (4) containing a hydraziniumylidene cation (LH = –CH=NH+–N=CH–) as the byproduct. The change of toluene to tetrahydrofuran (THF) results in the formation of 4 as the main product in nearly quantitative yield. The exchange reactions of catechol 2 with Ph2SnCl2 and SnCl4 give anionic catecholate complexes bridged with hydraziniumylidene cations even in the presence of excess base. Complexes (Fc‐LH‐Cat)SnPh2Cl (5), (Fc‐LH‐Cat)2SnPh2 (6), and (Fc‐LH‐Cat)2SnCl2 (7) were synthesized. The compounds obtained were characterized by IR spectroscopy, 1H and 13C NMR spectroscopy, elemental analysis, and cyclic voltammetry. The molecular structures of crystals of 5–7 were determined by X‐ray diffraction analysis. The formation of catecholates 4–7 with hydraziniumylidene cations is caused by intramolecular hydrogen bonding between the hydroxy and imine groups, which leads to proton transfer from the oxygen atom to the nitrogen atom of the hydrazine linker.

Mechanism of NHC-Catalyzed Conjugate Additions of Diboron and Borosilane Reagents to α,β-Unsaturated Carbonyl Compounds.

Broadly applicable enantioselective C-B and C-Si bond-forming processes catalyzed by an N-heterocyclic carbene (NHC) were recently introduced; these boryl and silyl conjugate addition reactions (BCA and SCA, respectively), which proceed without the need for a transition-metal complex, represent reaction pathways that are distinct from those facilitated by transition-metal-containing species (e.g., Cu, Ni, Pt, Pd, or Rh based). The Lewis-base-catalyzed (NHC) transformations are valuable to chemical synthesis, as they can generate high enantioselectivities and possess unique chemoselectivity profiles. Here, the results of investigations that elucidate the principal features of the NHC-catalyzed BCA and SCA processes are detailed. Spectroscopic evidence is provided illustrating why the presence of excess base and MeOH or H2O is required for efficient and enantioselective boryl and silyl addition reactions. It is demonstrated that the proton sources influence the efficiency and/or enantioselectivity of NHC-catalyzed enantioselective transformations in several ways. The positive, and at times adverse, impact of water (biphasic conditions) on catalytic enantioselective silyl addition reactions is analyzed. It is shown that a proton source can facilitate nonenantioselective background reactions and NHC decomposition, requiring the catalyst to surpass such complications. Stereochemical models are presented that account for the identity of the observed major enantiomers, providing a rationale for the differences in selectivity profiles of BCA and SCA processes.

Regeneration of β-Carotene from the Radical Cation by Tyrosine and Tryptophan.

The phenolic amino acid tyrosine (Tyr) was found more efficient in regenerating β-carotene (β-Car) from the radical cation (β-Car(•+)) than tryptophan (Trp) in the presence of base for conditions where the reduction potentials for Trp and Tyr are comparable. Electron transfer from Tyr in 4:1 chloroform/methanol to β-Car(•+) in the presence of excess base, (CH3)4N(+)OH(-), had a rate close to diffusion control and a second-order rate constant in agreement with the Marcus theory for electron transfer when compared to plant phenols. A maximum of 40% β-Car was regenerated for ten times excess of Tyr as studied by 532 nm laser flash photolysis followed by transient absorption spectroscopy in the visible and near-infrared regions. The nonregenerated fraction of β-Car is assigned to secondary degradation processes. For Trp, the rate constant for regeneration of β-Car(•+) was 1 order of magnitude smaller compared to Tyr and slower than expected from Marcus theory by comparison with plant phenols.

Homogeneous hydrogenation of CO₂ to methyl formate utilizing switchable ionic liquids.

