Nucleophilic Acyl Research Articles

ChemInform Abstract: Imidazole-2-thiones: Synthesis, Structure, Properties

Abstract The literature data concerning the methods for preparing imidazole-2-thiones and their benzo analogs have been systematized, and the structure, physico-chemical properties and chemical conversions of these compounds have been considered. The methods for the synthesis of imidazole-2-thiones are classified according to reaction types including cyclization, reactions of halo- and oxoimidazole derivatives with sulfur-containing nucleophiles, and direct insertion of sulfur into position 2 of the imidazole ring. The structure of imidazole-2-thiones is discussed in terms of quantum-chemical calculations, X-ray diffraction data, dipole moments, UV, and IR as well as 1H and 15N NMR spectroscopy. Much attention has been given to nucleophilic addition of imidazole-2-thiones to acetylene and its derivatives as well as to alkenes with an activated double bond. The reactions of imidazole-2-thiones as nucleophilic agents, including alkylation, acylation, and interaction with carbonyl halides are discussed. Some...

ChemInform Abstract: Intramolecular Nucleophilic Acyl Substitution Reactions of Halo- Substituted Esters and Lactones. New Applications of Organosamarium Reagents.

Intramolecular nucleophilic acyl substitution reactions involving a broad range of halo substituted carboxylic acid derivatives have been accomplished in excellent yield employing samarium(II) iodide as the reductive coupling agent. Although particular substrates cyclized most effectively in THF in the presence of tripiperidinophosphine oxide, carboxylic acid esters, the focus of this report, cyclize equally well without such an additive in the presence of a catalytic quantity of iron(III) complexes. Thus a comprehensive series of halo substituted esters were cyclized in excellent yield to the corresponding 4-, 5-, and 6-members carbocycles. The reaction is extremely mild and selective as demonstrated by experiments wherein alkyl chlorides, acetals, and olefins remain completely intact under the reaction conditions. In addition to introducing a convenient procedure for preparing stereodefined spirocyclic systems, a new ring expansion sequence has been developed that appears extremely general for the preparation of various ring systems

A Novel Family of Onium Salts Based Upon Isonitroso Meldrum's Acid Proves Useful as Peptide Coupling Reagents

AbstractA new family of uronium salts (HTMU, HMMU, and HDmPyMU) based on isonitroso Meldrum's acid (HONM) are reported as stand‐alone coupling reagents. Amide bond formation with the use of these reagents occurred more quickly than that with other uronium salts as a result of the presence of a neighboring group effect with a cyclic structure. Thus, these novel onium salts were often more effective in the acylation of poor nucleophiles and in the control of optical purity than related Oxyma‐ and benzotriazole‐based reagents. Among the HONM derivatives, HMMU showed the best performance in reducing racemization and assembling demanding sequences such as the Aib‐ACP decapeptide or analogues of Leu‐enkephalin pentapeptide. Furthermore, the scope and limitations of the use of HONM as an additive in combination with carbodiimides is discussed.

ChemInform Abstract: Flowing Afterglow Study of the Gas Phase Nucleophilic Reactions of Some Formyl, Acetyl and Cyclic Esters.

A variety of nucleophiles have been investigated for their reactions with formyl and acetyl esters in the gas phase in our flowing afterglow. The reactions that are permitted in the gas phase are more varied than those seen in the condensed phase. The rates of reactions of methyl and ethyl esters as well as various lactones have been undertaken with various nucleophiles: H2N–, HO–, CH3O–, NCCH2–, F–, CH3C(O)CH2–, CH3S– and O2NCH2– . For example, the reaction rate of NCCH2– + HCO2CH2CH3 has been found to be (1.3 ± 0.2) × 10–10 cm3 molecule–1 s–1 and the only product is HC(O–)CHCN which results from nucleophilic acyl substitution (BAC2) followed by a proton transfer within the ion–molecule complex. Other reaction mechanisms that have been observed include β-elimination (E2), bimolecular nucleophilic substitution at the alkyl group (BAL2), and the Riveros reaction (elimination of CO). A mechanism for the F– + HCO2CH3 reaction has been determined at the B3LYP/6-31+G(d) level. Most notably, channels were determined computationally (BAL2 and Riveros), and these channels are also observed experimentally. Furthermore, the BAC2 pathway which proceeds via nucleophilic attack on the carbonyl group also leads to the Riveros products, F–(CH3OH) and CO.

