Competitive proton and hydride transfer reactions via ion‐neutral complexes: fragmentation of deprotonated benzyl N‐phenylcarbamates in mass spectrometry

The gas‐phase chemistry of deprotonated benzyl N‐phenylcarbamates was investigated by electrospray ionization tandem mass spectrometry. Characteristic losses of a substituted phenylcarbinol and a benzaldehyde from the precursor ion were proposed to be derived from an ion‐neutral complex (INC)‐mediated competitive proton and hydride transfer reactions. The intermediacy of the INC consisting of a substituted benzyloxy anion and a phenyl isocyanate was supported by both ortho‐site‐blocking experiments and density functional theory calculations. Within the INC, the benzyloxy anion played the role of either a proton abstractor or a hydride donor toward its neutral counterpart. Relative abundances of the product ions were influenced by the nature of the substituents. Electron‐withdrawing groups at the N‐phenyl ring favored the hydrogen transfer process (including proton and hydride transfer), whereas electron‐donating groups favored direct decomposition to generate the benzyloxy anion (or substituted benzyloxy anion). By contrast, electron‐withdrawing and electron‐donating substitutions at the O‐benzyl ring exhibited opposite effects. Copyright © 2015 John Wiley & Sons, Ltd.     

Generation and reactions of substituted phenide anions in an electrospray triple quadrupole mass spectrometer

Substituted benzoic acid anions undergo decarboxylation in the medium-pressure region of an electrospray ion source yielding in most cases the correspondingly substituted phenide anions in high yield. The location of the anionic center is specified by the position of the carboxylic group. The only exceptions are compounds with substituents containing acidic hydrogen atoms, like OH and NH(2) groups. For such compounds, either an intra- or an intermolecular (mediated by the molecules of methanol or water) proton transfer from the more acidic position to the benzene ring is observed. The generated anions can be selected using the first quadrupole for studying their ion-molecule chemistry in the second quadrupole of a triple quadrupole mass spectrometer. Their reactions with CO(2), O(2), CH(3)COCH(3) and CCl(4) may serve as typical examples. The general applicability of this method for the generation of phenide anions has been confirmed on three different mass spectrometers. Experiments performed using carboxylic acids other then benzoic acid and its derivatives show that this method is not limited to phenide anions and can be used for the generation of a much wider range of carbanions in the gas phase.     

Synthesis of 4‐Substituted Piperidines via a Mild and Scalable Two‐Step Cu2O‐Mediated Decarboxylation of Cyanoesters

A four‐step, high‐yielding, kilogram‐scale protocol to prepare aldehyde 5 is reported. The key reaction is a mild, two‐step Cu₂O‐mediated decarboxylation of cyanoester 3 that proceeds in excellent yield. The general applicability of this methodology has also been explored.     

The loss of carbon dioxide from activated perbenzoate anions in the gas phase: unimolecular rearrangement via epoxidation of the benzene ring

The unimolecular reactivities of a range of perbenzoate anions (X-C6H5CO3-), including the perbenzoate anion itself (X = H), nitroperbenzoates (X = para-, meta-, ortho-NO2), and methoxyperbenzoates (X = para-, meta-OCH3) were investigated in the gas phase by electrospray ionization tandem mass spectrometry. The collision-induced dissociation mass spectra of these compounds reveal product ions consistent with a major loss of carbon dioxide requiring unimolecular rearrangement of the perbenzoate anion prior to fragmentation. Isotopic labeling of the perbenzoate anion supports rearrangement via an initial nucleophilic aromatic substitution at the ortho carbon of the benzene ring, while data from substituted perbenzoates indicate that nucleophilic attack at the ipso carbon can be induced in the presence of electron-withdrawing moieties at the ortho and para positions. Electronic structure calculations carried out at the B3LYP/6-311++G(d,p) level of theory reveal two competing reaction pathways for decarboxylation of perbenzoate anions via initial nucleophilic substitution at the ortho and ipso positions, respectively. Somewhat surprisingly, however, the computational data indicate that the reaction proceeds in both instances via epoxidation of the benzene ring with decarboxylation resulting--at least initially--in the formation of oxepin or benzene oxide anions rather than the energetically favored phenoxide anion. As such, this novel rearrangement of perbenzoate anions provides an intriguing new pathway for epoxidation of the usually inert benzene ring.     

