Addition-elimination Sequence Research Articles

A chlorine-free microwave-assisted, ionic liquid-catalyzed esterification of arylsulfonic acids with alcohols: an experimental and theoretical study.

In the area of esterification of heteroatomic acids, after the microwave-assisted ionic liquid-catalyzed esterification of phosphinic acids, the esterification of arylsulfonic acids was also developed applying a 14-fold excess of alcohols at 200 °C in the presence of 10% butyl-methylimidazolium hexafluorophosphate as an additive. The esterifications were optimized, and the effect of the substituents in the aromatic ring was evaluated. At the same time, a similar procedure described by Mandal et al. using only one equivalent of alcohol at 120 °C for 5 min in toluene was refuted. The mechanism and energetics of the reaction of benzenesulfonic acid and butyl alcohol were determined at the B3LYPD3/def2TZVP[PCM(BuOH)] level of theory using the explicit-implicit solvent model, and, as a comparison, the implicit solvent model. Three possible reaction pathways were explored: the direct esterification of benzenesulfonic acid through an SN2 protocol including the nucleophilic addition of butyl alcohol to the SO function of the sulfonic acid via an intermediate with a hexavalent-pentacoordinated S atom (Route I), via protonation of the alcohol by the arenesulfonic acid followed by the recombination of the sulfonate anion and the alkyl cation formed by dehydration (Route II), and an SN1 route involving the initial formation of a sulfonium cation by dehydration of the protonated sulfonic acid followed by the nucleophilic attack of the alcohol (Route III). Judging from the energetics of the three potential pathways, the alkylating esterification (Route II) seems to be the predominant route. Microwave irradiation may overcome the enthalpy of activation of 132 kJ mol-1 required for this protocol. The addition-elimination (SN2) sequence (Route I) may also be operative as a minor reaction component.

Water Mediated Rearrangement of Alkynyl Cyclohexadienones: Access to meta-Alkenylated Phenols.

We report an efficient water mediated, Brønsted acid-catalyzed rearrangement of alkynyl cyclohexadienones to access meta-olefinated phenols under metal-free conditions. The reaction displayed excellent substrate scope and yields in water. Synthetic utility of the protocol was highlighted by carrying out gram scale synthesis, further functionalizations, and late stage modification. Mechanistic studies highlighted the key role of water, as the reaction proceeds via a water addition-elimination sequence on to a vinyl cation intermediate.

Cyanide-Mediated Synthesis of Sulfones and Sulfonamides from Vinyl Sulfones

We report a facile synthesis of sulfones, β-keto sulfones, and sulfonamides from vinyl sulfones via an addition–elimination sequence where in situ generation of nucleophilic sulfinate ion is mediated by cyanide. The use vinyl sulfones renders high selectivity for S-alkylation to produce sulfones in high yields. In the presence of N-bromosuccinimide, primary and secondary amines underwent sulfonamide formation. A preliminary mechanistic study showed the formation of acrylonitrile as an innocent byproduct, without interfering with the desired reaction pathway while generating a sulfinate nucleophile.

Multiscale Computational Study on the Catalytic Mechanism of the Nonmetallo Amidase Maleamate Amidohydrolase (NicF).

Maleamate amidohydrolase (NicF) is a key enzyme in vitamin B3 metabolism that catalyzes the hydrolysis of maleamate to produce maleic acid and ammonia. Unlike most members from the amidohydrolase superfamily it does not require a metal ion. Here, we use multiscale computational enzymology to investigate the catalytic mechanism, substrate binding, oxyanion hole, and roles of key active site residues of NicF from Bordetella bronchiseptica. In particular, molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) and QTAIM methods have been applied. The mechanism of the NicF-catalyzed reaction proceeds by a nucleophilic addition-elimination sequence involving the formation of a thioester enzyme intermediate (IC2 in stage 1) followed by hydrolysis of the thioester bond to form the products (stage 2). Consequently, the formation of IC2 in stage 1 is the rate-limiting step with a barrier of 88.8 kJ·mol-1 relative to the reactant complex, RC. Comparisons with related metal-dependent enzymes, particularly the zinc-dependent nicotinamidase from Streptococcus pneumonia (SpNic), have also been made to further illustrate unique features of the present mechanism. Along with -NH- donor groups of the oxyanion hole (i.e., HN-Thr146, HN-Cys150), the active site β-hydroxyl of threonine (HO-βThr146) is concluded to play a role in stabilizing the carbonyl oxygen of maleamate during the mechanism.

Concerted nucleophilic aromatic substitutions.

Nucleophilic aromatic substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of aromatic ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addition–elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C–F bonds.

Asymmetric Substitution Reactions Catalyzed by a Chiral Phosphoric Acid

Nucleophilic substitution reactions on the sp2- or sp3-hybridized carbon, including formal substitution such as addition-elimination sequence, are one of the fundamental transformations in organic synthesis. Compared with the addition reactions, development of catalytic enantioselective substitution reactions is still rare. This account summarizes our recent efforts to solve the problems by using chiral phosphoric acid catalysts. The first topic is the catalytic kinetic resolution of racemic secondary alcohols by an addition-elimination type acylation reaction. The desymmetrization of σ-symmetrical acid anhydrides is also described. The second topic is the enantioselective intramolecular SN2' reaction. We made clear that the choice of the leaving group is quite important. The last topic is the catalytic kinetic resolution of racemic β-aminoalcohols by nucleophilic benzylation reaction. Chiral phosphoric acid works as a nucleophilic catalyst to form the corresponding phosphonate in situ as a chiral electrophilic intermediate.