Combined capture of CO2 and subsequent hydrogenation allows for base/methanol-promoted homogeneous hydrogenation of CO2 to methyl formate. The CO2, captured as an amidinium methyl carbonate, reacts with H2 with no applied pressure of CO2 in the presence of a catalyst to produce sequentially amidinium formate, then methyl formate. The production of methyl formate releases the base back into the system, thereby reducing one of the flaws of catalytic hydrogenations of CO2: the notable consumption of one mole of base per mole of formate produced. The reaction proceeds under 20 atm of H2 with selectivity to formate favored by the presence of excess base and lower temperatures (110 °C), while excess alcohol and higher temperatures (140 °C) favor methyl formate. Known CO2 hydrogenation catalysts are active in the ionic liquid medium with turnover numbers as high as 5000. It is unclear as to whether the alkyl carbonate or CO2 is hydrogenated, as we show they are in equilibrium in this system. The availability of both CO2 and the alkyl carbonate as reactive species may result in new catalyst designs and free energy pathways for CO2 that may entail different selectivity or kinetic activity.

Pt Nanoparticles Loaded on Reduced Graphene Oxide as an Effective Catalyst for the Direct Oxidation of 5-Hydroxymethylfurfural (HMF) to Produce 2,5-Furandicarboxylic Acid (FDCA) under Mild Conditions

Abstract Reduced graphene oxide (RGO) is one of the most promising catalyst supports because it has faintly acidic sites together with a large amount of functional groups on its surface. In this report, we prove that, for the first time, Pt-loaded RGO (Pt/RGO) is an efficient, robust, and durable catalyst for oxidizing 5-hydroxymethylfurfural (HMF) directly to 2,5-furandicarboxylic acid (FDCA) under mild conditions. The selectivity of FDCA reaches up to 84% along with 100% HMF conversion in the presence of excess base. We deduce that the total reaction on the Pt/RGO catalyst includes several consecutive steps, in which 5-hydroxymethyl-2-furancarboxylic acid (HMFCA) acts as an intermediate. The finding in this report is a significant advancement not only for RGO-based catalyst development, but also for scalable FDCA production, because the total reaction is performed smoothly without using the previously reported harsh reaction conditions.

ChemInform Abstract: A Mild One‐Pot Method for Conversion of Various Steroidal Secondary Alcohols into the Corresponding Olefins.

AbstractThe use of Tf2O in the presence of excess base is investigated for the direct dehydration process.

A Mild One-Pot Method for Conversion of Various Steroidal Secondary Alcohols into the Corresponding Olefins

The addition of Tf 2 O to some hydroxy steroids in the presence of excess base directly leads to steroidal olefins. This methodology is useful for the one-pot synthesis of Δ 2 - or Δ 3 -steroids under mild conditions from the corresponding alcohols.

Synthesis of Stable Functional Titanocene Enolates

A modular approach to bench-stable titanocene enolates is described. The reaction of titanocenes containing pendent acid chlorides with activated methylene compounds in the presence of excess base ...

Gold‐Catalyzed Aerobic Oxidation of 5‐Hydroxymethylfurfural in Water at Ambient Temperature

The aerobic oxidation of 5-hydroxymethylfurfural, a versatile biomass-derived chemical, is examined in water with a titania-supported gold-nanoparticle catalyst at ambient temperature (30 °C). The selectivity of the reaction towards 2,5-furandicarboxylic acid and the intermediate oxidation product 5-hydroxymethyl-2-furancarboxylic acid is found to depend on the amount of added base and the oxygen pressure, suggesting that the reaction proceeds via initial oxidation of the aldehyde moiety followed by oxidation of the hydroxymethyl group of 5-hydroxymethylfurfural. Under optimized reaction conditions, a 71% yield of 2,5-furandicarboxylic acid is obtained at full 5-hydroxymethylfurfural conversion in the presence of excess base.

A multi-technique study of the effect of aqueous aluminium speciation on hydrolytic gelation of aluminium (oxy)hydroxide

The sol–gel transformation of aqueous solutions of aluminium ions into aluminium (oxy)hydroxides induced by the addition of a ‘soft base’—‘Tris-buffer’ ( p K a = 8.2 ) has been investigated using monotonous single-batch titrations and a combination of four complimentary techniques for monitoring pH, conductivity, viscosity and ultrasound parameters (velocity and attenuation). The multi-probe monitoring of the formation of aluminium (oxy)hydroxides enabled important stages of the sol–gel transformation process including: the structural conversion of aluminium Keggin-like polynuclear clusters into nanoparticles of aluminium (oxy)hydroxide; the aggregation of primary nuclei of aluminium (oxy)hydroxide into larger particles, and the ‘arrested growth’ of the aggregates with the formation of the three-dimensional gel network to be followed. The effect of aluminium ion molecular speciation on the sol–gel transformation stages is discussed. The data presented show that ultrasonic spectrometry, although a novel tool for sol–gel studies, is beneficial for the non-invasive monitoring of the latter stages of aluminium (oxy)hydroxide formation and its eventual breakdown in the presence of excess base.

