Green Synthetic Approaches for

Biologically Relevant Heterocycles

Volume 1: Advanced Synthetic
Techniques Book • Second Edition •
2021 Goutam Brahmachari
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Green Synthetic Approaches for
Biologically Relevant Heterocycles
Volume 1: Advanced Synthetic Techniques
Advances in Green and Sustainable Chemistry

Green Synthetic
Approaches for
Biologically Relevant
Heterocycles
Volume 1: Advanced Synthetic Techniques

Second Edition
Edited by

Goutam Brahmachari
Laboratory of Natural Products & Organic Synthesis, Department of
Chemistry, Visva-Bharati (A Central University), Santiniketan, India
Elsevier
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 Dedication

Professor (Dr.) Srinivasan Chandrasekaran,

Indian Institute of Science (IISc), Bangalore
Contents

List of contributors xvii

Editor xxi
Foreword xxiii
Preface xxv

1. Green synthetic approaches for biologically relevant

heterocycles: advanced synthetic techniques—an
overview
Goutam Brahmachari
1.1 Introduction 1
1.2 An overview of the book 2
1.2.1 Chapter 2 2
1.2.2 Chapter 3 3
1.2.3 Chapter 4 3
1.2.4 Chapter 5 4
1.2.5 Chapter 6 4
1.2.6 Chapter 7 4
1.2.7 Chapter 8 5
1.2.8 Chapter 9 5
1.2.9 Chapter 10 6
1.2.10 Chapter 11 6
1.2.11 Chapter 12 7
1.2.12 Chapter 13 7
1.2.13 Chapter 14 7
1.2.14 Chapter 15 7
1.2.15 Chapter 16 8
1.3 Concluding remarks 8

2. High-pressure cycloaddition reactions in the

synthesis of biologically relevant heterocycles
Davor Margetić
2.1 Introduction 9
2.2 Diels-Alder cycloadditions 10
2.2.1 Furan cycloadditions 10
2.2.2 Pyrrole cycloadditions 23
2.2.3 Cycloadditions of other heterocycles 25

vii
viii Contents

2.2.4 Hetero Diels-Alder cycloadditions 30

2.2.5 Diels-Alder cycloadditions of heterocycles as
dienophile components 33
2.3 Dipolar cycloadditions 37
2.4 [2 1 2]-Cycloadditions 40
2.5 Concluding Remarks 41
Abbreviations 41
References 41

3. Microwave-assisted synthesis of medicinally

privileged heterocycles
Debasish Bandyopadhyay and Bimal Krishna Banik
3.1 Introduction 49
3.2 Microwave irradiation: mechanism 54
3.3 Microwave-induced synthesis of heterocycles of
medicinal interests 57
3.3.1 Three-membered heterocycles with one heteroatom 57
3.3.2 Four-membered heterocycles with one heteroatom 58
3.3.3 Five-membered heterocycles 61
3.3.4 Six-membered heterocycles 87
3.3.5 Seven-membered heterocycles 95
3.4 Concluding remarks 100
Acknowledgments 100
Abbreviations 100
References 101

4. Application of microwave irradiation in the

synthesis of P-heterocycles
György Keglevich
4.1 Introduction 111
4.2 Functionalization of cyclic phosphinic acids 112
4.2.1 Direct esterification and amidation of cyclic
phosphinic acids 112
4.2.2 Interpretation and modeling the rate enhancing
effect of microwaves 118
4.2.3 Alkylating esterification of cyclic phosphinic acids 121
4.2.4 The propylphosphonic anhydride-promoted
esterification of cyclic phosphinic acids 122
4.2.5 Hydrolysis of cyclic phosphinates 124
4.3 Diels
Alder cycloadditions, fragmentation-related
phosphorylations, and inverse Wittig-type reactions 126
4.4 Phospha-Michael reactions 127
4.5 Kabachnik
Fields reactions 130
4.6 The deoxygenation of 2,5-dihydro-1H-phosphole 1-oxides 132
 Contents ix

4.7 Synthesis and reactions of new 7-phosphanorbornene

derivatives 133
4.8 Concluding remarks 135
Acknowledgments 135
References 135

5. Microwave-assisted multicomponent reactions

as a green synthetic approach to heterocycles:
special reference to Hantzsch, Biginelli, and
Groebke
Blackburn
Bienayme reactions
Felicia Phei Lin Lim and Anton V. Dolzhenko
5.1 Introduction 143
5.2 Hantzsch reaction 146
5.3 Biginelli reaction 149
5.4 Groebke
Blackburn
Bienayme reaction 156
5.5 Concluding remarks 163
References 163

