Edited by
Lutz F. Tietze
Domino Reactions

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Edited by Lutz F. Tietze

Domino Reactions
Concepts for Efficient Organic Synthesis

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Editor
Prof. Dr. Lutz F. Tietze
Georg-August University
Institute of Organic and Biomolecular
Chemistry
Tammannstr. 2
37077 Găottingen
Germany

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V

Contents

Preface XIII
List of Contributors XV
List of Abbreviations XIX
Introduction 1
References 4
1

1.1
1.2
1.2.1
1.2.2
1.2.3
1.2.4
1.3

2
2.1
2.1.1
2.1.2
2.2
2.2.1
2.2.2
2.2.3
2.2.4
2.2.5
2.2.6

Transition-Metal-Catalyzed Carbonylative Domino Reactions 7
Xiao-Feng Wu, Helfried Neumann, and Matthias Beller
Introduction 7
Transition-Metal-Catalyzed Carbonylative Domino Reactions 8
Ruthenium-Catalyzed Carbonylative Domino Reactions 8
Rhodium-Catalyzed Carbonylative Domino Reactions 13
Palladium-Catalyzed Carbonylative Domino Reactions 16
Iron-, Copper-, Nickel-, and Cobalt-Catalyzed Carbonylative Domino
Reactions 24
Outlook 27

References 27
Metathesis Reactions in Domino Processes 31
Kamal M. Dawood and Peter Metz
Domino Processes Featuring Solely Metathesis Events 31
Reactions Involving Only Alkenes 31
Reactions Involving Alkenes and Alkynes 41
Domino Processes Featuring Metathesis and Non-metathesis
Events 52
Metathesis/Redox Transformation 52
Metathesis/Isomerization 53
Metathesis/Cycloaddition 56
Metathesis/Substitution 58
Metathesis/Conjugate Addition 59
Metathesis/Carbonyl Olefination 62

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VI

Contents

2.3

Conclusion and Outlook
Acknowledgments 63
References 63

3


C–H Activation Reactions in Domino Processes 67
Gavin Chit Tsui and Mark Lautens
Heck Reactions/C–H Activations 67
Carbopalladations and Aminopalladations of Alkynes/C–H
Activations 72
Palladium-Catalyzed/Norbornene-Mediated ortho C–H Activations
Domino Reactions Involving Heteroatom-Directed C–H
Activations 96
Conclusions 101
References 101

3.1
3.2
3.3
3.4
3.5

4
4.1
4.2
4.3

5
5.1
5.2
5.3
5.4
5.5
5.6
5.6.1

5.6.2
5.7

6
6.1
6.2
6.2.1
6.2.2
6.2.3
6.2.4

63

80

Domino Reactions Initiated by Nucleophilic Substitution 105
Hiriyakkanavar Ila, Anand Acharya, and Saravanan Peruncheralathan
Domino SN /Michael Addition and Related Reactions 106
Domino Reactions Initiated by Nucleophilic Ring Opening of
Aziridines, Epoxides, and Activated Cyclopropanes 115
Domino SN /Brook Rearrangements 127
References 138
Radical Reactions in Domino Processes 141
Guanghui An and Guigen Li
Introduction 141
Radical/Cation Domino Processes 143
Radical/Anionic Domino Processes 148
Domino Radical/Radical Process 154
Radical/Pericyclic Domino Processes 172
Asymmetric Radical Domino Processes 174

Chiral Auxiliary-Directed Asymmetric Radical Domino Processes 174
Chiral Catalyst-Driven Asymmetric Radical Domino Processes 176
Conclusion and Outlook 178
Acknowledgments 179
References 179
Pericyclic Reactions in Domino Processes 183
Lukas J. Patalag and Daniel B. Werz
Introduction 183
Cycloadditions 184
Cycloaddition/Cycloaddition 184
Cycloaddition/Cycloreversion 185
Cycloaddition/Sigmatropic Rearrangement 188
Cycloaddition/Electrocyclization 189