Trans-dioxo Manganese(V) Porphyrins

The relatively stable oxoMn(V) porphyrins generated by oxidation of Mn(III) porphyrins in alkaline solutions using peroxides are unambiguously identified as trans-dioxo species. Raman spectra revealed symmetric OMnVO stretching frequencies between 741 and 744 cm-1 for five porphyrin complexes while the IR of dioxo-MnV-tetrapentafluoroporphyrin [MnV(O2)(TPFPP)]- displayed an antisymmetric stretch at 805 cm-1. Both half-labeled and fully labeled 18O−MnV porphyrin complexes were prepared, and the Raman and IR shifts correspond well with a linear, three-body OMnO oscillator model. Terminal, monooxo formulations such as HO−MnVO or five-coordinate MnVO are excluded by the data. The 1H NMR spectrum of [MnV(O2)(TMP)]-, which shows a single, sharp resonance for the two ortho methyl groups, is also consistent with octahedral coordination of D4h symmetry. The force constant F for the MnO double bond was calculated to be 454 N/m with a stretch−stretch force constant k = 67.2 N/m. Comparison with other Mn−O force constants revealed a very good agreement with Badger's rule spanning five Mn oxidation states. These dioxo-MnV porphyrins were shown to not exchange the oxo oxygens with bulk water solvent. Dioxo MnV porphyrins, which are anionic species [Por-MnV(O)2]-, are unreactive toward olefins in the presence of excess base but efficiently epoxidize cyclooctene upon protonation at −70 °C. These compounds are the only trans-dioxomanganese complexes of any type to be characterized as such, thus extending the known π-bonding arrangements for first-row transition metals.

Investigation of the role of the base in the synthesis of [ 18F]FLT

The role of the base in the synthesis of 3′-deoxy-3′-[ 18F]fluorothymidine, [ 18F]FLT, via nucleophilic substitution of the nosyl group with [ 18F]fluoride was investigated. The rate of 18F-incorporation into the molecule dramatically changed as a function of the precursor-to-base ratio. In the presence of excess base, the precursor was consumed by elimination before substitution was complete. When the precursor-to-base ratio was optimal, an overall [ 18F]FLT yield of 30–40% was achieved even if the precursor amount was as small as 8–13 mg.

Synthesis of Diazeniumdiolates from the Reactions of Nitric Oxide with Enolates

[reaction: see text] Reactions of nitric oxide with enolates derived from aliphatic methyl ketones containing alpha-methylene or alpha-methine groups and with enolates derived from alpha,alpha'-dimethylene or alpha,alpha'-dimethine ketones yield mono- or bis(diazeniumdiolate) products. Diazeniumdiolation occurs in the following order: alpha-methine > alpha-methylene > alpha-methyl. The amount of the base used alters the extent of diazeniumdiolation and the course of the reaction. Mono- and bis(diazeniumdiolate)-substituted methyl ketones are cleaved in the presence of excess base before and after the subsequent diazeniumdiolation of the alpha-methyl group. Similar to the trihalogenated methyl groups in the base-assisted halogenation reactions of methyl ketones, the bis(diazeniumdiolate)-substituted alpha-methylene and alpha-methyl groups act as leaving groups in the presence of excess base. The reaction of nitric oxide with a (approximately 20:80, cis/trans) mixture of 2,6-cyclohexananone yields the cis and trans isomers of 2,6-dimethylcyclohexanone-2,6-bis(diazeniumdiolate) in 12.9% and 57.6% yield. Single-crystal X-ray diffraction data determined for potassium cis-2,6-dimethylcyclohexanone-2,6-bis(diazeniumdiolate), cis-14b, reveal that the N(2)O(2-) substituent is planar with considerable delocalization of a double bond over the anionic four-atom group. Except for one of the diazeniumdiolate products, namely, potassium propanoate 2,2-bis(diazeniumdiolate), 8b, all are stable in neutral and basic aqueous media. Compound 8b slowly decomposes in neutral aqueous solution releasing nitrous oxide and nitric oxide gases but is stable in basic aqueous media. Differential scanning calorimetry data measured for the diazeniumdiolate products indicate that they decompose exothermally with most of them undergoing explosive decomposition at moderately high temperatures (181-274 degrees C).

