Grob Fragmentation Research Articles

Theoretical investigation on pyrolysis mechanism of glycerol

Four possible channels of glycerol unimolecular pyrolysis were investigated theoretically by means of the quantum chemistry calculation based on density functional theory. Energy barriers and reaction rate constants were employed to analyze the possible pyrolysis mechanisms. Mechanism A was the most possible channel for glycerol pyrolysis based on the calculated results. According to this mechanism, C-2 of glycerol transferred into acetaldehyde as its aldehyde group carbon atom following the Cyclic Grob Fragmentation. The rate constants for mechanism B-p2-1 which transferred C-2 of glycerol into acetaldehyde as its methyl group was three orders magnitude lower than that of mechanism A. The above information should be useful to understand the pyrolysis mechanism of more complex carbohydrates such as glucose and cellulose.

ChemInform Abstract: Grob Fragmentation of Norbornyl α‐Diketones: A Route to α‐Ketoenols and Aromatic Compounds.

AbstractNorbornyl α‐diketones undergo facile Grob fragmentation to afford α‐ketoenols such as (II).

Pyrolysis of D-Glucose to Acrolein

Despite of its great importance, the detailed molecular mechanism for carbohydrate pyrolysis remains poorly understood. We perform a density functional study with a newly developed XYG3 functional on the processes for D-glucose pyrolysis to acrolein. The most feasible reaction pathway starts from an isomerization from D-glucose to D-fructose, which then undergoes a cyclic Grob fragmentation, followed by a concerted electrocyclic dehydration to yield acrolein. This mechanism can account for the known experimental results.

Grob Fragmentation of Norbornyl α-Diketones: A Route to α-Ketoenols and Aromatic Compounds

An efficient acid-catalyzed Grob fragmentation of symmetrical and asymmetrically substituted norbornyl α-diketones to the corresponding six-membered α-ketoenols is reported. The regio- and stereochemical outcome of the Grob fragmentation of C2 mono- and disubstituted α-diketones was investigated. A single regioisomer resulting from a favorable half-chair intermediate was normally observed. A departure from the normal course was noticed for C2 disubstituted α-diketones possessing an exo-methyl and an endo-methoxycarbonyl derivative, giving the opposite regioisomers due to initial formation of the hemiketal. The bromo analogues of the C2 disubstituted α-diketones furnished an unusual byproduct, which appears to have been formed through highly reactive fused four-membered bicyclo[2.2.0]hexane intermediates. A plausible mechanistic proposal involving the gem-dihalo intermediate, which in one case was actually isolated as its BF(2)-complex, is outlined. The fragmentation protocol was applied to various norbornyl substrates including bis-α-diketone derivatives. The methodology was successfully utilized for the synthesis of substituted aromatic compounds.

Synthesis of (−)-Homogalanthamine from Naltrexone

Acetylcholinesterase inhibitor (-)-homogalanthamine 3 was synthesized from μ opioid antagonist naltrexone (2) in 16% total yield. The synthesis features Grob fragmentation as a key reaction, which was especially accelerated in the presence of 15-crown-5.

Synthesis of (-)-209I and (-)-223J

Piperidines and indolizidines provide the core of many biologically active natural products and pharmaceutical drugs. Previous methodology by Charette has involved the formation of dihydropyridinium salts from a Grob fragmentation using a stoichiometric amount of an expensive silver salt. The above work demonstrates a silver-free process via the use of an O-triflyl intermediate (H) to generate such species, with the synthesis of natural products (-)-209I and (-)-223J showcasing this methodology.

Stereoselective Synthesis of 2,3,6-Trisubstituted Tetrahydropyridines via Tf2O-Mediated Grob Fragmentation: Access to Indolizidines (−)-209I and (−)-223J

Herein we describe the γ-amino hydroxide Grob fragmentation of the aza-bicyclo[2.2.2]octene 1 using triflic anhydride as the activating agent. The resulting dihydropyridinium ion can react with a wide variety of Grignard reagents, giving access to 2,3,6-trisubstituted tetrahydropyridines (2) with high regio- and stereoselectivities. This methodology has been applied to the short synthesis of natural indolizidines (-)-209I (3) and (-)-223J (4).

