Subsequent Retro Research Articles

Aromatic Heterocycles as Productive Dienophiles in the Inverse Electron-Demand Diels-Alder Reactions of 1,3,5-Triazines.

Heterocycles are often found as the structural nucleus in natural products and biological active compounds. Consequently, research toward the discovery and development of novel and efficient synthetic methodologies is of constant interest to organic chemists. Diels-Alder reactions are powerful at forming multiple bonds simultaneously, often with stereoselectivity, and thus are one of the most widely used synthetic methodologies in organic syntheses. Inverse electron-demand Diels-Alder (IEDDA) reactions, a subclass of Diels-Alder reactions, have been developed for the efficient synthesis of various heterocycles, with 1,3,5-triazines used as azadienes. The initial 1,3,5-triazine IEDDA reactions mostly included nonaromatic, electron-rich species such as vinyl ethers, enamines, ynamines, and amidines as dienophiles, producing in high yields pyrimidine derivatives with excellent regioselectivity. We hypothesized that some electron-rich aromatic heterocycles could be studied as potential dienophiles for 1,3,5-triazine IEDDA reactions; 5-aminopyrazoles proved to be productive dienophiles leading to high yields of pyrazolopyrimidines. Subsequently, many studies were reported to investigate the mechanism and scope of this new type of IEDDA reaction. Mechanistically, this new type of IEDDA reaction is quite interesting since it entails two aromatic compounds proceeding through a perceived high energy nonaromatic transition state, leading to a new aromatic compound, a counterintuitive process. Both theoretical and experimental studies provide key insights to this reaction mechanism, with learnings from these studies possibly stimulating unconventional thinking in other areas. Theoretical calculations of these cascade reactions of amino-substituted heterocycles with 1,3,5-triazines indicate that the reactions occur in a stepwise fashion via a highly polar zwitterionic intermediate; elimination of ammonia from IEDDA adducts and subsequent retro Diels-Alder reaction drive the reaction toward the fully aromatized IEDDA products. This amino substituent is critical in determining the regioselectivity and driving the cascade reactions to completion. With regard to reaction scope, many amino-heterocycles such as pyrroles, imidazoles, furans, thiophenes, and indoles all proved to be productive dienophiles for this new IEDDA reaction, leading to various fused-pyrimidines in a single step with moderate to high yields and high regioselectivity. Application of this new IEDDA reaction with 1,3,5-triazines was reported to lead to interesting heterocyclic compounds such as nucleoside natural product nebularine and analogues, as well as fluorine-containing fused pyrimidines with potential for biological activities.Herein, the scope of various aromatic heterocycles as dienophiles in the 1,3,5-triazine IEDDA reaction is reviewed. Moreover, both experimental and theoretical studies of the mechanisms for this interesting cascade IEDDA reaction are discussed. Finally, applications of this new type (aromatic heterocycles as dienophiles with 1,3,5-triazines as azadienes) of IEDDA reaction are also covered.

Simple 3D printed stainless steel microreactors for online mass spectrometric analysis

A simple flow chemistry microreactor with an electrospray ionization tip for real time mass spectrometric reaction monitoring is introduced. The microreactor was fabricated by a laser-based additive manufacturing technique from acid-resistant stainless steel 316L. The functionality of the microreactor was investigated by using an inverse electron demand Diels-Alder and subsequent retro Diels-Alder reaction for testing. Challenges and problems encountered are discussed and improvements proposed. Adsorption of reagents to the rough stainless steel channel walls, short length of the reaction channel, and making a proper ESI tip present challenges, but the microreactor is potentially useful as a disposable device.

Metal-free approach for the ʟ-proline mediated synthesis of nitrones from nitrosobenzene

An efficient, and metal-free approach for the ʟ-proline mediated synthesis of nitrones from nitrosobenzene and benzaldehydes has been established. The reaction undergoes very efficiently at room temperature in methanol as a solvent. The reaction is assumed to involve that the initial formation of azomethine ylide and [2 + 3] cycloaddition of nitrosobenzene, followed by the subsequent retro [2 + 3] cycloaddition could offer the desired nitrone.

