Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis

Antti Kataja

Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis

Julkaisun otsikon käännös: Organokatalyysi ja jatkuvatoimiset virtausreaktorit mahdollistavina työkaluina orgaanisessa synteesissä

Antti Kataja

Tutkimustuotos: Doctoral Thesis › Monograph

Abstrakti

Mahdollistavat synteesiteknologiat ovat kokoelma uudenaikaisia työkaluja, joiden tavoitteena on auttaa orgaanisia kemistejä monimutkaisten reaktiotuotteiden nopeassa ja tehokkaassa synteesissä ja analysoimisessa. Näihin tekniikoihin kuuluvat mm. mikroaaltoreaktorit, immobilisoidut katalyytit sekä jatkuvatoimiset virtausreaktorit. Mahdollistavien synteesiteknologioiden soveltaminen tunnettuihin orgaanisiin synteesimenetelmiin kuten organokatalyysiin on ensiarvoisen tärkeää sopeuduttaessa muuttuvaan maailmaan, missä luonnonvarojen helppo saatavuus ei ole itsestäänselvyys. Tämän väitöskirjan ensimmäisessä osassa on tutkittu kinkona-alkaloidien tioureajohdannaisia sekä niiden reaktiomekanismeja. N-Trityylisubstituoidun tioureakatalyytin aktiivisuutta tutkittiin Meldrumin hapon ja muiden pehmeiden hiilinukleofiilien asymmetrisessä Michael-additiossa nitroalkeeneihin. Katalyytin huomattiin olevan tehoton malonaattidiesterien suhteen, ja jatkotutkimukset osoittivat, ettei katalyytti pysty tehokkaasti aktivoimaan ei-enolimuotoisia nukleofiilejä, estäen siten katalyyttisen syklin. Tämän väitöskirjan toisessa osakokonaisuudessa on tutkittu ketonin asymmetrisen organokatalyyttisen aldoliaddition käyttöä meriperäisen alkaloidin (–)-hennoksatsoli A:n kokonaissynteesissä. Kahta eri reittiä tutkittiin läntisen pyraanifragmentin synteesiä varten. Parhaaksi katalyytiksi osoittautui proliinin amidijohdannainen. Asetonin additio bisoksatsolialdehydiin optimoitiin ensin panosolosuhteissa ja sitä tutkittiin sen jälkeen virtausreaktorissa. Aldoliadditiotuotteen O-metyloinnille tutkittiin myös eri olosuhteita. Tämän väitöskirjan viimeisessä osassa on tutkittu jatkuvatoimisten virtausreaktorien käyttöä teollisesti merkittävässä aromaattisessa nitrausreaktiossa. Vanilliinin nitrausta tutkittiin mallireaktiona. Virtauskanavien tukkeutuminen tuotteen saostumisen vuoksi osoittautui vakavaksi ongelmaksi, ja lähtöaineiden varastoliuosten konsentraatiota sekä reaktiolämpötilaa säädettiin tämän perusteella. Reaktion selektiivisyys ei olennaisesti eronnut panosolosuhteista huolimatta huomattavan erilaisista olosuhteista, mutta tuotteen eristäminen oli haasteellisempaa. Vanilliinin metoksiryhmän O-demetyloituminen ja sitä seurannut nitrautuminen tunnistettiin tärkeimmäksi sivureaktioksi deformyloivan ipso-nitrautumisen ohella. Nitrausmetodia sovellettiin myös muihin lähtöaineisiin ja sen todettiin toimivan parhaiten suhteellisen elektronirikkaiden aromaattisten yhdisteiden kohdalla.

Julkaisun otsikon käännös	Organokatalyysi ja jatkuvatoimiset virtausreaktorit mahdollistavina työkaluina orgaanisessa synteesissä
Alkuperäiskieli	Englanti
Pätevyys	Tohtorintutkinto
Myöntävä instituutio	Aalto-yliopisto
Ohjaaja	Koskinen, Ari, Vastuuprofessori
Kustantaja	Aalto University
Painoksen ISBN	978-952-60-5061-4
Sähköinen ISBN	978-952-60-5062-1
Tila	Julkaistu - 2013
OKM-julkaisutyyppi	G4 Monografiaväitöskirja