Synthesis, enantiomeric resolution, F-18 labeling and biodistribution of reboxetine analogs: promising radioligands for imaging the norepinephrine transporter with positron emission tomography

Racemic and enantiomerically pure (( S, S) and ( R, R)) 2-[α-(2-(2-[ 18F]fluoroethoxy)phenoxy)benzyl]morpholine ([ 18F]FRB) and its tetradeuterated form [ 18F]FRB-D 4, analogs of the highly selective norepinephrine reuptake inhibitor reboxetine (2-[α-(2-ethoxyphenoxy)benzyl]morpholine, RB), have been synthesized for studies of norepinephrine transporter (NET) system with positron emission tomography (PET). The [ 18F]fluorinated precursor, ( S, S)/( R, R)- N- tert-butyloxycarbonyl-2-[α-(2-hydroxyphenoxy)benzyl]morpholine (( S, S)/( R, R)- N-Boc-desethylRB), was prepared by the N-protection of ( S, S)/( R, R)-2-[α-(2-hydroxyphenoxy)benzyl]morpholine (( S, S)/( R, R)-desethylRB) with a tert-butyloxycarbonyl (Boc) group followed by enantiomeric resolution with chiral HPLC to provide both ( S, S) and ( R, R) enantiomers with >99% enantiomeric purity. These compounds were then used for radiosynthesis to prepare enantiomerically pure [ 18F]FRB and [ 18F]FRB-D 4 via the following three-step procedure: (1) formation of 1-bromo-2-[ 18F]fluoroethane ([ 18F]BFE or [ 18F]BFE-D 4) by nucleophilic displacement of 2-bromoethyl triflate (or D 4 analog) with no-carrier added [ 18F]F − in THF; (2) reaction of [ 18F]BFE (or [ 18F]BFE-D 4) with N-Boc-desethylRB in DMF in the presence of excess base; and (3) deprotection with trifluoroacetic acid. The racemates, ( S, S) and ( R, R) enantiomers of [ 18F]FRB and [ 18F]FRB-D 4 were obtained in 11–27% (decay corrected to the end of bombardment, EOB) in 120-min synthesis time with a radiochemical purity of >98% and specific activities of 21–48 GBq/μmol (EOB). The results of the whole-body biodistribution studies with ( S, S)-[ 18F]FRB-D 4 were similar to those with ( S, S)-[ 18F]FRB but showed relatively faster blood clearance and no significant in vivo defluorination. Positron emission tomography studies in baboon brain also showed that ( S, S)-[ 18F]FRB-D 4 may be a potentially useful ligand for imaging NET with PET.

Synthesis, enantiomeric resolution, and selective C-11 methylation of a highly selective radioligand for imaging the norepinephrine transporter with positron emission tomography.

Reboxetine, 2-[alpha-(2-ethoxyphenoxy)benzyl]morpholine, is a highly selective norepinephrine transporter (NET) blocker that has been used for the treatment of depression. Its methyl analogue, 2-[alpha-(2-methoxyphenoxy)benzyl]morpholine (MRB), has been radiolabeled with C-11 for studies of the NET system with positron emission tomography (PET). The normethyl precursor, 2-[alpha-(2-hydroxyphenoxy)benzyl]morpholine (desethylreboxetine), was synthesized in 6% overall yield via a multi-step regio- and stereo-specific synthesis, starting from a mono-O-protected catechol. The resulting racemic mixture of desethylreboxetine was resolved by chiral HPLC to provide the (2S,3S) and (2R,3R) enantiomers in >98% enantiomeric excess. These enantiomers were then used as precursors for radiosynthesis to prepare enantiomerically pure individual 11C-labeled MRB enantiomers for comparative PET studies in baboons. Selective C-11 methylation at the phenolic oxygen with [11C]CH3I was achieved in the presence of excess base. After HPLC purification, racemic ((2S,3S)/(2R,3R)) or enantiomerically pure ((2S,3S) or (2R,3R)) [11C]MRB was obtained in 61-74% decay-corrected radiochemical yields from [11C]CH3I in a synthesis time of 40 min with a radiochemical purity of >96% and a specific activity of 1.7-2.3 Ci/micromol (63-85 GBq/micromol) corrected from the end of bombardment (EOB).