Synthesis of E7 peptide-modified biodegradable polyester with the improving affinity to mesenchymal stem cells

As the most promising stem cell, bone marrow-derived mesenchymal stem cells (BMSCs) has attracted many attentions and applied widely in regenerative medicine. A biodegradable polyester with tunable affinity to BMSCs plays critical role in determining the properties of the BMSCs-based constructs. In this study, maleimide functionalized biodegradable polyester (P(MTMC-LA)) was synthesized through ring-opening copolymerization between l-lactide (LA) and furan-maleimide functionalized trimethylene carbonate (FMTMC) and a subsequent retro Diels-Alder reaction. P(MTMC-LA) was modified by different amounts of BMSCs specific affinity peptide (EPLQLKM, E7) through click-chemistry to investigate the effect on BMSCs. The E7 peptide modified P(MTMC-LA) was casted into films on glass slides and BMSCs were seeded onto the films. In vitro study showed that E7 peptide modified P(MTMC-LA) films supported BMSCs adhesion and proliferation compared to unmodified P(MTMC-LA) film. Besides, the adhesion and proliferation were enhanced by the increasing peptide grafting ratio. These results indicated that the novel biodegradable polyester can serve as a biomaterial with great potential application in tissue engineering and regenerative medicine.

Synthesis of functionalized poly(ester carbonate) with laminin-derived peptide for promoting neurite outgrowth of PC12 cells.

Maleimide-functionalized poly(ester carbonate)s are synthesized by ring-opening copolymerization of furan-maleimide functionalized trimethylene carbonate (FMTMC) with L-lactide and a subsequent retro Diels-Alder reaction. The maleimide groups on poly(ester carbonate)s are amenable to Michael addition with thiol-containing molecules such as 3-mercapto-1-propanol, 2-aminoethanethiol hydrochloride, and mercaptoacetic acid under mild conditions, enabling the formation of biodegradable materials with various functional groups (e.g., hydroxyl, amine, and carboxyl). In particular, the maleimide-functionalized poly(ester carbonate) is clicked with a laminin-derived peptide CQAASIKVAV. In vitro culture of PC12 cells shows that the maleimide-functionalized polymers, especially the CQAASIKVAV-grafted one, could support cell proliferation and neurite outgrowth. The maleimide-functionalized poly(ester carbonate)s provide a versatile platform for diverse functionalization and have comprehensive potential in biomedical engineering.

Formation of β-(diphenylphosphoryl)pyrroles via reactions of dibromocyclobutenylphosphine oxides with aniline

1-Phenyl-2-methyl(phenyl)-4-(diphenylphosphoryl)pyrroles are obtained, unexpectedly instead of the 1-phenyl-4-methyl(phenyl)-2-(diphenylphosphoryl)pyrrole regioisomers from a series of reactions between 1,4-dibromo-2-methyl(phenyl)-4-diphenylphosphorylcyclobutenes and aniline via nucleophilic substitution accompanied by an allylic shift, subsequent retro electrocyclization and pyrrole ring closure.

Insertion of Benzynes into the P═N Bond of P-Alkenyl(alkynyl)-λ5-phosphazenes

Benzynes, generated from 2-(trimethylsilyl)phenyl triflates, have been found to react with P-Alkenyl-λ(5)-phosphazenes via a formal π-insertion into the P═N bond. A subsequent retro [2 + 2] cycloaddition/6π electrocyclization/protonation cascade explains the formation of the resulting 1,4-benzazaphosphorinium triflates. P-Alkynyl λ(5)-phosphazenes and phosphane sulfides undergo similar transformations.

ChemInform Abstract: Intramolecular Diels-Alder Reactions of Pyrimidines and a Computational Study Toward Their Structure and Reactivity.

The syuntheses of 2-(prop-2-ynyloxy)carbonylpyrimidine (1), 5-(prop-2-ynyloxy)carbonylpyrimidine (2), 5-phenyl-22-(1-prop-2-ynylpyrryl)pyrimidine (8), 5-phenyl-2-2-(1-prop-2-ynylpysrrolidinyl)pyrimidine (9) and 2-2-(prop-2-ynyloxy)phenyl-4,6-R 2 -5-R 1 -pyrimidine (R 1 = H, Cl, Ph; R 2 = H, Me) (14a-d) are described.Upon heating, the compounds 1, 9, and 14 undergo an intramolecular Diels-Alder reaction and a subsequent retro Diels-Alder reaction to yield the annelated pyridines 15, 16, and 17, respectively

Synthesis of π-expanded BODIPYs and their fluorescent properties in the visible–near–infrared region

A series of π-expanded boron–dipyrromethenes (BODIPYs) fused with aromatic rings at β,β-positions, such as benzene, acenaphthylene, and benzofluoranthene were prepared by the reaction of BF 3·OEt 2 with bicyclo[2.2.2]octadiene-fused dipyrromethene and the subsequent retro Diels–Alder reaction. These BODIPYs exhibited the absorptions and the fluorescence emissions over wide range of visible–near–infrared region at 500–800 nm. BODIPYs composed of two fluorantho[8,9- f]isoindoles absorbed and emitted at red-region over 750 nm with absolute fluorescence quantum yield ( Φ f) of ca. 0.3, although they are unstable under air in room light. BODIPY composed fluorantho[8,9- f]isoindole and acenaphtho[1,2-c]pyrrole was stable and showed a bright fluorescence emission at 695 nm with high Φ f of 0.70.