The NHCs-mediated cross-coupling of aromatic aldehydes with benzyl halides: synthesis of α-aryl ketones

Abstract A new NHCs-mediated synthetic method was found to produce α-aryl ketones in 22–63% yields in one-pot process from the corresponding aromatic aldehydes and benzyl halides. This method is the first example of the NHCs-mediated intermolecular nucleophilic acylation of aromatic aldehydes with benzyl halides.

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed Nucleophilic Acylation of Trifluoromethyl Ketimines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Nucleophilic Acyl Substitution via Aromatic Cation Activation of Carboxylic Acids: Rapid Generation of Acid Chlorides under Mild Conditions

The first example of aromatic cation-activated nucleophilic acyl substitution has been achieved. The conversion of carboxylic acids to their corresponding acid chlorides occurs rapidly in the presence of 3,3-dichlorocyclopropenes via the intermediacy of cyclopropenium carboxylate complexes. The effect of cyclopropene substituents on the rate of conversion is examined. The addition of tertiary amine base is found to dramatically accelerate reaction, and conditions were developed for the preparation of acid sensitive acid chlorides. Preparative scale peptide couplings of two N-Boc amino acids were achieved with this method.

ポリマー／現像液間の反応を鍵とした新規画像形成法―反応現像画像形成―によるエンジニアリングプラスチックの感光化

Photosensitive polyimides have been used to form thermally and mechanically stable fine patterns utilized for such as buffer-coat layers and inter-layer dielectrics in electronic devices. Conventional photosensitive polyimides usually contain poly(amic acid)s as polyimide precursors or functionalized polyimides as their polymer component. Here, we report a novel design for preparation of photosensitive polyimides, reaction development patterning(RDP). RDP utilizes nucleophilic acyl substitution reaction of nucleophiles in developer with imide groups in polyimides as the key reaction of pattern formation, and therefore, no introduction of specific functional groups into polyimide framework is needed. In addition, RDP can afford photosensitivity to engineering plastics having carboxylic-acid-derivative linkages other than polyimide. We have developed both positive- and negative-tone RDPs. Positive-tone RDP utilizes main-chain scission of engineering plastics by amines in developer for pattern formation. Negative-tone RDP realizes higher sensitivity with smaller amount of photosensitive agent than positive-tone RDP. Application of industrially-used alkaline developer to negative-tone RDP is also achieved. Further reduction of the amount of photosensitive agent with increasing sensitivity is examined by introduction of chemical amplification mechanism to RDP.

Solvent-Free Iron(III) Chloride Catalyzed O-, S-, and N-Acylation under Mild Conditions

An efficient, eco-friendly, and mild method for the acylation of various nucleophiles with acid anhydrides using iron(III) chloride is described. The addition of only 0.1―2 mol% of iron chloride catalyzed the acylation under solvent-free conditions at room temperature to give the acylated products in good yields.

Coupling Isocyanide-Based Multicomponent Reactions with Aliphatic or Acyl Nucleophilic Substitution Processes

This account summarizes the results of studies carried out by the authors during the last 10 years aimed at expanding the utility of the venerable Passerini and Ugi reactions. Particular emphasis is given to efforts that focus on coupling these processes with post-condensation, intramolecular, aliphatic nucleophilic substitution and acyl nucleophilic substitution reactions. The methodologies developed in these investigations serve as the basis for short sequences for the preparation of a diverse number of interesting drug-like structures.

N-Heterocyclic Carbene Catalyzed Nucleophilic Acylation of Trifluoromethyl Ketimines

An efficient N-heterocyclic carbene (NHC)-catalyzed nucleophilic acylation of trifluoromethyl ketimines has been developed. The combination of N-aryl trifluoromethyl ketimines with various furan-2-carbaldehydes leads chemoselectively to the corresponding α-amino-a-trifluoromethyl ketones in moderate to very good yields (32-87%) providing ready access to this pharmaceutically important class of compounds.

