Substituent Migration Research Articles

Highly substituted benzo[b]furan synthesis through substituent migration.

An unusual benzofuran synthesis from 2,6-disubstituted phenols and alkynyl sulfoxides is disclosed. Various highly substituted benzofurans were synthesized via the charge-accelerated [3,3]-sigmatropic rearrangement and subsequent substituent migration. Multiaryl-substituted benzofurans and fully substituted benzofurans were prepared on the basis of the unique reaction mechanism.

Systematic Evaluation of 1,2-Migratory Aptitude in Alkylidene Carbenes.

Alkylidene carbenes undergo rapid inter- and intramolecular reactions and rearrangements, including 1,2-migrations of β-substituents to generate alkynes. Their propensity for substituent migration exerts profound influence over the broader utility of alkylidene carbene intermediates, yet prior efforts to categorize 1,2-migratory aptitude in these elusive species have been hampered by disparate modes of carbene generation, ultrashort carbene lifetimes, mechanistic ambiguities, and the need to individually prepare a series of 13C-labeled precursors. Herein we report on the rearrangement of 13C-alkylidene carbenes generated in situ by the homologation of carbonyl compounds with [13C]-Li-TMS-diazomethane, an approach that obviates the need for isotopically labeled substrates and has expedited a systematic investigation (13C{1H} NMR, DLPNO-CCSD(T)) of migratory aptitudes in an unprecedented range of more than 30 alkylidene carbenes. Hammett analyses of the reactions of 26 differentially substituted benzophenones reveal several counterintuitive features of 1,2-migration in alkylidene carbenes that may prove of utility in the study and synthetic application of unsaturated carbenes more generally.

Phosphine Carboxylate-Probing the Edge of Stability of a Carbon Dioxide Adduct with Dihydrogenphosphide.

We present a new adduct of carbon dioxide with dihydrogenphosphide, that may be prepared either by direct reaction of NaPH2 with carbon dioxide or by hydrolysis of the phosphaethynolate ion (PCO- ). In this hydrolysis transformation, a new mechanism is proposed for the electrophilic reactivity of the phosphaethynolate ion. Protonation to form phosphine carboxylic acid (PH2 COOH) and functionalization to form esters is shown to increase the strength of the P-C interaction, allowing for comparisons to be drawn between this species and the analogous carbamic (NH2 COOH) and carbonic acids (H2 CO3 ). Functionalization of the oxygen atom is found to stabilize the phosphine carboxylate while also allowing solubility in organic solvents whereas phosphorus functionalization is shown to facilitate decarboxylation. Substituent migration occurs in some cases.

Phosphine Carboxylate—Probing the Edge of Stability of a Carbon Dioxide Adduct with Dihydrogenphosphide

AbstractWe present a new adduct of carbon dioxide with dihydrogenphosphide, that may be prepared either by direct reaction of NaPH2 with carbon dioxide or by hydrolysis of the phosphaethynolate ion (PCO−). In this hydrolysis transformation, a new mechanism is proposed for the electrophilic reactivity of the phosphaethynolate ion. Protonation to form phosphine carboxylic acid (PH2COOH) and functionalization to form esters is shown to increase the strength of the P–C interaction, allowing for comparisons to be drawn between this species and the analogous carbamic (NH2COOH) and carbonic acids (H2CO3). Functionalization of the oxygen atom is found to stabilize the phosphine carboxylate while also allowing solubility in organic solvents whereas phosphorus functionalization is shown to facilitate decarboxylation. Substituent migration occurs in some cases.

Ab initio MO and DFT study for the isomerisation of bicyclo[1.1.0]tetrasilane and the germanium analogues

The mechanism of the unimolecular isomerisation reaction of the silicon and germanium analogues of bicyclo[1.1.0]butane with various kinds of substituents (X4R6; X = Si and Ge, R=H, CH3, t-Bu and SiH3) to the corresponding cyclobutene analogues has been investigated by ab initio molecular orbital and DFT methods. Several reaction mechanisms were considered. They are roughly divided into two types; (1) skeletal rearrangement and (2) substituent migration. It was found that substituents (R) have the leading effect on the reaction mechanism but the partial or full replacement of the skeletal silicon atoms by germanium atoms has some important effects as well. Furthermore, the character of the bridge bond of the long-bond and short-bond isomers of these bicyclic compounds was investigated and discussed in comparison with the π bond in ethene and disilene by the CiLC analysis.