Efficient construction of 3-substituted-quinazolin-4(3H)-ones and theoretical investigation on the reaction pathways

GRAPHICAL ABSTRACT

Uncatalyzed CO2Li-Mediated SNAr Reaction of Unprotected Benzoic Acids via Silicon Trickery

The alkyl and aryllithium nucleophilic aromatic substitution (SNAr) displacement of a fluoro or methoxy group from unprotected 2-fluoro/methoxybenzoic acids is discussed. It was discovered that a TMS group located at the C6-position ortho to the carboxyl group shields effectively the carboxylate against nucleophilic attack, thus reducing dramatically ketone formation, and reorients nucleophilic substitution to the C2-position. The reactions with fluoro-substituted substrate 7 proceed efficiently; in contrast, the use of methoxy-functionalized benzoic acid 8 only affords moderate yields with s-BuLi and PhLi. This uncatalyzed coupling reaction, which provides a direct access to biaryl compounds, presumably proceeds by an addition–elimination sequence via intermediate formation of a resonance-stabilized pentavalent silalactone-Meisenheimer complex.

Regioisomeric and Substituent Effects upon the Outcome of the Reaction of 1-Borodienes with Nitrosoarene Compounds.

A study of the reactivity of 1-borodienes with nitrosoarene compounds has been carried out showing an outcome that differs according to the hybridization state of the boron moiety. Using an sp(2) boron substituent, a one-pot hetero-Diels-Alder/ring contraction cascade occurred to afford N-arylpyrroles with low to good yields depending on the electronic properties of the substituents on the borodiene, whereas an sp(3) boron substituent led to the formation of stable boro-oxazines with high regioselectivity in most of the cases, in moderate to good yields. (1)H and (11)B NMR studies on two boro-oxazine regioisomers showed that selective deprotection can be performed. Formation of either the pyrrole or the furan derivative is pH- and regioisomer-structure-dependent. The results obtained, together with previous B3LYP calculations, support mechanistic proposals which suggest that pyrrole, or furan, formation proceeds via oxazine formation, followed by a boryl rearrangement and an intramolecular addition-elimination sequence.

Synthetic utility of 2,3,3,3-tetrafluoroprop-1-ene (HFO-1234yf)

Abstract 2,3,3,3-Tetrafluoroprop-1-ene, known as the environmentally benign fluorinated olefin recently employed for the car air-conditioning system, was proved to follow the addition–elimination sequence at its C2 position by the reaction of a variety of alkoxides, forming CF3-containing vinyl ethers in excellent yields.

ChemInform Abstract: Regio‐ and Chemoselective Formation of Spiroindolinone‐Isoindolinone by a Palladium‐Catalyzed Buchwald—Hartwig Addition—Elimination Sequence.

AbstractThe title reaction occurs under mild conditions with a broad scope for the reactive ortho‐halogen atoms as well as a variety of N‐ and aryl substituents.

Regio‐ and Chemoselective Formation of Spiroindolinone–Isoindolinone by a Palladium‐Catalyzed Buchwald–Hartwig Addition–Elimination Sequence

AbstractThe usual way to synthesize spiroindolinones is the application of isatin derivatives. Here, we report the first Pd‐catalyzed Buchwald–Hartwig addition–elimination strategy for the formation of the spiroindolinone–isoindolinone architecture. The application of the Ugi‐4‐component reaction (Ugi‐4CR) allows the facile introduction of diversity and increases the practicality of this protocol.

ChemInform Abstract: A New Efficient Synthesis of Pyrazoles from Hydrazonoyl Halides and β‐Oxophosphonates.

Abstract A new practical and efficient synthesis of 1,3,5-trisubstituted pyrazoles has been developed by reacting of hydrazonoyl halides with β-oxophosphonates under mild conditions in good yields with excellent regioselectivity. This process employs an addition–elimination sequence. Wide scope, functional group compatibility has been established.

A new efficient synthesis of pyrazoles from hydrazonoyl halides and β-oxophosphonates

A new practical and efficient synthesis of 1,3,5-trisubstituted pyrazoles has been developed by reacting of hydrazonoyl halides with β-oxophosphonates under mild conditions in good yields with excellent regioselectivity. This process employs an addition–elimination sequence. Wide scope, functional group compatibility has been established.