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Contents

6.2.5
6.3
6.3.1
6.3.2
6.3.3
6.3.4
6.4
6.4.1
6.4.2
6.4.3
6.4.4

6.5
6.5.1
6.5.2
6.5.3
6.6

Cycloaddition/Mixed Transformations 191
Sigmatropic Rearrangements 192
Sigmatropic Rearrangement/Sigmatropic Rearrangement 192
Sigmatropic Rearrangement/Cycloaddition 195
Sigmatropic Rearrangement/Electrocyclization 196
Sigmatropic Rearrangement/Mixed Transformations 199
Electrocyclizations 201
Electrocyclization/Electrocyclization 201
Electrocyclization/Cycloaddition 202
Electrocyclization/Sigmatropic Rearrangement 205
Electrocyclization/Mixed Transformations 208
Mixed Transformations 209
Mixed Transformations Followed by Pericyclic Reactions 209
Cascades of Carbopalladations Followed by Pericyclic Reactions 211
Domino Knoevenagel/Hetero Diels–Alder Reaction 214
Concluding Remarks 214
Acknowledgments 215
References 215

7

Modern Domino Reactions Containing a Michael Addition Reaction 219
Scott G. Stewart
Introduction 219

Formation of Acyclic Products 221
Formation of Carbocycles 225
Formation of O-Heterocycles 236
Formation of N-Heterocycles 250
Formation of S-Heterocycles 257
Formation of Heterocycles Containing Nitrogen and Oxygen 260
References 262

7.1
7.2
7.3
7.4
7.5
7.6
7.7

8
8.1
8.2
8.2.1
8.2.2
8.2.3
8.2.4
8.2.5
8.3
8.3.1
8.3.1.1
8.3.1.2
8.3.1.3
8.3.1.4


Aldol Reactions in Domino Processes 267
Christoph Schneider and Michael Boomhoff
Introduction 267
Domino Processes with the Aldol Reaction as First Step 267
Aldol-Lactonization Reactions 267
Aldol/Prins Reactions 270
Aldol/Acetalization Reactions 272
Aldol–Tishchenko Reactions 273
Vinylogous Aldol/Michael Reactions 276
Domino Processes with the Aldol Reaction as Subsequent Step
Conjugate Addition/Aldol Reactions 277
Addition of Carbon Nucleophiles 277
Addition of Sulfur Nucleophiles 281
Addition of Oxygen and Nitrogen Nucleophiles 283
Iodo-Aldol Reactions 285

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277

VII


VIII

Contents

8.3.1.5
8.3.2

8.3.3
8.3.4
8.4

Reductive Aldol Reactions 287
Isomerization/Aldol Reactions 289
Wittig Rearrangement/Aldol Reactions 290
Cycloaddition/Aldol Reactions 290
Conclusion and Outlook 292
References 292

9

Oxidations and Reductions in Domino Processes 295
Govindasamy Sekar, Iyyanar Karthikeyan, and Dhandapani Ganapathy
Introduction 295
Domino Reactions Initiated by Oxidation or Reduction Reaction 296
Domino Reactions Initiated by an Oxidation Reaction 296
Domino Reactions Initiated by Reduction Reaction 301
Domino Reactions Having Oxidation in Middle of the Sequence 312
Domino Reactions Terminated by Oxidation or Reduction
Reaction 313
Domino Reactions Terminated by Oxidation Reaction 313
Domino Reactions Terminated by Reduction Reaction 314
Conclusion 319
Acknowledgments 319
References 319

9.1
9.2

9.2.1
9.2.2
9.3
9.4
9.4.1
9.4.2
9.5

10
10.1
10.2
10.2.1
10.2.1.1
10.2.1.2
10.2.1.3
10.2.1.4
10.2.1.5
10.2.1.6
10.2.1.7
10.2.1.8
10.2.1.9
10.2.2
10.2.2.1
10.2.2.2
10.2.2.3
10.2.2.4
10.3
10.3.1
10.3.1.1


Organocatalysis in Domino Processes 325
H´el`ene Pellissier
Introduction 325
One- and Two-Component Domino Reactions 326
Domino Reactions Initiated by the Michael Reaction 327
Domino Michael/Michael Reactions 327
Domino Michael/Aldol Reactions 334
Domino Michael/Intramolecular Heterocyclization Reactions 340
Domino Michael/Intramolecular Alkylation Reactions 349
Domino Michael/(aza)–Henry Reactions 352
Domino Michael/Knoevenagel Reactions 355
Domino Michael/aza-Morita–Baylis–Hillman Reactions 357
Domino Michael/Mannich Reactions 357
Other Domino Reactions Initiated by the Michael Reaction 359
Domino Reactions Initiated by Other Reactions 361
Domino Reactions Initiated by the Indirect Mannich Reaction 361
Domino Reactions Initiated by the (Aza)-Morita–Baylis–Hillman
Reaction 363
Domino Reactions Initiated by the Friedel–Crafts Reaction 364
Miscellaneous Domino Reactions 365
Multicomponent Reactions 371
Multicomponent Reactions Initiated by the Michael Reaction 371
Michael Reactions of α,β-Unsaturated Aldehydes 371