Fmoc Solid‐Phase Synthesis of C‐Terminal Peptide Thioesters by Formation of a Backbone Pyroglutamyl Imide Moiety

Activating an inactive bond: A new concept in synthetic peptide chemistry, backbone amide activation, proceeds through the selective conversion of a backbone amide into an imide, followed by nucleophilic acyl displacement (see scheme; Boc=tert-butoxycarbonyl, Pg=protecting group). This methodology represents a new approach to solid-phase synthesis of C-terminal peptide thioesters, and may become a general tool for the synthesis of peptide thioesters.

Nucleophilic Acyl Substitution of Acyl Diimides

The nucleophilic acyl substitution of the acyl diimide intermediate formed by the oxidation of isoniazid was found to involve two methanol molecules in a six-membered cyclic transition state. Calculations were performed in the gas phase at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory and solvation effects were included both explicitly and implicitly by using CPCM. The effect of electron withdrawing and donating groups on the aryl ring was also explored. The results obtained are in good agreement with experimental observations for the oxidation of isoniazid.

A Conserved Tyrosyl−Glutamyl Catalytic Dyad in Evolutionarily Linked Enzymes: Carbapenam Synthetase and β-Lactam Synthetase

Beta-lactam-synthesizing enzymes carbapenam synthetase (CPS) and beta-lactam synthetase (beta-LS) are evolutionarily linked to a common ancestor, asparagine synthetase B (AS-B). These three relatives catalyze substrate acyl-adenylation and nucleophilic acyl substitution by either an external (AS-B) or internal (CPS, beta-LS) nitrogen source. Unlike AS-B, crystal structures of CPS and beta-LS revealed a putative Tyr-Glu dyad (CPS, Y345/E380; beta-LS, Y348/E382) proposed to deprotonate the respective internal nucleophile. CPS and beta-LS site-directed mutagenesis (Y345/8A, Y345/8F, E380/2D, E380/2Q, E380A) resulted in the reduction of their catalytic efficiency, with Y345A, E380A, and E382Q producing undetectable amounts of beta-lactam product. However, [(32)P]PP(i)-ATP exchange assays demonstrated Y345A and E380A undergo the first half-reaction, with the remaining active mutants showing decreased forward commitment to beta-lactam cyclization. pH-rate profiles of CPS and beta-LS supported the importance of a Tyr-Glu dyad in beta-lactam formation and suggested its reverse protonation in beta-LS. The kinetics of CPS double-site mutants reinforced the synergism of Tyr-Glu in catalysis. Furthermore, significant solvent isotope effects on k(cat) ((D)k(cat)) for Y345F (1.9) and Y348F (1.7) maintained the assignment of Y345/8 in proton transfer. A proton inventory on Y348F determined its (D)(k(cat)/K(m)) = 0.2 to arise from multiple reactant-state fractionation factors, presumably from water molecule(s) replacing the missing Tyr hydroxyl. The role of a CPS and beta-LS Tyr-Glu catalytic dyad was solidified by a significant decrease in mutant k(cat) viscosity dependence with respect to the wild-type enzymes. The evolutionary relation and potential for engineered biosynthesis were demonstrated by beta-LS acting as a carbapenam synthetase.

Greener Solutions for the Organic Chemistry Teaching Lab: Exploring the Advantages of Alternative Reaction Media

A major approach for implementing green chemistry is the discovery and development of synthetic strategies that reduce the quantity of solvent needed, eliminate it altogether, or rely on new reaction media. An increasing number of examples have demonstrated that greener reaction solvents or media can enhance performance as well as reduce hazard. Here we describe four experiments designed for the undergraduate organic chemistry laboratory that illustrate both enhanced performance and a greener approach: (i) a solventless aldol condensation that involves the reaction of two solid reagents, (ii) a solvent-free, room temperature Diels–Alder reaction followed by an intramolecular nucleophilic acyl substitution, (iii) a Diels–Alder reaction in water, and (iv) a Diels–Alder reaction in polyethylene glycol (PEG) that may be conducted using microwave heating. The alternative solvents or reaction media used in these experiments not only reduce the use of hazardous and volatile organic solvents but also enhance the transformations by increasing the rate of reaction or facilitating recovery of the product. These thoroughly tested laboratory experiments are convenient, inexpensive, and rapid, thereby providing an opportunity to introduce green chemistry into educational settings easily.