A new specific mechanism for thioacid/azide amidation: electronic and solvent effects

Abstract Detailed theoretical studies of azide/thioacid amidation are performed using density functional theory. The calculated results indicate that electronic properties of azide have significant effects on reaction pathways, which result in two distinct mechanisms for electron-rich and electron-poor azide coupling in the base-promoted amidation. For electron-rich azide amidation, after the concerted [3+2] cycloaddition of azide/thiocarboxylate, a new reaction channel is found challenging that recently mentioned, which follows two consecutive, unimolecular reactions with very low activation barriers (−1) to give an anionic amide and a nitrous sulfide (N2S). Distinct from electron-rich azide amidation, electron-poor azide first couples with thiocarboxylate to form a linear stable adduct, and then passes through the transition state of the rate-controlling step to afford the anionic amide, rather than the thiatrazoline. The free energy barrier of this step is 4.2 kcal mol−1 lower than that previously proposed. Comparatively, the azide/thioacid amidations undergo the concerted [3+2] cycloaddition and the subsequent retro-[3+2] cycloaddition process to give cis-enol form of the amide, which have higher activation barriers than those in the based-promoted amidation. Solvent effects investigated indicate that non-polar solvents, such as chloroform, are more preferable for the base-promoted thioacid/azide amidation.

A New Synthesis of Acenaphthobenzoporphyrin and Fluoranthobenzoporphyrin

Benzoporphyrins fused with acenaphthylene or fluoranthene (3) and (4) were prepared by the condensation of bicyclo[2.2.2]octadiene(BCOD)-fused tripyrrane (5) with appropriate pyrrole dialdehydes (13) or (14) and the subsequent retro Diels-Alder reaction. The absorptions of these new porphyrins were very intense at both Soret and Q bands, which might be useful as organic dyes for solar cells.

Gas-phase Fe +-assisted cycloaddition reactions of cyclopentadiene with small alkenes and alkynes

Gas-phase Fe +-assisted Diels–Alder reactions of cyclopentadiene with small alkenes and alkynes were studied using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. The reaction of FeC 5H 6 + with ethene is proposed to be direct [4 + 2] Diels–Alder cycloaddition followed by dehydrogenation. The formation of FeC 8H 10 + from the reaction of FeC 5H 6 + with propene can be explained by an allylic C–H insertion and reductive elimination of H 2. It is also possible for the reaction to proceed by [4 + 2] Diels–Alder coupling reaction and further dehydrogenation. The most intriguing reactions are the ones with ethyne and propyne, where Fe(tropylium) + and Fe(cyclooctatetraene) + are the predominant products. Reaction of FeC 5H 6 + with ethyne can proceed either through [4 + 2] addition followed by [1,3]-shift and H loss or from [2 + 2] addition, subsequent retro [2 + 2] reaction and H loss. The reaction with propyne is more likely to undergo a [2 + 2] addition and subsequent retro [2 + 2] followed by dehydrogenation to form major product ion, FeC 8H 8 +. A retro-alkyne cycloaddition process is believed to be responsible for the formation of the secondary reaction product FeC 6H 6 +. For comparison with propyne, the reaction of FeC 5H 6 + with allene was also studied. It turned out to be the same major product, Fe(cyclooctatetraene) +. This reaction is proposed to proceed by either [2 + 2] or [4 + 2] cycloaddition and subsequent dehydrogenation to form Fe(C 8H 8) +. Further kinetics studies on these reactions indicate that they follow linear pseudo-first-order kinetics, suggesting that FeC 5H 6 + is thermalized and consists of one isomeric structure under our experimental conditions.

Functionalized organolithium compounds: Generation via reductive lithiation and nucleophilic addition to N-phenethylimides. Access to functionalized dihydropyrrolo[2,1- a]isoquinolinones

A procedure for producing 1,4-dianion equivalents consists of reductive lithiation, induced by 4,4.-di- tert-butylbiphenylide, of functionalized phenyl sulfides. Nucleophilic addition of 4-lithio-2-(trimethylsilylmethyl)but-1-ene 1 and 2-(3-lithiopropyl)-2-trimethylsilyl-1,3-dithiane 2 thus prepared to N-phenethyl- cis-norbor-5-en-2,3-dicarboximide 9 afforded the corresponding α-hydroxy lactams in good yields. Besides, access to C-10b substituted α,β-unsaturated pyrroloisoquinolinones 3 was efficiently achieved via a tandem organolithium nucleophilic addition — N-acyliminium ion cyclization sequence and subsequent retro Diels-Alder reaction. The methodology can be extended to functionalized organolithiums, but the N-acyliminium cyclization fails if the allylsilane moiety is present.