Borane to Boryl Hydride to Borylene Dihydride: Explicit Demonstration of Boron-to-Metal α-Hydride Migration in Aminoborane Activation

The sequence of fundamental steps implicit in the conversion of a dihydroborane to a metal borylene complex have been elucidated for an [Ir(PMe(3))(3)] system. B-H oxidative addition has been applied for the first time to an aminodihydroborane, H(2)BNR(2), leading to the generation of a rare example of a primary boryl complex, L(n)(H)M{B(H)NR(2)}; subsequent conversion to a borylene dihydride proceeds via a novel B-to-M α-hydride migration. The latter step is unprecedented for group 13 ligand systems, and is remarkable in offering α- substituent migration from a Lewis acidic center as a route to a two-coordinate ligand system.

Cyclotrimetallenes: Bridged and Distorted Structures

The geometry and the energetic aspects of the stable isomers of trimetallenes (X2YR4: X, Y = Si, Ge) were investigated, and some exotic di- and monobridge structures were found. Many of the bridge structures were identified as stable intermediates or transition states during the two-step substituent migration reactions. The effect of bulky substituents on the stability and geometry of the monobridge structures was studied. The bulkier bridging substituents cause a larger deviation from the ideal bridge structure. SiH3 and Si(SiH3)3 substituents confer a direct benefit on the bridge geometry, in spite of their bulkiness, via electronic effects. According to these results and considering the electronic effect of the Si(SiCnHm)3-type substituents, there is hope to synthesize bridge silicon compounds with bulky substituents.

Structure and isomerization of cyclotrimetallenes

The substituent migration on the X2Y rings (X, Y=C, Si, Ge) was studied by theoretical method with silyl and hydrogen substituents and it was found that all the reactions (with the exception of cyclopropene) proceed in a two-step mechanism via a stable intermediate. The rate determining step of the reaction is the first step. The barrier of the second step is small and the energy of the intermediate is close to that of the reactant. Both the first transition state (T1) and the intermediate (I) are of monobridge structures of different types. Since the intermediate bridge structure is almost as stable as the product, it may be observed in the substituent migration reactions.

Accumulation of Multiple Intermediates in the Catalytic Cycle of (4-Hydroxyphenyl)pyruvate Dioxygenase from Streptomyces avermitilis

(4-Hydroxyphenyl)pyruvate dioxygenase (HPPD) catalyzes the conversion of (4-hydroxyphenyl)pyruvate (HPP) to homogentisate (HG). This reaction involves decarboxylation, substituent migration, and aromatic oxygenation in a single catalytic cycle. HPPD is a unique member of the alpha-keto acid dependent oxygenases that require Fe(II) and an alpha-keto acid substrate to oxygenate or oxidize an organic molecule. We have examined the reaction coordinate of HPPD from Streptomyces avermitilis using rapid mixing pre-steady-state methods in conjunction with steady-state kinetic analyses. Acid quench reactions and product analysis of homogentisate indicate that HPPD as isolated is fully active and that experiments limited in dioxygen concentration with respect to that of the enzyme do involve a single turnover. These experiments indicate that during the course of one turnover the concentration of homogentisate is stoichiometric with enzyme concentration by approximately 200 ms, well before the completion of the catalytic cycle. Subsequent single turnover reactions were monitored spectrophotometrically under pseudo-first-order and matched concentration reactant conditions. Three spectrophotometrically distinct intermediates are observed to accumulate. The first of these is a relatively strongly absorbing species with maxima at 380 and 480 nm that forms with a rate constant (k(1)) of 7.4 x 10(4) M(-)(1) s(-)(1) and then decays to a second intermediate with a rate constant (k(2)) of 74 s(-)(1). The rate constant for the decay of the second intermediate (k(3)) is 13 s(-)(1) and is concomitant with the formation of the product, homogentisate, based on rapid quench and pre-steady-state fluorescence measurements. The rate constant for this process decreases to 7.6 s(-)(1) when deuterons are substituted for protons in the aromatic ring of the substrate. The release of product from the enzyme is rate limiting and occurs at 1.6 s(-)(1). This final event exhibits a kinetic isotope effect of 2 with deuterium oxide as the solvent, consistent with a solvent isotope effect on V(max) of 2.6 observed in steady-state experiments.

4-Hydroxyphenylpyruvate dioxygenase

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an Fe(II)-dependent, non-heme oxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. This reaction involves decarboxylation, substituent migration and aromatic oxygenation in a single catalytic cycle. HPPD is a member of the α-keto acid dependent oxygenases that typically require an α-keto acid (almost exclusively α-ketoglutarate) and molecular oxygen to either oxygenate or oxidize a third molecule. As an exception in this class of enzymes HPPD has only two substrates, does not use α-ketoglutarate, and incorporates both atoms of dioxygen into the aromatic product, homogentisate. The tertiary structure of the enzyme would suggest that its mechanism converged with that of other α-keto acid enzymes from an extradiol dioxygenase progenitor. The transformation catalyzed by HPPD has both agricultural and therapeutic significance. HPPD catalyzes the second step in the pathway for the catabolism of tyrosine, that is common to essentially all aerobic forms of life. In plants this pathway has an anabolic branch from homogentisate that forms essential isoprenoid redox cofactors such as plastoquinone and tocopherol. Naturally occurring multi-ketone molecules act as allelopathic agents by inhibiting HPPD and preventing the production of homogentisate and hence required redox cofactors. This has been the basis for the development of a range of very effective herbicides that are currently used commercially. In humans, deficiencies of specific enzymes of the tyrosine catabolism pathway give rise to a number of severe metabolic disorders. Interestingly, HPPD inhibitor/herbicide molecules act also as therapeutic agents for a number of debilitating and lethal inborn defects in tyrosine catabolism by preventing the accumulation of toxic metabolites.