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Contents

10.3.1.2 Michael Reactions of Other α,β-Unsaturated Carbonyl

Compounds 378
10.3.1.3 Michael Reactions of Nitroolefins 380
10.3.2
Multicomponent Reactions Initiated by the Knoevenagel Reaction 385
10.3.3
Multicomponent Reactions Based on the Mannich Reaction 388
10.3.4
Multicomponent Reactions Based on the Biginelli Reaction 392
10.3.5
Multicomponent Reactions Based on the Hantzsch Reaction 394
10.3.6
Multicomponent Reactions Based on the Strecker Reaction 395
10.3.7
Multicomponent Reactions Based on the Petasis Reaction 397
10.3.8
1,3-Dipolar Cycloaddition-Based Multicomponent Reactions 398
10.3.9
Miscellaneous Multicomponent Reactions 400
10.4
Conclusions 405
References 405
11

11.1
11.1.1
11.1.2
11.1.3
11.2
11.2.1
11.3

11.3.1
11.3.2
11.4
11.4.1
11.4.2
11.4.3
11.4.4
11.4.5
11.5
11.5.1
11.6

12

12.1
12.2
12.2.1
12.2.2
12.2.3

Metal-Catalyzed Enantio- and Diastereoselective C–C Bond-Forming
Reactions in Domino Processes 419
Shinobu Takizawa and Hiroaki Sasai
Domino Reaction Initiated by C–C Bond Formation 419
Domino Reaction Initiated by Conjugate Addition 419
Domino Reaction Initiated by Cycloaddition 433
Domino Reaction Initiated by Carbometalation 435
Domino Reaction Initiated by C–H Bond Formation 435
Domino Reaction Initiated by Conjugate Addition 435
Domino Reaction Initiated by C–N Bond Formation 442

Domino Reaction Initiated by Imine Formation 442
Domino Reaction Based on Cycloaddition 443
Domino Reaction Initiated by C–O Bond Formation 445
Domino Reaction Initiated by Carbonyl Ylide Formation 445
Domino Reaction Initiated by Oxonium Ylide Formation 450
Domino Reaction Based on Cycloaddition 452
Domino Reaction Based on Pd(II)/Pd(IV) Catalysis 454
Domino Reaction Based on a Wacker Oxidation 454
Domino Reaction Initiated by C–B and C–Si Bond Formation 455
Domino Reaction Initiated by Conjugate Addition 456
Conclusion and Outlook 457
References 458
Domino Processes under Microwave Irradiation, High Pressure, and in
Water 463
Bo Jiang, Shu-Jiang Tu, and Guigen Li
Introduction 463
Microwave-Assisted Domino Reactions 464
Intramolecular Domino Reactions under Microwave Heating 464
Two-Component Domino Reaction under Microwave Heating 465
Multicomponent Domino Reactions under Microwave Heating 472

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IX


X

Contents


12.3
12.3.1
12.3.2
12.4
12.5

Aqueous Domino Reactions 480
Two-Component Domino Reactions in Water 480
Multicomponent Domino Reaction in Water 484
High-Pressure-Promoted Domino Reactions 489
Conclusion and Outlook 491
Acknowledgments 492
References 492

13

Domino Reactions in Library Synthesis 497
Vincent Eschenbrenner-Lux, Herbert Waldmann, and Kamal Kumar
Introduction 497
Domino Reactions in Natural-Product-Inspired Compound Collection
Syntheses 498
Coinage Metal-Catalyzed Domino Synthesis 498
Multicatalytic Domino Processes 500
Synthesis of Natural-Product-Inspired Centrocountins Using Domino
Reactions 503
Domino Approaches Targeting Scaffold Diversity 506
Substrate-Based Approach: the Metathesis/Metathesis Domino
Process 507
Reagent-Based Domino Approaches 509
Domino Reactions in the Build–Couple–Pair Approach for Library

Synthesis 515
Solid-Phase Domino Syntheses of Compound Collections 516
Conclusion 519
References 520