Total Synthesis of Natural Enantiomers of Heliespirones A and C via the Diastereoselective Intramolecular Hosomi-Sakurai Reaction

A full account of the development of a novel type of the intramolecular Hosomi-Sakurai reactions of the substrates with a p-benzoquinone and an allylsilane moieties connected by an ether linkage is described. This transformation proceeds via an addition-elimination sequence and provides the products with two stereogenic centers through a 1,3(or 1,4)-asymmetric induction in good to excellent diastereoselectivities. A reasonable mechanistic possibility for the reaction, determination of the stereochemistry for the product, and scope and limitation of the transformation are also discussed. The methodology developed here can successfully be applied to the enantiocontrolled total synthesis of the natural enantiomers of (-)-heliespirone A and (+)-heliespirone C, which have been isolated from sunflower Helianthus annuus L. as allelochemicals.

Reversible 1,3-anti/syn-Stereochemical Courses in Copper-Catalyzed γ-Selective Allyl–Alkyl Coupling between Chiral Allylic Phosphates and Alkylboranes

The stereochemical courses of the copper-catalyzed allyl-alkyl coupling between enantioenriched chiral allylic phosphates and alkylboranes were switchable between 1,3-anti and 1,3-syn selectivities by the choice of solvents and achiral alkoxide bases with different steric demands. The reactions with γ-silylated allylic phosphates allow efficient synthesis of enantioenriched chiral allylsilanes with tertiary or quaternary carbon stereogenic centers. Cyclic and acyclic bimodal participation of alkoxyborane species in an organocopper addition-elimination sequence is proposed to account for the phenomenon of the anti/syn-stereochemical reversal.

Structure and Catalytic Mechanism of Nicotinate (Vitamin B3) Degradative Enzyme Maleamate Amidohydrolase from Bordetella bronchiseptica RB50

The penultimate reaction in the oxidative degradation of nicotinate (vitamin B(3)) to fumarate in several species of aerobic bacteria is the hydrolytic deamination of maleamate to maleate, catalyzed by maleamate amidohydrolase (NicF). Although it has been considered a model system for bacterial degradation of N-heterocyclic compounds, only recently have gene clusters that encode the enzymes of this catabolic pathway been identified to allow detailed investigations concerning the structural basis of their mechanisms. Here, the Bb1774 gene from Bordetella bronchiseptica RB50, putatively annotated as nicF, has been cloned, and the recombinant enzyme, overexpressed and purified from Escherichia coli, is shown to catalyze efficiently the hydrolysis of maleamate to maleate and ammonium ion. Steady-state kinetic analysis of the reaction by isothermal titration calorimetry (ITC) established k(cat) and K(M) values (pH 7.5 and 25 °C) of 11.7 ± 0.2 s(-1) and 128 ± 6 μM, respectively. The observed K(D) of the NicF·maleate (E·P) complex, also measured by ITC, is approximated to be 3.8 ± 0.4 mM. The crystal structure of NicF, determined at 2.4 Å using molecular replacement, shows that the enzyme belongs to the cysteine hydrolase superfamily. The structure provides insight concerning the roles of potential catalytically important residues, most notably a conserved catalytic triad (Asp29, Lys117, and Cys150) observed in the proximity of a conserved non-proline cis-peptide bond within a small cavity that is likely the active site. On the basis of this structural information, the hydrolysis of maleamate is proposed to proceed by a nucleophilic addition-elimination sequence involving the thiolate side chain of Cys150.

Cu(I)/BINAP-Catalyzed Synthesis of Pyro-glutamates

A facile protocol for the rapid construction of pyroglutamate derivatives is reported. A Cu(I)/BINAP-catalyzed tandem Michael addition-elimination sequence followed by deprotection-lactamization affords the products bearing a quaternary stereogenic center in good yields with high enantioselectivities. The general reaction scale for this transformation is 0.3 mmol.

A Versatile Methodology for the Synthesis of α,β‐Unsaturated 3‐Iminophosphines

Phorteen phine phosphines: Fourteen new alpha,beta-unsaturated beta-chloroimines were synthesized from inexpensive ketones by using the Vilsmeier-Haack reagent followed by Schiff-base condensation. Each imine was subsequently converted to an alpha,beta-unsaturated 3-iminophosphine through either late-metal-catalyzed phosphorus-carbon cross-coupling or through an addition-elimination sequence (see scheme). This high-yield protocol serves as a general means to produce alpha,beta-unsaturated 3-iminophosphines.Fourteen new alpha,beta-unsaturated beta-chloroimines were synthesized from commercially available ketones using the Vilsmeier-Haack reagent, followed by Schiff-base condensation. Each imine was subsequently converted to an alpha,beta-unsaturated 3-iminophosphine through either late-metal-catalyzed phosphorus-carbon cross-coupling or through an addition-elimination sequence. Depending on the substituents present on the vinyl group, the resultant phosphines were isolated as either E or Z diastereomers with successful isolation of predominately single diastereomers for all fourteen new phosphines investigated. Full synthetic and spectroscopic details, as well as several X-ray crystal structures of these new imines and phosphines, are reported in addition to X-ray crystal structures of related palladium complexes.

Synthesis of functionalized Morita–Baylis–Hillman adducts by a conjugate addition–elimination sequence

We have developed a new conjugate addition-elimination sequence for the diastereoselective synthesis of protected allylic syn 1,3-diols which are Morita-Baylis-Hillman adducts. The synthesis of the substrates involves a challenging cross-metathesis reaction that leads to hindered trisubstituted olefins.