Kinetics of glycoluril template-directed Claisen condensations and mechanistic implications

Eight N-acetyl-N-aroyl-glycolurils were prepared and found to undergo efficient tert-butoxide-promoted Claisen-like condensation between the two acyl moieties. The kinetics for formation of each of the N-(aroylacetyl)gly coluril products were monitored by UV spectroscopy. The reaction exhibited pseudo-first-order kinetics in substrate in the presence of excess base. For the parent benzoyl compound the observed first-order rate constant (kobs) was linearly dependent on the concentration of the base, tert-butoxide. A Hammett plot of the resulting apparent second-order rate constants (kapp) vs. σ for each of the eight aroyl derivatives was linear and had a positive ρ value 1.04 ± 0.04), demonstrating that the substituent on the aromatic ring exerts a significant effect upon the condensation reaction. The corresponding plot for three [D3]acetyl analogues was also linear, but the slope was reduced by 20% relative to the protonated compounds. The isotope effect (kHapp/kDapp) thus increased from 1.4 (benzoyl) to 2.6 (p-nitrobenzoyl). The results are consistent with a three-step mechanism in which both deprotonation of the acetyl entity and the ensuing nucleophilic attack of the resulting enolate on the benzoyl group are partially rate-determining steps. The tetrahedral intermediate thus produced rapidly collapses to the product. For the [D3]acetyl benzoyl derivative, exchange of substrate deuterium with solvent hydrogen due to reprotonation of the enolate intermediate occurs at a rate that is similar to that of condensation, but the enolate partitions towards the product when electron withdrawing groups are present in the aroyl ring. Thus, despite the presence of a large excess of co-solvent tert-butanol, the efficiency with which the enolate undergoes condensation remains high. The clean kinetics observed allows further exploration of the details of this intramolecular Claisen-like condensation process.Key words: Claisen condensation, glycoluril, kinetics, Hammett, mechanism.

A Facile One-Pot Synthesis of 4,5-Diaryl-2,2-dimethyl-3(2H)-furanones

An efficient and practical one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones has been achieved from 1,2-diarylethanones and 2-bromoisobutyryl cyanide in the presence of excess base, by employing the ‘hard soft acid base’ principle. The reaction scope of 2-bromoisobutyryl cyanide could be expanded to prepare a variety of 2,2-dimethyl-3(2H)-furanone derivatives other than 4,5-diaryl-2,2-dimethyl-3(2H)-furanones.

Palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl- and ferrocenyldialkylphosphine ligands.

Palladium-catalyzed reactions of aryl bromides and chlorides with two common stabilized carbanions-enolates of dialkyl malonates and alkyl cyanoesters-are reported. An exploration of the scope of these reactions was conducted, and the processes were shown to occur in a general fashion. Using P(t-Bu)(3) (1), the pentaphenylferrocenyl ligand (Ph(5)C(5))Fe(C(5)H(4))P(t-Bu)(2) (2), or the adamantyl ligand (1-Ad)P(t-Bu)(2) (3), reactions of electron-poor and electron-rich, sterically hindered and unhindered aryl bromides and chlorides were shown to react with diethyl malonate, di-tert-butyl malonate, diethyl fluoromalonate, ethyl cyanoacetate, and ethyl phenylcyanoacetate. Although alkyl malonates and ethyl alkylcyanoacetates did not react with aryl halides using these catalysts, the same products were formed conveniently in one pot from diethylmalonate by cross-coupling of an aryl halide in the presence of excess base and subsequent alkylation.