Synthetic Applications of the Carbonyl Generating Grob Fragmentation

Synthetic Applications of the Carbonyl Generating Grob Fragmentation

(+)‐(R,Z)‐5‐Muscenone and (−)‐(R)‐Muscone by Enantioselective Aldol Reaction and Grob Fragmentation

(+)-(R,Z)-5-Muscenone ((R)-1) was synthesized by an enantioselective aldol reaction, catalyzed by new ephedrine-type Ti reagents (up to 70 % enantiomeric excess). Substrate-directed diastereoselective reduction of the aldol product and Grob fragmentation of the tosylate of the resultant 1,3-diol afforded (+)-1. This approach also gave access to (-)-(R,E)-5-muscenone and (-)-(R)-muscone.

Catalytic fast pyrolysis of glucose with HZSM-5: The combined homogeneous and heterogeneous reactions

The production of aromatics from glucose by catalytic fast pyrolysis occurs in two steps. First, glucose is thermally decomposed to smaller oxygenates through retro-aldol fragmentation, Grob fragmentation and dehydration reactions. At low temperatures (<300 °C), retro-aldol and Grob fragmentation reactions are favored with d-glyceraldehyde, hydroxyacetone and hydroxyacetaldehyde being the primary products. At higher temperatures (>300 °C), dehydration is favored with levoglucosan as the major product. The addition of ZSM-5 catalyst to the pyrolysis reactor lowers the temperature at which the fragmentation and dehydration reactions occur at 206 °C and 312 °C, and at 282 °C and 369 °C, respectively. In the second step of catalytic fast pyrolysis, the dehydrated products enter into the catalyst where they are converted into aromatics, CO, CO 2 and water. The catalytic conversion step is significantly slower than the initial pyrolysis reaction. The aromatic product selectivity is a function of catalyst to glucose weight ratio, heating rate and reaction temperature. At 600 °C, a maximum carbon yield of 32% aromatics is realized after 240 s with catalysts to feed ratio of 19. The major competing reaction to aromatic production is the formation of coke. Coke is most likely formed by polymerization of the furans on the external catalyst surface.

Searching for intermediates in Prins cyclisations: the 2-oxa-5-adamantyl carbocation

The 2-oxa-5-adamantyl carbocation 4 is shown to be a viable intermediate in several S(N)1 substitution reactions. However, attempts to observe the formation of 4 from various precursors by NMR methods (which succeed for the 1-adamantyl cation 5) failed, suggesting that 4 does not survive on longer timescales. DFT calculations suggest that the retro-Prins process (beta-cleavage, Grob fragmentation) to give enantiomeric (1R,5R)- and (1S,5S)-7-methylene-2-oxoniabicyclo[3.3.1]non-2-ene cations 22 is the only realistic unimolecular escape route for 4. With the 6-31G(d) basis set, B3LYP calculation predicts that 4 is only 11 kJ mol(-1) more stable than 22, and the barrier separating 4 and 22 is calculated to be only 15 kJ mol(-1), so rapid equilibration of these species is likely on the laboratory time scale. The implications of this study for the mechanism of the Prins cyclisation are discussed.

ChemInform Abstract: Silver Ion Induced Grob Fragmentation of γ‐Amino Iodides: Highly Stereoselective Synthesis of Polysubstituted Piperidines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.

Biomimetic Total Synthesis of (±)‐Pallavicinolide A

Piecing it together: The first total synthesis of naturally occurring diterpene pallavicinolide A was achieved. Notable features are highlighted by three key biomimetic transformations: a base-promoted Grob fragmentation, a singlet oxygen oxidation, and an intramolecular Diels-Alder cycloaddition.

Synthesis of 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones by addition of Grignard reagents to derivatives of o-aminobenzonitrile

Addition of organometallics to N-(alpha-haloacyl)-o-aminobenzonitrile resulted in the formation of 2,5-disubstituted 1,4-benzodiazepin-3-ones, whereas N-(beta-haloacyl)-o-aminobenzonitrile gave 2,6-disubstituted 1,5-benzodiazocin-4-ones under similar conditions. Initial cylization of N-(beta-haloacyl)-o-aminobenzonitrile to obtain the corresponding lactam (e.g.alpha,alpha-dimethyl-N-(2-cyanophenyl)-beta-lactam) increased the yield of 1,5-benzodiazocin-4-ones significantly. Somewhat surprisingly, addition of lithium reagents to N-(beta-haloacyl)-o-aminobenzonitrile gave 4,4-disubstituted quinazolines via Grob fragmentation.

