New Strategies for N-Heterocyclic Carbenes Catalyzed Annulations

132 Pages·2017·9.68 MB·English

by  Xiangyu Chen (auth.)

Springer Theses
Recognizing Outstanding Ph.D. Research
Xiangyu Chen

New Strategies
for N-Heterocyclic
Carbenes Catalyzed
Annulations
Springer Theses
Recognizing Outstanding Ph.D. Research
Aims and Scope
The series “Springer Theses” brings together a selection of the very best Ph.D.
theses from around the world and across the physical sciences. Nominated and
endorsed by two recognized specialists, each published volume has been selected
foritsscientificexcellenceandthehighimpactofitscontentsforthepertinentfield
of research. For greater accessibility to non-specialists, the published versions
includeanextendedintroduction,aswellasaforewordbythestudent’ssupervisor
explainingthespecialrelevanceoftheworkforthefield.Asawhole,theserieswill
provide a valuable resource both for newcomers to the research fields described,
and for other scientists seeking detailed background information on special
questions. Finally, it provides an accredited documentation of the valuable
contributions made by today’s younger generation of scientists.
Theses are accepted into the series by invited nomination only
and must fulfill all of the following criteria
(cid:129) They must be written in good English.
(cid:129) ThetopicshouldfallwithintheconfinesofChemistry,Physics,EarthSciences,
Engineeringandrelatedinterdisciplinary fields such asMaterials,Nanoscience,
Chemical Engineering, Complex Systems and Biophysics.
(cid:129) The work reported in the thesis must represent a significant scientific advance.
(cid:129) Ifthethesisincludespreviouslypublishedmaterial,permissiontoreproducethis
must be gained from the respective copyright holder.
(cid:129) They must have been examined and passed during the 12 months prior to
nomination.
(cid:129) Each thesis should include a foreword by the supervisor outlining the signifi-
cance of its content.
(cid:129) The theses should have a clearly defined structure including an introduction
accessible to scientists not expert in that particular field.
More information about this series at http://www.springer.com/series/8790
Xiangyu Chen
New Strategies
for N-Heterocyclic Carbenes
Catalyzed Annulations
Doctoral Thesis accepted by
Institute of Chemistry, Chinese Academy of Sciences,
Beijing, China
123
Author Supervisor
Dr. Xiangyu Chen Prof. SongYe
Institute of Chemistry Institute of Chemistry
ChineseAcademy of Sciences ChineseAcademy of Sciences
Beijing Beijing
China China
and
Institute of Organic Chemistry
RWTH Aachen University
Aachen
Germany
ISSN 2190-5053 ISSN 2190-5061 (electronic)
SpringerTheses
ISBN978-981-10-2898-4 ISBN978-981-10-2899-1 (eBook)
DOI 10.1007/978-981-10-2899-1
LibraryofCongressControlNumber:2016960031
©SpringerNatureSingaporePteLtd.2017
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart
of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar
methodologynowknownorhereafterdeveloped.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom
therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authorsortheeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinor
foranyerrorsoromissionsthatmayhavebeenmade.
Printedonacid-freepaper
ThisSpringerimprintispublishedbySpringerNature
TheregisteredcompanyisSpringerNatureSingaporePteLtd.
Theregisteredcompanyaddressis:152BeachRoad,#22-06/08GatewayEast,Singapore189721,Singapore
’
Supervisor s Foreword
Duetothepopulationofcyclicmotifsinpharmaceuticalsandnaturalproducts,the
construction of cyclic molecules is an important topic in organic synthesis.
N-heterocyclic carbenes can catalyze various reactions under mild reaction condi-
tions for the rapid construction of cyclic compounds. This thesis focuses on
N-heterocyclic carbenes-catalyzed cyclization of nitroalkenes, enals, and
a,b-unsaturated carboxylic acids.
(I) ItdemonstratedthatNHCwasapowerfulcatalystforthe[4+2]annulationof
b-substituted nitroalkenes with a,b-unsaturated ketones. The scope of
Rauhut–Currier reaction was successfully extended to the most challenging
b-substituted alkenes by this method.