Tutkimusalat

organokatalyysi
jatkuvatoimiset virtausreaktorit
bifunktionaaliset tioureakatalyytit
vetysidokset
proliini
enamiinikatalyysi
aldolireaktio
Michael-additio
aromaattinen nitraus

Pääsy asiakirjaan

http://urn.fi/URN:ISBN:978-952-60-5062-1

Siteeraa tätä

@phdthesis{2baf29a4c84849d1b0484c43d1ecae2a,

title = "Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis",

abstract = "Enabling synthetic technologies are a collection of modern tools created to aid synthetic organic chemists to achieve rapid and efficient synthesis and analysis of complex reaction products in the laboratory environment. These techniques include e.g. microwave reactors, heterogenized catalysts and continuous flow reactor systems. The application of enabling technologies to known methods of organic synthesis such as organocatalysis is paramount for chemists in adapting to a changing world where the ready availability natural resources is by no means a given. The first part of this thesis describes studies towards elucidating the mechanism of cinchona alkaloid derived bifunctional thiourea organocatalysts. The activity of N-trityl substituted thiourea catalyst in the asymmetric Michael addition of Meldrum{\textquoteright}s acid and other soft carbon nucleophiles to nitroalkenes was studied. The catalyst was found to be inactive with malonate diester nucleophiles, and subsequent studies revealed that the catalyst is unable to efficiently activate a non-enolic nucleophile, thus arresting the catalytic cycle. The second part of this thesis focuses on the use of asymmetric organocatalytic ketone aldol addition in the total synthesis of marine alkaloid (–)-hennoxazole A. Two routes were investigated for the synthesis of the western pyran fragment. A prolineamide derivative was identified as the optimal catalyst. The addition of acetone to a bisoxazole aldehyde was then optimized in batch conditions and studied further in continuous flow conditions. Conditions for the O-methylation of the aldol addition product were also identified. The final part of this thesis concentrates on the use of continuous flow reactors in industrially important aromatic nitration reactions. The nitration of vanillin was studied as the model reaction. Blockage of flow channels due to product precipitation was identified as a serious problem and the concentration of starting material stock solutions and reaction temperatures had to be adjusted accordingly. Reaction selectivity did not essentially differ from batch conditions in spite of radically different conditions, but product isolation was more difficult. Demethylation of the methoxy substituent of vanillin and subsequent nitration was identified to be the main side reaction, along with a deformylative ipso-nitration. The nitration protocol was studied with other substrates and it was found to function best for relatively electron rich aromatic compounds.",

keywords = "organocatalysis, continuous flow reactors, bifunctional thiourea catalysts, hydrogen bonding, proline, enamine catalysis, aldol reaction, Michael-addition, aromatic nitration, organokatalyysi, jatkuvatoimiset virtausreaktorit, bifunktionaaliset tioureakatalyytit, vetysidokset, proliini, enamiinikatalyysi, aldolireaktio, Michael-additio, aromaattinen nitraus, organocatalysis, continuous flow reactors, bifunctional thiourea catalysts, hydrogen bonding, proline, enamine catalysis, aldol reaction, Michael-addition, aromatic nitration",