The loss of a methyl radical and the retro diels—Alder reaction in the electron impact mass spectrometry of 2-cyclohexen-1-ol and related compounds

The electron impact mass spectra of 2-cyclohexen-1-ol and of several of its ²H and ¹³C labelled analogues show that the molecular ions lose a methyl radical by a completely different means from the mechanism described previously. Moreover, the retro Diels–Alder reaction also proceeds in a non-classical way; in addition to the elimination of an olefinic molecule from unrearranged molecular ions, a second more important route implies a formal 1,3 allylic rearrangement prior to the retro Diels–Alder reaction. The mass spectra of a series of alkyl substituted homologues show that the competition between the two processes is closely related to the size of the olefinic moiety that is expelled.     

Computational insight on the chalcone formation mechanism by the Claisen–Schmidt reaction

New insight of the formation mechanism of chalcones is presented in the current study. Ab initio calculations were applied in studying the mechanistic pathways for the base‐catalyzed Claisen–Schmidt condensation for obtaining chalcones (1,3‐diphenyl‐2‐propen‐1‐ons). The energies of the stationary points along the reaction coordinate were obtained at two levels of theory—MP2/6‐31 + G(d,p) and SCS‐MP2/6‐31 + G(d,p). The role of water in the reaction mechanisms is examined. The theoretical results show that the process is catalyzed by an ancillary water molecule. The reaction mechanism, proposed in this study, consists of two reactions—an activation of the acetophenone by a removal of proton is followed by the attack of the formed acetophenone anion to the aromatic aldehyde, which through few steps leads to the formation of the final product—chalcone. The first reaction proceeds very fast in one step while the second reaction goes through four steps and three intermediate complexes before the formation of the final product.     

Mechanistic Origin of Chemoselectivity in Thiolate‐Catalyzed Tishchenko Reactions

The thiolate‐catalyzed Tishchenko reaction has shown high chemoselectivity for the formation of double aromatic‐substituted esters. In the present study, the detailed reaction mechanism and, in particular, the origin of the observed high chemoselectivity, have been studied with DFT calculations. The catalytic cycle mainly consisted of three steps: 1,2‐addition, hydride transfer, and acyl transfer steps. The calculation results reproduce the experimental observations that 4‐chlorobenzaldehyde acts as the hydrogen donor (carbonyl part in the ester product), while 2‐methoxybenzaldehyde acts as the hydrogen acceptor (alcohol part in the product). The two main factors are responsible for such chemoselectivity: 1) in the rate‐determining hydride transfer step, the para‐chloride substituent facilitates the hydride‐donating process by weakening the steric hindrance, and 2) the ortho‐methoxy substituent facilitates the hydride‐accepting process by stabilizing the magnesium center (by compensating for the electron deficiency).     

Fragmentation pathways of deprotonated amide‐sulfonamide CXCR4 inhibitors investigated by ESI‐IT‐MSn,ESI‐Q‐TOF‐MS/MS and DFT calculations

Amide‐sulfonamides provide a potent anti‐inflammatory scaffold targeting the CXCR4 receptor. A series of novel amide‐sulfonamide derivatives were investigated for their gas‐phase fragmentation behaviors using electrospray ionization ion trap mass spectrometry and quadrupole time‐of‐flight mass spectrometry in negative ion mode. Upon collision‐induced dissociation (CID), deprotonated amide‐sulfonamides mainly underwent either an elimination of the amine to form the sulfonyl anion and amide anion or a benzoylamide derivative to provide sulfonamide anion bearing respective substituent groups. Based on the characteristic fragment ions and the deuterium–hydrogen exchange experiments, three possible fragmentation mechanisms corresponding to ion‐neutral complexes including [sulfonyl anion/amine] complex ( INC‐1 ), [sulfonamide anion/benzoylamide derivative] complex ( INC‐2 ) and [amide anion/sulfonamide] complex ( INC‐3 ), respectively, were proposed. These three ion‐neutral complexes might be produced by the cleavages of S–N and C–N bond from the amide‐sulfonamides, which generated the sulfonyl anion (Route 1), sulfonamide anion (Route 2) and the amide anion (Route 3). DFT calculations suggested that Route 1, which generated the sulfonyl anion (ion c ) is more favorable. In addition, the elimination of SO₂ through a three‐membered‐ring transition state followed by the formation of C–N was observed for all the amide‐sulfonamides.     