13.1
13.2
13.2.1
13.2.2
13.2.3
13.3
13.3.1
13.3.2
13.3.3
13.4
13.5

14
14.1
14.2
14.3
14.4
14.5
14.6
14.7

15
15.1
15.2
15.3

15.3.1
15.3.2

Domino Reactions in the Total Synthesis of Natural Products 523
Svenia-C. Dăufert, Judith Hierold, and Lutz F. Tietze
Cationic Domino Reactions 523
Anionic Domino Reactions 533
Radical Domino Reactions 549
Pericyclic Domino Reactions 551
Transition-Metal-Catalyzed Domino Reactions 554
Domino Reactions Initiated by Oxidation or Reduction 568
Conclusion 571
References 572
Multicomponent Domino Process: Rational Design and Serendipity 579
Qian Wang and Jieping Zhu
Introduction 579
Basic Considerations of MCRs 581
Substrate Design Approach in the Development of Novel MCRs 583
Chemistry of α-Isocyanoacetates 583
From α-Isocyanoacetates to α-Isocyanoacetamides 585

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Contents

15.3.3
15.3.4
15.3.5
15.3.5.1

15.3.5.2
15.3.6
15.3.6.1
15.3.6.2
15.3.6.3
15.4

From α-Isocyanoacetamides to α-Isocyanoacetic Acids 589
Back to α-Isocyanoacetates 590
Chemistry of Oxazoles 593
Dienophile as an Additional Component 593
Using Dienophile-Containing Inputs 597
Serendipity 601
Groebke–Blackburn–Bienaym´e Reaction 601
One-Carbon Oxidative Homologation of Aldehydes to Amides
One-Carbon Oxidative Homologation of Aldehydes to
α-Ketoamides 604
Conclusion 607
References 607
Index

611

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602

XI



XIII

Preface
The synthesis of chemical compounds is a key issue in chemistry, both in academia
and industry. A simple statement of general relevance is the saying ‘‘you cannot
investigate a compound which you do not have in your hands and you cannot
sell a substance which you did not make.’’ However, the aspects of synthesis have
changed over the years. At the beginning, the development of synthetic methods
such as the electrophilic aromatic substitution, the aldol reaction or the Diels–Alder
cycloaddition was in the focus. Then the selectivity as the chemo-, regio-, diastereo-,
and enantioselectivity was the main concern. Now, new aspects in synthesis have
arisen, which are part of green chemistry: efficiency, reduction of waste, saving our
resources, protecting our environment, and, finally, also economic advantages by
reducing the transformation time and the amount of chemicals needed. To meet
all these requirements, the domino concept was introduced by me, which, since its
presentation and the first reviews, has grown immensely in the last years. In this
book, experts in the different fields of domino reactions have put together their
knowledge, and I am very grateful to all of them for their excellent contributions.
Moreover, I would like to thank Martina Pretor for her fabulous help in preparing
the book. I am also grateful to the publishers Wiley/VCH, especially Dr. Elke Maase
and Dr. Bernadette Gmeiner, for their support.
Finally, I would like to express my deep thanks to the University of Găottingen,
the State of Lower Saxony, the German Research Foundation (DFG), the Volkswagen Foundation, the German Ministry of Education and Research (BMBF), the
European Community and the Fonds der Chemischen Industrie as well as the
Alexander von Humbold Foundation, the Konrad–Adenauer–Foundation and the
German National Academic Foundation for their continuous support of our work
on domino reactions and other topics. I am also very thankful to many Chemical
Companies worldwide, in particular the BASF and the Bayer AG.
Găottingen, June 6th , 2013


Lutz F. Tietze

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XV

List of Contributors
Anand Acharya
New Chemistry Unit
Jawaharlal Nehru Centre for
Advanced Scientific Research
Jakkur
Bangalore 560 064
Karnataka
India
Guanghui An
Texas Tech University
Department of Chemistry and
Biochemistry
Street Boston and Broadway
Lubbock
TX, 79409-1061
USA
Matthias Beller
Leibniz Institute for Catalysis
Albert-Einstein-Str. 29a
18059 Rostock
Germany
Michael Boomhoff

University of Leipzig
Institute of Organic Chemistry
Johannisallee 29
04103 Leipzig
Germany

Kamal M. Dawood
Technische Universităat Dresden
Department of Chemistry
Bergstrasse 66
01069 Dresden
Germany
Svenia-C. Dă
ufert
Georg-August University
Institute of Organic and
Biomolecular Chemistry
Tammannstr. 2
37077 Găottingen
Germany
Vincent Eschenbrenner-Lux
Max Planck Institute of Molecular
Physiology
Otto-Hahn-Str. 11
44227 Dortmund
Germany
Dhandapani Ganapathy
Indian Institute of Technology
Madras
Department of Chemistry