(II) The NHC-catalyzed [4+2] annulation of enals, having a c leaving group,
with azodicarboxylates bycadditionwas developed.Thisstrategyprovided
a more convenient and easier way to access dihydropyridazinones.
Tetrahydropyridazinones and c-amino acid derivatives could be easily pre-
pared by subsequent transformations of the resulting dihydropyridazinones.
(III) NHC was for the first time proved to be a powerful catalyst to generate
a,b-unsaturated acyl azolium from a,b-unsaturated carboxylic acids for
annulations with amino ketones and ketimines, giving a range of
N-heterocycles in good yields with high to excellent enantioselectivities.
Beijing, China Prof. Song Ye
November 2016
v
Parts of this thesis have been published in the following journal articles:
1. Chen X-Y, Sun L-H, Ye S* (2013) N-Heterocyclic Carbene Catalyzed [4+2]
Cycloaddition of Nitroalkenes with Oxodienes. Chem Eur J 19:4441–4445.
(Reproduced by permission of John Wiley & Sons Ltd)
2. Chen X-Y, Xia F, Cheng J-T, Ye S* (2013) Highly Enantioselective
c-Amination by N-Heterocyclic Carbene Catalyzed [4+2] Annulation of
Oxidized Enals and Azodicarboxylates. Angew Chem Int Ed 52:10644–10647.
(Reproduced by permission of John Wiley & Sons Ltd)
3. Chen X-Y, Gao Z-H, Song C-Y, Zhang C-L, Wang Z-X*, Ye S* (2014)
N-Heterocyclic Carbene Catalyzed Cyclocondensation of a,b-Unsaturated
Carboxylic Acids: Enantioselective Synthesis of Pyrrolidinone and
Dihydropyridinone Derivatives. Angew Chem Int Ed 53:11611–11615.
(Reproduced by permission of John Wiley & Sons Ltd)
vii
Contents
1 Introduction.... .... .... ..... .... .... .... .... .... ..... .... 1
1.1 NHC-Catalyzed Annulations Via Homoenolates.. .... ..... .... 1
1.1.1 Generation Via a,b-Unsaturated Aldehydes
for Construction of Heterocycles.... .... .... ..... .... 1
1.1.2 Generation Via a,b-Unsaturated Aldehydes
for Construction of All Carbon Cycles ... .... ..... .... 6
1.1.3 Generation Via Saturated Esters for Construction
of Heterocycles..... .... .... .... .... .... ..... .... 9
1.2 NHC-Catalyzed Annulations Via Azolium Enolates... ..... .... 10
1.2.1 Generation Via Ketenes .. .... .... .... .... ..... .... 10
1.2.2 Generation Via Functionalized Aldehydes. .... ..... .... 11
1.2.3 Generation Via a,b-Unsaturated Aldehydes ... ..... .... 16
1.2.4 Generation Via Easters and Aldehydes... .... ..... .... 18
1.3 NHC-Catalyzed Annulations Via a,b-Unsaturated Acyl
Azolium Intermediates ..... .... .... .... .... .... ..... .... 20
1.3.1 Generation Via a,b-Unsaturated Esters... .... ..... .... 20
1.3.2 Generation Via a,b-Unsaturated Acyl Fluorides ..... .... 21
1.3.3 Generation Via Oxidation of Homoenolate.... ..... .... 22
1.3.4 Generation Via Bromoenals ... .... .... .... ..... .... 23
1.3.5 Generation Via Ynals .... .... .... .... .... ..... .... 23
References.. .... .... .... ..... .... .... .... .... .... ..... .... 25
2 NHC-Catalyzed Annulations of Nitroalkenes .. .... .... ..... .... 29
2.1 Introduction .... .... ..... .... .... .... .... .... ..... .... 29
2.2 Optimization of Conditions.. .... .... .... .... .... ..... .... 30
2.3 Substrate Scope . .... ..... .... .... .... .... .... ..... .... 32