氢键活化的苯环上C-F键的亲核取代反应研究

以2,4,5-三氟苯乙酮在氢化钠作用下与碳酸二乙酯反应制得3,4-二氟-6-乙氧基苯甲酰乙酸乙酯(2);2经对甲基苯磺酸催化水解脱羧,合成3,4-二氟-6-乙氧基苯乙酮(3)路线为模型,研究了苯环上C-F键的亲核取代反应.实验结果证明,在形成分子内氢键的活化作用下,苯环上的C-F键能够被烷氧负离子亲核取代.2和3的结构经1H NMR, 19F NMR和MS表征.     

Theoretical studies on the methylsulfenyl chloride addition to propene

Thiiranium heterocycles play an important role in biocatalytic processes of cells. Usually formation of thiiranium ions is known to proceed by the electrophilic additions of sulfenylhalides to substituted olefins, subsequently undergoing the regioselective and stereoselective nucleophilic attack of the halide atom on either C‐1 or C‐2 carbon atom of the thiiranium intermediate to gave two isomeric adducts. The detailed sequence of the reaction mechanism, the nature of intermediates, and transition states that occur in this electrophilic addition reaction are not well understood. In our work, this reaction has been modeled using Ab initio methods at the MP2/6‐31+G(d,f) level of theory to look into the mechanism of the reaction and to explain how the regioselectivity of the reaction is controlled. We focused on the electrophilic addition reaction of the methylsulfenyl chloride to propene. Our calculations show that the reaction is predicted to proceed via two distinct directions. The first direction proceeds when the starting reacting molecules formed the cis‐methyl‐oriented thiiranium intermediate, and the second direction is when the starting reactants resulted in the trans‐methyl‐oriented thiiranium intermediate. The calculated reaction potential energy surface profile suggests that the minimum energy pathway via the first direction is energetically more preferred than that via trans one. Moreover, calculation of the intrinsic reaction coordinate on the minimum energy pathway revealed the stepwise mechanism for the addition reaction. Thus the energetically preferred first reaction direction consists of the addition of methylsulfenyl chloride to the double bond of propene undergoing synchronous concerted transition state leading to the thiiranium intermediate formation (the rate‐limiting step in the electrophilic addition reaction); regioselective thiiranium intermediate ring‐opening process by the chloride anion attack on the C‐2 carbon of the thiiranium intermediate forming 2‐chloro adduct of kinetically controlled addition reaction; the isomerization reaction of 2‐chloro adduct to more energetically favorable thermodynamically stable 1‐chloro product. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:1–13, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20571     

Electrochemical Studies on New Chelating Compounds of the Mono‐ and Bis(imidazolyl)pyridine Type

Recently designed and synthetized mono‐imidazolinone (I and III) and bisimidazolinone (II and IV) chelating ligands were electrochemically characterized at mercury and carbon paste electrodes. Based on polarographic, voltammetric and coulometric investigations in buffered aqueous media, the general reduction pathway has been suggested. Reduction of the mono‐imidazolinone derivatives proceeds in acidic and neutral media in two two‐electron steps. In the first step, the 2,3‐C?N double bond of the imidazolone ring is reduced yielding a mixture of two diastereoisomers (V and VI). In the second step, the 2,3‐C? N single bond (in protonated form) is further reductively split and as the only final product the compound VII was formed. Both intermediates (V and VI) as well as the final product (VII) were prepared using controlled potential electrolysis on the first and second wave, respectively, isolated and identified by means of NMR. The reduction of bis‐derivatives proceeds most probably in an analogical way: in the first step, both imidazoles are reduced simultaneously at the same potential, whereas the following reduction (ring‐opening) proceeds stepwise. In the case of compound III, the covalent hydration of the parent compound takes place in acidic media, partially preventing its reduction. Finally, voltammetric behaviour of mono‐ and bisimidazolinones at carbon paste electrode is also discussed and, in prospect, possible electroanalytical applications outlined.     

Asymmetric Diels–Alder Reaction of α‐Substituted and β,β‐Disubstituted α,β‐Enals via Diarylprolinol Silyl Ether for the Construction of All‐Carbon Quaternary Stereocenters

The asymmetric Diels–Alder reaction of α‐substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl‐substituted diarylprolinol silyl ether to afford the exo‐isomer with both excellent diastereoselectivity and high enantioselectivity. In the Diels–Alder reaction of a β,β‐disubstituted α,β‐unsaturated aldehyde, good exo‐selectivity and excellent enantioselectivity was obtained when the perchloric acid salt of the bulky triisopropyl silyl ether of trifluoromethyl substituted diarylprolinol was employed as an organocatalyst in the presence of water. In both cases, all‐carbon quaternary stereocenters are constructed enantioselectively.     