Chennai 600 036
Tamil Nadu
India

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XVI

List of Contributors

Judith Hierold
Georg-August University
Institute of Organic and
Biomolecular Chemistry
Tammannstr. 2
37077 Găottingen
Germany
Hiriyakkanavar Ila
New Chemistry Unit Jawaharlal
Nehru Centre for Advanced
Scientic Research
Jakkur
Bangalore 560 064
Karnataka
India
Bo Jiang
Jiangsu Normal University
School of Chemistry and
Chemical Engineering

Shanghai Road 101
New District of Tongshan
Xuzhou, 221116
P. R. China
Iyyanar Karthikeyan
Indian Institute of Technology
Madras
Department of Chemistry
Chennai 600 036
Tamil Nadu
India
Kamal Kumar
Max Planck Institute of Molecular
Physiology
Otto-Hahn-Str. 11
44227 Dortmund
Germany

Mark Lautens
Davenport Research Laboratories
University of Toronto
Department of Chemistry
80 St. George St.
Toronto
ON M5S 3H6
Canada
USA
Guigen Li
Texas Tech University
Department of Chemistry and

Biochemistry
Street Boston and Broadway
Lubbock
TX, 79409-1061
USA
and
Nanjing University
Institute of Chemistry &
BioMedical Sciences
22 Hankou Road
Nanjing 210093
P. R. China
Peter Metz
Technische Universităat Dresden
Department of Chemistry
Bergstrasse 66
01069 Dresden
Germany
Helfried Neumann
Leibniz Institute for Catalysis
Albert-Einstein-Str. 29a
18059 Rostock
Germany

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List of Contributors

Lukas J. Patalag

Technical University of
Braunschweig
Institute of Organic Chemistry
Hagenring 30
38106 Braunschweig
Germany

Govindasamy Sekar
Indian Institute of Technology
Madras
Department of Chemistry
Chennai 600 036
Tamil Nadu
India

Hel`ene Pellissier
Aix Marseille Universite`
CNRS, iSm2 UMR 7313
13397 Marseille
France

Scott G. Stewart
The University of Western
Australia
School of Chemistry and
Biochemistry
35 Stirling Highway
Crawley
WA 6009
Australia


Saravanan Peruncheralathan
National Institute of Science
Education and Research
Institute of Physics Campus
School of Chemical Sciences
Bhubaneswar 751 005
Orissa
India
Hiroaki Sasai
Osaka University
The Institute of Scientific and
Industrial Research (ISIR)
Mihogaoka Ibaraki-shi
Osaka 567-0047
Japan
Christoph Schneider
University of Leipzig
Institute of Organic Chemistry
Johannisallee 29
04103 Leipzig
Germany

Shinobu Takizawa
Osaka University
The Institute of Scientific and
Industrial Research (ISIR)
Mihogaoka Ibaraki-shi
Osaka 567-0047
Japan

Lutz F. Tietze
Georg-August University
Institute of Organic and
Biomolecular Chemistry
Tammannstr. 2
37077 Găottingen
Germany
Gavin Chit Tsui
Max-Planck-Institut făur
Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Măulheim an der Ruhr
Germany

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XVII


XVIII

List of Contributors

Shu-Jiang Tu
Jiangsu Normal University
School of Chemistry and
Chemical Engineering
Shanghai Road 101
New District of Tongshan
Xuzhou, 221116

P. R. China
Herbert Waldmann
Max Planck Institute of Molecular
Physiology
Otto-Hahn-Str. 11
44227 Dortmund
Germany
Qian Wang
Ecole Polytechnique F´ed´erale de
Lausanne
Institute of Chemical Sciences
and Engineering
1015 Lausanne
Switzerland

Daniel B. Werz
Technical University of
Braunschweig
Institute of Organic Chemistry
Hagenring 30
38106 Braunschweig
Germany
Xiao-Feng Wu
Leibniz Institute for Catalysis
Albert-Einstein-Str. 29a
18059 Rostock
Germany
Jieping Zhu
Ecole Polytechnique F´ed´erale de
Lausanne

Institute of Chemical Sciences
and Engineering
1015 Lausanne
Switzerland

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XIX

List of Abbreviations

(S,S)-MeDuPhos
(TMS)2 NH
[Bmim]
Ac
acac
ACCN
Ac2 O
AcOH
AIBN
All
Ar
ARC
ASG
ATBT
atm
BAIB
BER
BF3 ·OEt2