Silver Ion-Induced Grob Fragmentation of γ-Amino Iodides: Highly Stereoselective Synthesis of Polysubstituted Piperidines

A new concerted silver ion-mediated Grob fragmentation process is described in which a 1,2-dihydropyridinium ion is formed and trapped in situ with Grignard reagents in a highly regio- and diastereoselective fashion. Using this methodology, 2,3,6-trisubstituted piperidines were synthesized in good yields and further derivatized to polysubstituted indolizidine.

Arylation and Vinylation of Alkenes Based on Unusual Sequential Semipinacol Rearrangement/Grob Fragmentation of Allylic Alcohols

Alkenes can be stereoselectively arylated and vinylated without transition-metal catalyst under mild conditions through an interesting NBS-promoted semipinacol rearrangement and a subsequent unusual NaOH-mediated Grob fragmentation.

Carbohydrate pyrolysis mechanisms from isotopic labeling: Part 4. The pyrolysis of d-glucose: The formation of furans

The use of 13C isotopically labeled d-glucose has led to an improved understanding of the mechanisms of pyrolytic formation of furan and 15 of its derivatives. The cyclic Grob fragmentation of 1,3-diols as applied to d-glucose leads to rationalizations of important observed labeling patterns among the 11 furans that resulted from carbon-loss during the pyrolytic sequence. A copyrolysis of 13carbo-ubiquilog and naturalomer d-glucose established that the preponderance of each of the furans arose in unimolecular fashion. Copyrolysis of 13carbo-ubiquilog d-glucose and naturalomer d-fructose provided relative product formation ratios consistent with the involvement of fructose in some of the mechanistic pathways. Formation of nine of the furans from d-glucose (furfural, 5-hydroxymethylfurfural, furan, 3-[2H]-furanone, hydroxymethyl furyl ketone, furfuryl alcohol, alpha-angelica lactone, “Miyazaki's substance”, and furan-3-carboxaldehyde) can be rationalized without need to invoke oxidation–reduction steps. Prospective mechanistic schemes are presented for most of these. Six of the furans (5-methylfurfural, 2-methylfuran, 3-methylfuran, 2,5-dimethylfuran, 2-(1,2-dihydroxyethyl)furan, and butyrolactone) need the intervention of redox chemistry to account for their formation, and their relation to similar products that can form without need for redox chemistry is discussed.

A novel approach to the taxane ABC ring system through chemical conversion from C 19-diterpenoid alkaloid deltaline

A novel approach to the highly functionalized taxane ABC ring system through chemical conversion of the C 19-diterpenoid alkaloid deltaline ( 1) was achieved in six steps ( 1→ 17) in 18% overall yield mainly by Grob fragmentation, fission of the Δ 9(14) double bond, followed by aldol condensation, and Pelletier's cleavage process.

A Concise Approach to Vinigrol

Short and sweet: A simple and practical route to the unusual tricyclic ring system found in the biologically active diterpene vinigrol is described. A remarkable proximity-induced intramolecular cycloaddition and mild Grob fragmentation allow rapid construction of the core ring system in less than 10 steps and with a minimal reliance on protecting groups.

Two Novel Skeletal Rearrangements Involving in the C Ring of C19-Diterpenoid Alkaloid Deltaline Derivatives

Treatment of compounds 2 and 5, both from the C19-diterpenoid alkaloid deltaline 1, with 5% NaOH methanol (room temperature, 16 h) and NaOH-N,N-dimethylformamide (reflux, 10 h) led to the two novel skeletal rearrangement products 4 (90%) and 6 (62%), respectively, involving Wagner-Meerwein rearrangement and Grob fragmentation. Their structures were fully characteristized based on 2D NMR and HR-MS data.