Negative charge induced dissociation: fragmentation of deprotonated N‐benzylidene‐2‐hydroxylanilines in electrospray ionization mass spectrometry

Unimolecular reactivities of different N‐benzylidene‐2‐hydroxylaniline anions were investigated in gas phase by electrospray ionization tandem mass spectrometry. All the collision‐induced dissociation spectra of N‐benzylidene‐2‐hydroxylaniline anions show similar ions at phenyl anions, neutral loss of benzonitrile and benzoxazole anions, respectively. The possible fragmentation pathway was probed through deuterium labeling and various group substituents experiments. Computational results were applied to shed light on the mechanism of fragmentation patterns. The proton in the CH=N is reactive in the formation of the concerned ions. Its direct transfer to the oxygen results in 2‐hydroxyphenyl anion. Proton abstraction between benzoxazole and phenyl anion leads to the formation of benzene and benzoxazole anion. Copyright © 2014 John Wiley & Sons, Ltd.     

An Unexpected Reaction of Allylic Propynoate under Palladium(II) Catalysis

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Diels-alder reactions of 2-pyrones with acyclic dienophiles and hydrolyses of the mono-adducts

Diels-Alder reactions of 2-pyrone (1) with fumaronitrile and maleonitrile afforded regio- and stereo-specific mono-adducts 3a and 3b , respectively. The reaction of 1 with acrylonitrile gave a bis-adduct. The reaction of 4,6-dimethyl-2-pyrone (7) with dimethyl fumarate and dimethyl maleate at higher temperature gave benzene derivatives. The low reactivity of 7 and the instability of the mono-adducts with 7 were considered from the existence of back reaction and easy elimination of methyl formate, respectively. Hydrolyses of the mono-adducts of 2-pyrones gave polyfunctionalized cyclohexenes and elimination products generated from the preferencial trans-elimination of the leaving groups.     

CuBr‐catalysed one‐pot multicomponent synthesis of 3‐substituted 2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one derivatives

A novel methodology is presented for the synthesis of 3‐substituted 2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one derivatives based on an efficient tandem multicomponent reaction using copper bromide as catalyst. This methodology is based on the multicomponent one‐pot reaction of methyl 2‐bromobenzoate, phenylisothiocyanate derivatives and sodium azide in the presence of copper bromide and l ‐proline under basic conditions. To show the generality of the method, various phenylisothiocyanates bearing electron‐donating or electron‐withdrawing functionalities were used and the desired products were obtained in high isolated yields.     

Base‐Catalyzed Intramolecular Hydroamination of Cyclohexa‐2,5‐dienes: Insights into the Mechanism through DFT Calculations and Application to the Total Synthesis of epi‐Elwesine

The base‐catalyzed intramolecular hydroamination of 1‐ethylaminocyclohexa‐2,5‐dienes is described. The transformation proceeds through isomerization of the cyclohexa‐1,4‐dienyl fragment into the corresponding conjugated 1,3‐diene prior to the hydroamination step. Attaching a chiral glycinol ether auxiliary on the amino group allows the protonation to occur with complete diastereocontrol. The resulting lithium amide then adds onto the 1,3‐dienyl moiety, affording the desired fused pyrrolidine ring along with the corresponding lithium allylic anion. Protonation of the latter then proceeds with high regiocontrol to favor the resulting allylic amines. In contrast, when the reaction was performed on primary amines, fused pyrrolidines bearing a homoallylic amino group were obtained. The stereochemical course of the process and determination of the reaction pathways were established based on calculations performed at the DFT level. Finally, application of the methodology to the enantioselective synthesis of (+)‐epi‐elwesine, a crinane alkaloid, is described.     

Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A)

A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a) is described. The synthesis proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective alpha-alkoxyallylation reactions using the gamma-alkoxy substituted allylstannanes 17 and 19, as well as a thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn aldehyde 4.     

Three-component coupling sequence for the regiospecific synthesis of substituted pyridines

A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control.