BHT
BINAP
BINAPO
BINOL
Biphep
Bn
Boc
borsm
bpz
Bu
Bz
CA
CAN

(+)-1,2-bis[(2S,5S)-2,5-dimethylphospholano]benzene
hexamethyldisilazane or bis(trimethylsilyl)amine
1-butyl-3-methylimidazolium
acetyl
acetylacetone
1,1 -azobis(cyclohexanecarbonitrile)
acetic anhydride
acetic acid
2,2 -azobisisobutyronitrile
allyl
aryl
anionic relay chemistry
anion stabilizing group
allyltri-n-butyltin
standard atmosphere
(diacetoxyiodo)benzene

borohydride exchange resin
boron trifluoride–diethyl ether complex
butylhydroxytoluene
2,2 -bis(diphenylphosphino)-1,1 -binaphthalene
2-diphenylphosphino-2 -diphenylphosphinyl-1,1 binaphthalene
1,1 -bi-2-naphthol
1,1 -biphenyl-2,2 -diphenylphosphine
benzyl
tert-butoxycarbonyl
based on recovered starting material
2,2 -bipyrazine
butyl
benzoyl
cycloaddition
ceric ammonium nitrate

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XX

List of Abbreviations

Cbz
CD
cf .
CM
cod
coe
Cp

CR
CSA
Cy
d
DA
DABCO
DAIB
dba
DBU
DCB
DCE
DCM
DDQ
de
DFT
DHQ
DHQD
DIBAL
DIOP
DIPEA
DKP
DLP
DMA
DMAD
DME
DMF
DMP
DMPU
DMSO
DOS

dpm
dppe
dppf
dppp
dr
DTBP
E

carbonylbenzyloxy
circular dichroism
compare (lat. confer)
cross-metathesis
1,5-cyclooctadiene
cyclooctene
cyclopentadienyl
cycloreversion
camphorsulfonic acid
cyclohexyl
day
Diels–Alder reactions
1,4-diazabicyclo[2.2.2]octane
(diacetoxyiodo)benzene
dibenzylidenacetone
1,8-diazabicyclo[5.4.0]undec-7-ene
1,2-dichloroisobutane
1,2-dichloroethane
dichloromethane
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
diastereomeric excess
density functional theory

hydroquinine
dihydroquinidine
diisobutylaluminum hydride
4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane
diisopropylethylamine
diketopiperazine
1,2-dichloroethane with lauroyl peroxide
N,N-dimethylacetamide
dimethyl acetylenedicarboxylate
dimethoxyethane
N,N-dimethylformamide
Dess–Martin-periodinane
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,
N,N-dimethyl propylene urea
dimethyl sulfoxide
diversity-oriented synthesis
dipivaloylmethane
1,2-bis(diphenylphosphino)ethane
1,2-bis(diphenylphosphino)ferrocene
1,3-bis(diphenylphosphino)propane
diastereomeric ratio
2,6-di-tert-butylpyridine
electrophile

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List of Abbreviations

EC

ee
equiv
ERO
et al.
Et
EWG
Fmoc
fod
GAP
h
HAT
HFIP
HIV
HMPA
HOMO
i.e.
IBX
IMDA
L
LDA
LiHMDS
LUMO
MAOS
MBH
MDRs
Me
MeCN
MEK
MEM
Mes

MOM
MTM
MW
NADH
NBS
NCS
NMM
NMO
NMP
Ns
Nu
Oct
o-DCB
PCC

electrocyclization
enantiomeric excess
equivalent
electrocyclic ring-opening
and others (lat. et alii)
ethyl
electron-withdrawing group
9-fluorenylmethoxycarbonyl
(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyloctane-3,5-dionate
group-assisted purification
hour
hydrogen atom transfer
hexafluoroisopropanol
human immunodeficiency virus
hexamethylphosphortriamide

highest occupied molecular orbital
that means (lat. id est)
2-iodoxybenzoic acid
intramolecular Diels–Alder reaction
ligand
lithium diisopropylamide
lithium hexamethyldisilazide
lowest unoccupied molecular orbital
microwave-assisted organic synthesis
Morita–Baylis–Hillman
multicomponent domino reactions
methyl
acetonitrile
methyl ethyl ketone
(2-methoxyethoxy)methyl
mesityl
methoxymethyl
methylthiomethyl
microwave
nicotinamide adenine dinucleotide
N-bromosuccinimide
N-chlorosuccinimide
N-methyl morpholine
N-methylmorpholine-N-oxide
N-methyl-2-pyrrolidinone
p-nitrobenzenesulfonyl
nucleophile
octyl
ortho-dichlorobenzene
pyridinium chlorochromate