author = "Antti Kataja",

year = "2013",

language = "English",

isbn = "978-952-60-5061-4",

series = "Aalto University publication series DOCTORAL DISSERTATIONS",

publisher = "Aalto University",

number = "43",

address = "Finland",

school = "Aalto University",

}

TY - BOOK

T1 - Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis

AU - Kataja, Antti

PY - 2013

Y1 - 2013

N2 - Enabling synthetic technologies are a collection of modern tools created to aid synthetic organic chemists to achieve rapid and efficient synthesis and analysis of complex reaction products in the laboratory environment. These techniques include e.g. microwave reactors, heterogenized catalysts and continuous flow reactor systems. The application of enabling technologies to known methods of organic synthesis such as organocatalysis is paramount for chemists in adapting to a changing world where the ready availability natural resources is by no means a given. The first part of this thesis describes studies towards elucidating the mechanism of cinchona alkaloid derived bifunctional thiourea organocatalysts. The activity of N-trityl substituted thiourea catalyst in the asymmetric Michael addition of Meldrum’s acid and other soft carbon nucleophiles to nitroalkenes was studied. The catalyst was found to be inactive with malonate diester nucleophiles, and subsequent studies revealed that the catalyst is unable to efficiently activate a non-enolic nucleophile, thus arresting the catalytic cycle. The second part of this thesis focuses on the use of asymmetric organocatalytic ketone aldol addition in the total synthesis of marine alkaloid (–)-hennoxazole A. Two routes were investigated for the synthesis of the western pyran fragment. A prolineamide derivative was identified as the optimal catalyst. The addition of acetone to a bisoxazole aldehyde was then optimized in batch conditions and studied further in continuous flow conditions. Conditions for the O-methylation of the aldol addition product were also identified. The final part of this thesis concentrates on the use of continuous flow reactors in industrially important aromatic nitration reactions. The nitration of vanillin was studied as the model reaction. Blockage of flow channels due to product precipitation was identified as a serious problem and the concentration of starting material stock solutions and reaction temperatures had to be adjusted accordingly. Reaction selectivity did not essentially differ from batch conditions in spite of radically different conditions, but product isolation was more difficult. Demethylation of the methoxy substituent of vanillin and subsequent nitration was identified to be the main side reaction, along with a deformylative ipso-nitration. The nitration protocol was studied with other substrates and it was found to function best for relatively electron rich aromatic compounds.

AB - Enabling synthetic technologies are a collection of modern tools created to aid synthetic organic chemists to achieve rapid and efficient synthesis and analysis of complex reaction products in the laboratory environment. These techniques include e.g. microwave reactors, heterogenized catalysts and continuous flow reactor systems. The application of enabling technologies to known methods of organic synthesis such as organocatalysis is paramount for chemists in adapting to a changing world where the ready availability natural resources is by no means a given. The first part of this thesis describes studies towards elucidating the mechanism of cinchona alkaloid derived bifunctional thiourea organocatalysts. The activity of N-trityl substituted thiourea catalyst in the asymmetric Michael addition of Meldrum’s acid and other soft carbon nucleophiles to nitroalkenes was studied. The catalyst was found to be inactive with malonate diester nucleophiles, and subsequent studies revealed that the catalyst is unable to efficiently activate a non-enolic nucleophile, thus arresting the catalytic cycle. The second part of this thesis focuses on the use of asymmetric organocatalytic ketone aldol addition in the total synthesis of marine alkaloid (–)-hennoxazole A. Two routes were investigated for the synthesis of the western pyran fragment. A prolineamide derivative was identified as the optimal catalyst. The addition of acetone to a bisoxazole aldehyde was then optimized in batch conditions and studied further in continuous flow conditions. Conditions for the O-methylation of the aldol addition product were also identified. The final part of this thesis concentrates on the use of continuous flow reactors in industrially important aromatic nitration reactions. The nitration of vanillin was studied as the model reaction. Blockage of flow channels due to product precipitation was identified as a serious problem and the concentration of starting material stock solutions and reaction temperatures had to be adjusted accordingly. Reaction selectivity did not essentially differ from batch conditions in spite of radically different conditions, but product isolation was more difficult. Demethylation of the methoxy substituent of vanillin and subsequent nitration was identified to be the main side reaction, along with a deformylative ipso-nitration. The nitration protocol was studied with other substrates and it was found to function best for relatively electron rich aromatic compounds.

KW - organocatalysis

KW - continuous flow reactors

KW - bifunctional thiourea catalysts

KW - hydrogen bonding

KW - proline

KW - enamine catalysis

KW - aldol reaction

KW - Michael-addition

KW - aromatic nitration

KW - organokatalyysi

KW - jatkuvatoimiset virtausreaktorit

KW - bifunktionaaliset tioureakatalyytit

KW - vetysidokset

KW - proliini

KW - enamiinikatalyysi

KW - aldolireaktio

KW - Michael-additio

KW - aromaattinen nitraus

KW - organocatalysis

KW - continuous flow reactors

KW - bifunctional thiourea catalysts

KW - hydrogen bonding

KW - proline

KW - enamine catalysis

KW - aldol reaction

KW - Michael-addition

KW - aromatic nitration

M3 - Doctoral Thesis

SN - 978-952-60-5061-4

T3 - Aalto University publication series DOCTORAL DISSERTATIONS

PB - Aalto University

ER -

Organocatalysis and Continuous Flow Reactors as Enabling Tools in Organic Synthesis

Abstrakti

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