(4-Hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis: the basis for ordered substrate addition.

(4-hydroxyphenyl)pyruvate dioxygenase (HPPD) catalyzes the second step in the pathway for the catabolism of tyrosine, the conversion of (4-hydroxyphenyl)pyruvate (HPP) to homogentisate (HG). This reaction involves decarboxylation, substituent migration, and aromatic oxygenation. HPPD is a member of the alpha-keto acid dependent oxygenases that require Fe(II) and an alpha-keto acid substrate to oxygenate an organic molecule. We have examined the binding of ligands to HPPD from Streptomyces avermitilis. Our data show that HPP binds to the apoenzyme and that the apo-HPPD.HPP complex does not bind Fe(II) to generate active holoenzyme. The binding of HPP, phenylpyruvate (PPA), and pyruvate to the holoenzyme produces a weak ligand charge-transfer band at approximately 500 nm that is indicative of bidentate binding of the 1-carboxylate and 2-keto pyruvate oxygen atoms to the active site metal ion. For HPPD from this organism the 4-hydroxyl group of (4-hydroxyphenyl)pyruvate is a requirement for catalysis; no turnover is observed in the presence of phenylpyruvate. The rate constant for the dissociation of Fe(II) from the holoenzyme is 0.0006 s(-)(1) and indicates that this phenomenon is not significantly relevant in steady-state turnover. The addition of HPP and molecular oxygen to the holoenzyme is formally random. The basis of the ordered bi bi steady-state kinetic mechanism previously observed by Rundgren (Rundgren, M. (1977) J. Biol. Chem. 252, 5094-9) is the 3600-fold increase in oxygen reactivity when holo-HPPD is in complex with HPP. This complex reacts with molecular oxygen with a second-order rate constant of 1.4 x 10(5) M(-)(1) s(-)(1) inducing the formation of an intermediate that decays at the catalytically relevant rate of 7.8 s(-)(1).

Intra‐ and interannular substituent migration and intramolecular ipso substitution of biphenyl derivatives in mass spectrometry

AbstractBiphenyl derivatives undergo extensive intraannular substituent migrations and subsequent intramolecular ipso substitutions giving rise to a fluorenyi cation and a biphenylene radical cation as common products in mass spectrometry. For biphenyls bearing an alkyl group, interannular substituent migration resulting in a substituted tropylium ion is also observed. Electron‐withdrawing groups are found to be much more favourable to these reactions than the electron‐donating ones.

ChemInform Abstract: Synthesis of N.epsilon.‐(p‐Bromophenyl)‐L‐lysine and Nγ‐(p‐ Bromophenyl)‐L‐histidine as Models for Adducts of Bromobenzene 3,4‐ Oxide to Protein. Observation of an Unusual Pd‐Catalyzed Nγ‐ to Nπ‐Aryl Substituent Migration.

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.

Synthesis of N.epsilon.-(p-Bromophenyl)-L-lysine and N.tau.-(p-Bromophenyl)-L-histidine as Models for Adducts of Bromobenzene 3,4-Oxide to Protein. Observation of an Unusual Pd-Catalyzed N.tau. to N.pi.-Aryl Substituent Migration

Bromobenzene 3,4-oxide (1), the putative toxic metabolite of bromoben- zene, is known to alkylate protein sulfur nucleophiles in vivo and is postulated to alkylate protein nitrogen nucleophiles, the expected products of which would include, after hydrolysis, N τ -(p-bromophenyl)- L-histidine (8) and N e -(p-bromophenyl)-L-lysine (7). These non-protei- nogenic amino acids have now been synthesized by unambiguous routes and their stability under protein hydrolysis conditions demonstrated. Trea- tment of N α -Cb 2 -lysine with sodium nitroprusside gave the e-lysinol derivative, which by successive treatment with CBr 4 /Ph 3 P and excess p-bromoaniline and deprotection (6.0 M HCl, 110 o C) afforded an overall 14% yield of (7). Alkylation of N α -Ac-L-histidine methyl ester with p-fluoronitrobenzene, followed by reduction, a modified Sandmeyer bromo- dediazotization (tert-BuONO/CuBr 2 ), and deprotection afforded (8) in 10% overall yield. An unexpected N τ - to N π -aryl migration was observed during hydrogenation of a N τ -(p-nitrophenyl)histidine derivative over Pd/charcoal; it was avoided by use of SnCl 2 /ethanol for nitro reduc- tion. The N α -acetyl derivatives of (7) and (8), of interest as haptens for use in raising antibodies against proteins alkylated by epoxide (1), were also prepared and characterized