2.4 Reduction of the Nitro Group of Dihydropyran .. .... ..... .... 35
2.5 Studies on the Enantioselectivity of the Annulation Process.. .... 36
ix
x Contents
2.6 Mechanistic Studies .. ..... .... .... .... .... .... ..... .... 37
2.7 Summary .. .... .... ..... .... .... .... .... .... ..... .... 38
2.8 Experimental Part.... ..... .... .... .... .... .... ..... .... 40
2.8.1 Materials. .... ..... .... .... .... .... .... ..... .... 40
2.8.2 [4+2] Annulation of Nitroalkenes with a-Cyano-a,
b-Unsaturated Ketones Catalyzed by NHC-Precursor
Cat.8b... .... ..... .... .... .... .... .... ..... .... 40
2.8.3 [4+2] Annulation of Nitroalkenes with a-Cyano-a,
b-Unsaturated Ketones Catalyzed by NHC-Precursor
Cat.8c ... .... ..... .... .... .... .... .... ..... .... 52
2.8.4 Reduction of the Nitro Group of 2.3. .... .... ..... .... 58
2.8.5 Recation Catalyzed by Chiral NHC-Precursor Cat.2d. .... 60
References.. .... .... .... ..... .... .... .... .... .... ..... .... 60
3 NHC-Catalyzed Enantioselective Annulations of Enals .. ..... .... 63
3.1 Introduction .... .... ..... .... .... .... .... .... ..... .... 63
3.2 Optimization of Conditions.. .... .... .... .... .... ..... .... 66
3.3 Substrate Scope . .... ..... .... .... .... .... .... ..... .... 67
3.4 Applications.... .... ..... .... .... .... .... .... ..... .... 67
3.5 Mechanistic Studies .. ..... .... .... .... .... .... ..... .... 70
3.6 Conclusion. .... .... ..... .... .... .... .... .... ..... .... 71
3.7 Experimental Section . ..... .... .... .... .... .... ..... .... 72
3.7.1 NHC-Catalyzed [4+2] Annulation of Enals
and Azodicarboxylates ... .... .... .... .... ..... .... 72
3.7.2 Synthesis of Tetrahydropyridazinones.... .... ..... .... 82
3.7.3 Synthesis of c-Amino Esters... .... .... .... ..... .... 83
References.. .... .... .... ..... .... .... .... .... .... ..... .... 84
4 NHC-Catalyzed Cyclocondensation of a,b-Unsaturated
Carboxylic Acids.... .... ..... .... .... .... .... .... ..... .... 87
4.1 Introduction .... .... ..... .... .... .... .... .... ..... .... 87
4.2 Optimization of Conditions.. .... .... .... .... .... ..... .... 89
4.3 Substrate Scope . .... ..... .... .... .... .... .... ..... .... 90
4.4 Mechanistic Studies .. ..... .... .... .... .... .... ..... .... 93
4.5 Optimization of Conditions.. .... .... .... .... .... ..... .... 93
4.6 Substrate Scope . .... ..... .... .... .... .... .... ..... .... 94
4.7 Summary .. .... .... ..... .... .... .... .... .... ..... .... 97
4.8 Experimental Part.... ..... .... .... .... .... .... ..... .... 99
4.8.1 Enantioselective [3+2] Annulation with Amino
Ketones.. .... ..... .... .... .... .... .... ..... .... 99
4.8.2 Enantioselective [3+3] Annulation
with Sulfamate-Derived Cyclic Imines ... .... ..... .... 107
Contents xi
4.8.3 Enantioselective [3+3] Annulation
with Sultam-Derived Cyclic Imines.. .... .... ..... .... 112
4.8.4 Reaction with Acyclic Imine 4.9.... .... .... ..... .... 117
References.. .... .... .... ..... .... .... .... .... .... ..... .... 117
5 Summary.. .... .... .... ..... .... .... .... .... .... ..... .... 121
References.. .... .... .... ..... .... .... .... .... .... ..... .... 123