Synthese von 6,6‐Dimethylfulven‐2‐carbonsäure‐methylester und ‐2,3‐dicarbonsäure‐dimethylester sowie deren Umsetzung zu 2,3,5,6‐substituierten Nordbornadienen

Synthesis of Methyl 6,6‐Dimethylfulvene‐2‐carboxylate and Dimethyl 6,6‐Dimethylfulvene‐2,3‐dicarboxylate as well as their Reaction to 2,3,5,6‐Substituted NorbornadienesFulvenes 5 and 6 were synthesized by Diels‐Alder reaction of 6,6‐dimethylfulvene with methyl prop‐2‐ynoate and dimethyl but‐2‐ynedioate, catalytic reduction of the unsubstituted norbornadiene double bond, and a subsequent retro Diels‐Alder reaction under flash vacuum pyrolysis conditions, 5 and 6 are used as the diene component in synthesizing 2,5‐, 2,3,5‐, and 2,3,5,6‐substituted norbornadienes 7–9 by Diels‐Alder reaction with electron‐deficient alkynes.

Intramolecular Diels-Alder reactions of pyrimidines and a computational study toward their structure and reactivity

The syuntheses of 2-(prop-2-ynyloxy)carbonylpyrimidine (1), 5-(prop-2-ynyloxy)carbonylpyrimidine (2), 5-phenyl-22-(1-prop-2-ynylpyrryl)pyrimidine (8), 5-phenyl-2-2-(1-prop-2-ynylpysrrolidinyl)pyrimidine (9) and 2-2-(prop-2-ynyloxy)phenyl-4,6-R 2 -5-R 1 -pyrimidine (R 1 = H, Cl, Ph; R 2 = H, Me) (14a-d) are described.Upon heating, the compounds 1, 9, and 14 undergo an intramolecular Diels-Alder reaction and a subsequent retro Diels-Alder reaction to yield the annelated pyridines 15, 16, and 17, respectively

Computational studies towards the selectivity and reactivity of 5-propynyloxyclycloalkanepyrimidines in intramolecular diels-alder reactions.

Computational studies (MNDO/PM3 and MMX) were performed towards the selectivity and reactivity of the ringtransformation reactions of the 5-(1-propynyloxyethyl)pyrimidine derivatives A1 -8. Determination of the energy and dipole moments of the transition states of the different possible reaction pathways revealed that the ratio of the product formation was determined by the polarity of the transition states, as expressed by their dipole moments, in combination with the dipole moment of the reaction medium. Also the reactivity of the compounds under study appeared to depend on the polarity of the transition state of the initial Diels-Alder reaction. The differences in dipole moments of the different TS's are ascribed to the geometry of the molecules in the TS's. Furthermore, a comparison of the heats of activation of the initial Diels-Alder reaction and the subsequent retro Diels-Alder reaction showed that the first one is the rate determining step.

Synthesis of 5-propynyloxycycloalkanepyrimidines and their selectivity and reactivity in intramolecular Diels-Alder reactions.

The 5-propynyloxycycloalkane pyrimidines IIIA ( 17 – 20), IIIB ( 21 – 24), and IIIC ( 25, 26) and the 5-(1-propynyloxyethyl) pyrimidines IIID ( 27,28), easily undergo intramolecular Diels-Alder reactions with inverse electron demand and a subsequent retro Diels-Alder reaction in which R 1CN (R 1 = H, Me) or X-CH 2CN (X = −CH 2, −CH 2CH 2, −H) is expelled. For the compounds IIIA and IIIB the extrusion of X-CH 2CN is favoured, yielding 3-(3-cyanopropyl)-1,3 dihydro-6-phenyl-R 1-R 2-furo[3,4- c ]pyridines ( 29 – 36). The compounds 17 and 21 also yielded 4-phenyl-2 H-6,7,8,8a-tetrahydro-furo[4,3,2- de ]quinoline ( 38), by expulsion of HCN or MeCN respectively, which constitute a new class of heterocyclic compounds. For the compounds IIIC and IIID the extrusion of HCN is favoured as compared to the extrusion of X-CH 2CN. In case of IIIC this also gives a hitherto unknown class of heterocyclic ring systems namely 2 H- 1,6,7,8,9,9a-hexahydro-4-phenyl-9a-R 1-5-aza-1-oxo-benz[ c , d ]azulenes ( 39, 40). The reactivity of the compounds III towards the cycloaddition appears to be strongly influenced by the nature of the substituent R 2 if R 1 = H. However, if R 1 = Me the effect of R 2 on the reactivity was very small. The ratio of the products V and VI appears to depend mainly on the nature of -X-.