Efficient Construction of Stereodefined α-Alkylidene Aza-cycloketones via β-Amino-alkenyllithium: Straightforward and Protection-Free Synthesis of Allopumiliotoxin 267A

Intramolecular nucleophilic acyl substitution of highly functionalized beta-amino-alkenyllithium species provided facile access to alpha-alkylidene aza-cycloketones with defined olefin geometry and rich structural diversity. A concise total synthesis of allopumiliotoxin 267A has been accomplished in 5 steps from 4 featuring this key transformation.

Nano-patterning of an iCVD polymer, followed by covalent attachment of QDs

A novel method for processing sub-50 nm structures by using carbon nanotube (CNT) masks and integrating quantum dots (QDs) on patterned polymer substrates has been established. Poly(styrene-alt-maleic anhydride) (PSMa) was prepared by the initiated chemical vapor deposition (iCVD) method, an alternative to spin-on deposition. The sub-50 nm PSMa polymer patterns were prepared by low energy oxygen plasma etching by using CNTs as the masks. The water soluble, amine-functionalized QDs underwent the nucleophilic acyl substitution reaction with the PSMa containing anhydride functional groups. This integration method was designed to incorporate high performance QDs on inexpensive, lightweight flexible substrates.

Nucleophilic reactivity of a d0 molybdenum oxo moiety

The previously reported complexes [Mo(N(t)Bu)(O)(2,6-Me(2)C(6)H(3)O)(2)(py)] () and [Mo(N(t)Bu)(O)(2,6-(i)Pr(2)C(6)H(3)O)(2)(py)] () have been shown to contain a nucleophilic oxo ligand. The reaction of and tert-butylacetyl chloride gave the novel complex [Mo(N(t)Bu)(2,6-(i)Pr(2)C(6)H(3)O)(2)(O(2)CCH(2)(t)Bu)Cl] () in 63% yield as the product of nucleophilic acyl substitution. Complex undergoes a clean reaction with triflic anhydride to give the novel complex [{Mo(N(t)Bu)(2,6-Me(2)C(6)H(3)O)(2)}(micro-O)(micro-OTf)(2)] () in 75% yield. Complex appears to be formed from nucleophilic attack of the oxo ligand on triflic anhydride, followed by nucleophilic attack of a second oxo moiety on the cationic intermediate. The solid-state structures of and have been determined by X-ray crystallography. These are rare examples of nucleophilic oxo ligands bound to a d(0) transition metal centre.

Au-Catalyzed Synthesis of 5,6-Dihydro-8H-indolizin-7-ones from N-(Pent-2-en-4-ynyl)-β-lactams

Au-catalyzed synthesis of 5,6-dihydro-8H-indolizin-7-ones from readily available N-(pent-2-en-4-ynyl)-beta-lactams is developed. In this reaction, a 5-exo-dig cyclization of the beta-lactam nitrogen to the Au-activated C-C triple bond is followed by heterolytic fragmentation of the amide bond, forming a highly nucleophilic acyl cation. An expedient formal synthesis of indolizidine 167B was easily achieved using this new method.

Lessons from Nature: Biomimetic Organocatalytic Carbon−Carbon Bond Formations

Nature utilizes simple C2 and C3 building blocks, such as dihydroxyacetone phosphate (DHAP), phosphoenolpyruvate (PEP), and the "active aldehyde" in various enzyme-catalyzed carbon-carbon bond formations to efficiently build up complex organic molecules. In this Perspective, we describe the transition from using enantiopure chemical synthetic equivalents of these building blocks, employing our SAMP/RAMP hydrazone methodology and metalated chiral alpha-amino nitriles, to the asymmetric organocatalytic versions developed in our laboratory. Following this biomimetic strategy, the DHAP equivalent 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) has been used in the proline-catalyzed synthesis of carbohydrates, aminosugars, carbasugars, polyoxamic acid, and various sphingosines. Proline-catalyzed aldol reactions involving a PEP-like equivalent have also allowed for the asymmetric synthesis of ulosonic acid precursors. By mimicking the "active aldehyde" nucleophilic acylations in Nature catalyzed by the thiamine-dependent enzyme, transketolase, enantioselective N-heterocyclic carbene-catalyzed benzoin and Stetter reactions have been developed. Finally, based on Nature's use of domino reactions to convert simple building blocks into complex and highly functionalized molecules, we report on our development of biomimetic asymmetric multicomponent domino reactions which couple enamine and iminium catalysis.