Novel peripheral substituent migration reactions in tetrapyrrole macrocycles

Copper(II) promoted cyclizations of a,c-biladiene salts bearing large terminal (1′,8′) substituents afford intermediates which suffer a variety of cleavage and cyclization reactions, in a stepwise manner, to yield mono-mesosubstituted porphyrins, chlorins, and di-meso-substituted porphyrins via facile migration reactions.

Mass spectrometric study on 2‐amino‐as‐triazino[6,5‐c]quinoline and some of its derivatives

AbstractElectron impact induced fragmentations of 2‐amino‐as‐triazino[6,5‐c]quinoline and its 2‐methylamino, 2‐dimethylamino and 2‐benzylamino analogues have been investigated. The main primary decomposition route of both the singly and the doubly charged molecular ions is the N2 loss. For the singly charged ions the critical energy of this reaction is 110±10 kJ mol−1 and the kinetic energy release is 61±4 kJ mol−1. For the doubly charged ions these values are 90±10 kJ mol−1 and 5±2 kJ mol−1, respectively, indicating a significantly different reaction profile. The further fragmentation of [MN2]+˙ ions consists of radical eliminations from the 2‐amino group with cleavages of the α‐ and β‐bonds. Here a significant substituent effect is eliminations found suggesting an intramolecular cyclization reaction with a substituent migration. D and 15N labelling experiments have shown a minor extent of randomization of the labelled atoms and the occurrence of other hidden skeletal rearrangements during the fragmentation.

ChemInform Abstract: 1‐PHENYLAZULENE → 2‐PHENYLAZULENE REARRANGEMENT ; SUBSTITUENT MIGRATION OR FRAMEWORK REARRANGEMENT?

Chemischer InformationsdienstVolume 13, Issue 38 Preparative Organic Chemistry ChemInform Abstract: 1-PHENYLAZULENE → 2-PHENYLAZULENE REARRANGEMENT ; SUBSTITUENT MIGRATION OR FRAMEWORK REARRANGEMENT? K.-P. ZELLER, K.-P. ZELLERSearch for more papers by this author K.-P. ZELLER, K.-P. ZELLERSearch for more papers by this author First published: September 21, 1982 https://doi.org/10.1002/chin.198238109Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume13, Issue38September 21, 1982 RelatedInformation

A 13C nuclear magnetic resonance study of the reversible substituent migration in several 2-acyl and 2-silyl derivatives of tropolone. Troponoid-IV

The energy barrier for the reversible substituent migration was determined for a number of 2-acyl and 2-silyl derivatives of tropolone. The energy barrier is found to be dependent on the nature of the migrating group. Asymmetric monosubstitution on the ring shifts the equilibrium in favor of one dynamic isomer. In the two cases studied (3-bromotropolone and 3-bromotropolone acetate) it is found that the equilibrium is shifted towards the isomer bearing the bromine atom at the 7-position.

The Loss of a hydroxyl group from the molecular ions of alkylnitrobenzenes

AbstractIt is confirmed that the loss of HO˙ from the molecular ion of o‐nitrotoluene involves exclusively a hydrogen from the methyl group. However, in higher homologues hydrogen atoms from non‐benzylic sites are also implicated. With such compounds this fragmentation mode is shown not only by the ortho but, to a lesser extent, by the meta and para isomers as well. The proportion of the total ion current borne by the [M – 17]+ ion follows the order ortho > meta > para, which is attributed to substituent migration around the ring with a hydroxyl radical only being lost when the groups are on adjacent ring atoms. Other ions present in the spectra point to interaction between substituents to form a new heterocyclic ring.

Zum Mechanismus der Substituentenwechselwirkung bei der elektronenstoßinduzierten Äther-Spaltung in para-substituierten Methoxymethylaromaten / On the Mechanism of Substituent Interaction During the Electron Impact Induced Ether Cleavage from para-Substituted Methoxymethyl Benzenes

The unusual methyl elimination from para-substituted methoxy-methyl benzenes has been elucidated. It can be shown that two entirely different mechanisms contribute to the reaction: i) intramolecular hydrogen transfer onto the benzene ring (π-complex formation) and ii) substituent migration via ring expansion. Alternative mechanisms as for instance transanular protonation of the ester function or substituent migration via valence bond isomers are not involved in the formation of the [M-methyl]+-ions.