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XXI


XXII

List of Abbreviations

PET
PEG
PFBA
PG
Ph
Phen
PhMe
PIDA
Piv
PMB
PNO
PPh3
PPTS
Pr
PS–BEMP

photochemical electron transfer
polyethylene glycol
pentafluorobenzoic acid
protecting group

phenyl
9,10-phenanthroline
toluene
phenyliodine diacetate
pivalate
p-methoxybenzyl
pyridine-N-oxide
triphenylphosphine
pyridinium p-toluenesulfonate
propyl
polystyrene–(2-tert-butylimino-2-diethylamino-1,-dimethylperhydro-1,3,2-diazaphosphorine)
PS–DMAP
polystyrene–dimethylaminopyridine
p-TsOH or p-TSA p-toluenesulfonic acid
PVE
propargyl vinyl ether
Py
pyridine
R
rest
rac
racemic
RCM
ring-closing metathesis
ROM
ring-opening metathesis
RRM
ring-rearrangement metathesis
rt
room temperature

SEM
2-trimethylsilylethoxymethyl
SET
single electron transfer
sigR
sigmatropic rearrangement
nucleophilic substitution
SN
substitution nucleophilic unimolecular
SN 1
substitution nucleophilic bimolecular
SN 2
SolFC
solvent free condition
SOMO
singly occupied molecular orbital
SPPS
solid-phase peptide synthesis
t
tert
TADDOL
(−)-(4R,5R)- or (+)(4S,5S)-2,2-dimethyl-α,α,α ,α -tetraphenyl1,3-dioxolane-4,5-dimethanol
TBA
tetra-n-butylammonium
TBA
tribromoacetic acid
TBAB
tetra-n-butylammonium bromide
TBAF
tetra-n-butylammonium fluoride

TBAI
tetra-n-butylammonium iodide
TBCHD
2,4,4,6-tetrabromo-2,5-cyclohexadienone
TBD
1,5,7-triazabicyclo[4.4.0]dec-5-ene

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List of Abbreviations

TBDMS or TBS
TBDPS or TBPS
t-Bu
t-BuOH
t-BuOK
TC
TEA
TEBA
TEMPO
TES
TESOTf
Tf
TFA
TFE
TfO
TFP
THF
TMSOTf

Thio
TIPS
TMEDA
TMS
TMSI
Tol
Ts
TS
TsOH
TTMSS
VAPOL
vs.
XPhos

tert-butyldimethylsilyl
tert-butyldiphenylsilyl
tert-butyl
tert-butyl alcohol
tert-butylate potassium
thiophene-2-carboxylate
triethylamine
benzyltriethylammonium chloride
(2,2,6,6-tetramethylpiperidin-1-yl)oxy
triethylsilyl
triethylsilyltrifluoromethanesulfonate
trifluoromethanesulfonyl
trifluoroacetic acid
2,2,2-trifluorethanol
trifluoromethanesulfonate
tri-(2-furyl)phosphine

tetrahydrofuran
trimethylsilyl trifluromethanesulfonate
thiophene
triisopropylsilyl
tetramethylethylendiamine
trimethylsilyl
trimethylsilyl iodide or iodotrimethylsilane
tolyl
4-toluenesulfonyl (tosyl)
transition state
p-toluenesulfonic acid
tris(trimethylsilyl)silane
2,2 -diphenyl-(4-biphenanthrol)
as opposed to (lat. versus)
2-dicyclohexylphosphino-2 ,4 ,6 -triisopropylbiphenyl

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XXIII


1

Introduction
The beginning of organic synthesis can be dated back to the year 1824 when
Wăohler, later professor of chemistry at the Georg-August University in Găottingen,
showed that inorganic matter could be transformed into organic matter without the
vis vitalis, the so-called power of life. At that time, he prepared the natural product
oxalic acid from dicyan by simple hydrolysis. Better known is the transformation
of ammonium cyanate into urea by simple heating, in 1828 (Scheme 1) [1].

A second milestone in organic synthesis is the total synthesis of the indole
alkaloid reserpine by Woodward in 1956 [2] using a Diels–Alder reaction as the key
step (Scheme 2), and finally with the total synthesis of palytoxin in 1994, the toxin
of dinoflagellate Ostreopsis siamensis, with 64 stereogenic centers and several (E)and (Z)-double bonds, Kishi [3] has shown that chemists can prepare any organic
compound (Scheme 3).
However, the synthesis of such a big molecule as palytoxin using a conventional
stepwise approach with more than 100 steps is a singular great feat and can almost
not be repeated. Thus, a 100-step synthesis with 80% yield per step would lead to
only 0.00 000 002% as the total yield.
In contrast, a much better efficiency could be accomplished using domino
reactions, which have been defined by us as processes of two or more bond forming
reactions under identical reaction conditions, in which the latter transformations
take place at the functionalities obtained in the former bond forming reactions
[4]. In the processes one, two, three, or more substrates can be involved. Thus,
multicomponent transformations are domino reactions per definition. In the
meantime, several excellent reviews have also been published by other authors on
this topic [5].
The quality and the usefulness of domino reactions are related to the increase
of complexity and diversity in the final product compared to the starting material.
Thus, the more steps a domino-process includes the greater is the probability to
transform simple substrates to huge compounds. A further great advantage of the
domino concept is its benefit to our environment and our natural resources, as it
allows reducing the waste produced compared to normal procedures and minimize
the amount of chemicals required for the preparation of a product. This also makes
them economically favorable; moreover, they grant a decrease of the production
time, which altogether would reduce furthermore the costs of any product.
Domino Reactions: Concepts for Efficient Organic Synthesis, First Edition. Edited by Lutz F. Tietze.
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.

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Introduction

2

1824

C N

Hydrolysis

COOH
COOH

C N

Scheme 1

O
NH2

ă
Synthesis of oxalic acid and urea without a vis vitalis by Wohler.

N

N
H H


MeO

NH2

Δ

N C O− NH4+

1828

H
O

H
MeO2C

OMe

O
OMe

OMe

Reserpin (16 steps)

OMe

CHO

MeO2C


N
H

MeO

O

NH2
O

MeO2C
OMe
Diels–Alder

O

MeO
+
O

O

Scheme 2

Synthesis of the indole alkaloid reserpine by Woodward 1956.

Domino reactions usually show a good stereocontrol and good overall yields.
Also very important is the fact that novel pathways can be developed, which cannot
be followed in a stepwise approach, as in domino reactions intermediates can be

unstable compounds, which are consumed as they are formed in a further step.
In our previous book on domino reactions [4h], we have classified domino reactions according to the mechanism of the different steps. This organizing principal
will also be used in this book, and you will find chapters about transition metal
catalysis including carbonylation, metathesis and CH-activation, nucleophilic substitutions, radical reactions, pericyclic reactions, Michael reactions, aldol reactions,
oxidations, and reductions.

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Introduction
84

OH
O
O

O

99

OH
HO

OH
O

98

H2 N


HO

O

77

OH
OH

OH
HO
HO

OH

OH

1

HO

N
H

N
H

7

OH


76

75

OH
OH

O

OH
OH

OH

115

OH

OH

85

O

8

H
HO


OH

OH

OH

O

OH
OH

OH

23

O

OH

22

HO

OH

O

O
HO


38

O

OH

37

OH
OH

HO
Palytoxin (>100 steps)

52
51

53

H
OH

OH
OH

OH

OH

Scheme 3 Synthesis of palytoxin by Kishi 1994.


In addition, we have also included chapters that are related to the type of process
as organocatalysis, enantio- and diastereoselective reactions, and multicomponent
reactions as well as domino processes under microwave irradiation, high pressure,
and in water. Finally, two chapters that are more product oriented have been
included on the synthesis of compound collections and the synthesis of natural
products and analogs.
This arrangement clearly leads to some overlap, which we have tried to minimize
by discussing related subjects in-depth only in one chapter. However, to allow a
correlation, some domino-processes are mentioned in more than one chapter.
Besides giving information to the reader about the development of domino
reactions in the past years, the main purpose of this book is also to stimulate the
design of novel domino reactions and use them in the synthesis of natural products
and analogs, pharmaceuticals, agrochemicals, polymers, and materials not only in
academic institutions but also in industry.
Per definition, all domino reactions take place in one reaction vessel without
isolating any intermediates; however, they are much more than the so-called onepot reactions, where you just put together different substrates and reagents after
each other. The planning of domino reactions is like playing chess, where to be a
reasonable player you will have to analyze four to five steps in advance. Thus, you
have to predict the reaction pathways of all substrates and intermediates in your
reaction mixture and in contrast to chess, where the movement of the different
chess pieces is fixed, the reactivity of the chemical compounds can even be altered,
for instance, by changing the pH-value or using different catalysts.
For the use and design of domino reactions in the synthesis of natural products, it
is sometimes useful to look at the biosynthesis of these compounds. Thus, Nature
is also using the concept of domino reactions and one of the most impressive

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3