6. Use of ball milling for the synthesis of biologically

active heterocycles
Nirmalya Mukherjee, Pintu Maity and Brindaban C. Ranu
6.1 Introduction 167
6.2 Synthesis of heterocycles 169
6.2.1 Nitrogen-containing heterocycles 169
6.2.2 Oxygen-containing heterocycles 176
6.2.3 Nitrogen
oxygen/sulfur-containing heterocycles 179
6.2.4 Boron-containing heterocycles 181
6.3 General green aspects of mechanochemical reaction 182
6.4 Concluding remarks 182
Acknowledgments 183
References 183

7. Recent advances in photocatalytic Minisci reaction:

an eco-friendly functionalization of biologically
relevant heteroarenes
Andrea Fiorati, Cristian Gambarotti, Lucio Melone, Nadia Pastori,
Carlo Punta, Giuseppina Raffaini and Ada Truscello
7.1 Introduction 189
7.2 Minisci reaction: a synthetic tool for bioactive molecules 190
7.2.1 Mechanistic insight 190
7.2.2 Applications in medicinal chemistry 191
7.3 Minisci reaction: the TiO2-mediated photocatalytic
approach 193
x Contents

7.3.1 TiO2-mediated photocatalytic Minisci reaction:

the synthetic implications 194
7.3.2 Adsorption on the most stable TiO2 anatase surface:
molecular dynamics study 196
7.4 Minisci reaction: recent advances in the photocatalytic
approach 199
7.4.1 N-Hydroxyphthalimide esters: versatile
radical precursors 199
7.4.2 Visible light
mediated Minisci reaction catalyzed
by Ir-photoredox catalyst 201
7.5 Concluding remarks 203
References 203

8. Recent advances for construction and late-stage

diversification of indole core via C
H bond
activation/functionalization
Arun Kumar Sinha and Rakesh Kumar
8.1 Introduction 207
8.2 Methods for the synthesis of indoles 208
8.3 C
H bond activation 209
8.4 C
H bond activation approaches for synthesis of
functionalized indole framework 210
8.4.1 Transition-metal mediated construction of indole
core via C
H bond activation 211
8.5 Late-stage diversification of indole system
(C
H activation of preformed indole framework) 223
8.5.1 C
H bond functionalization of indole at C4 position 224
8.5.2 C
H bond functionalization of indole at C5 position 230
8.6 C
H bond functionalization of indole at C6 position 233
8.6.1 C
H bond functionalization of indole at C7 position 237
8.7 Concluding remarks 242
References 243

9. Cycloaddition reactions in ionic liquids for the

synthesis of biologically relevant heterocycles
Beeraiah Baire, Ramesh Gardas and Soniya Gandhi
9.1 Introduction 249
9.1.1 Cycloaddition reactions and their
heteroatomic versions 250
9.1.2 Ionic liquids 251
9.2 The hetero-cycloaddition reactions in ionic liquids 252
9.2.1 [4 1 2]-Cycloaddition reactions 252
9.2.2 1,3-Dipolar [3 1 2]-cycloaddition reactions 260
9.2.3 The hetero-[2 1 1]-cycloaddition reactions
in ionic liquids 275
 Contents xi

9.2.4 [2 1 2]-Cycloaddition reactions 277

9.2.5 Ionic liquid as catalysts in hetero-cycloaddition
reactions 279
9.3 Concluding remarks 287
Acknowledgments 287
References 287

10. Advances in greener processes for triazole synthesis

via azide-alkyne cycloaddition reactions
Prasun Choudhury and Basudeb Basu
10.1 Introduction 297
10.2 Methods of synthesis of triazoles using greener processes 299
10.2.1 Reactions promoted by solid
surface/heterogeneous catalysts 300
10.2.2 Reactions promoted by carbonaceous nanomaterials 304
10.2.3 Polymer supported reactions 308
10.2.4 “On-water” synthesis 310
10.2.5 Solvent-free synthesis 312
10.2.6 Ionic liquid mediated reactions 313
10.2.7 Microwave-assisted reactions 315
10.2.8 Photocatalytic reactions 321
10.2.9 Combinatorial approaches 322
10.2.10 Copper-free catalytic processes 327
10.2.11 Other catalytic processes 333
10.3 Concluding remarks 340
References 340

11. Employing arynes in transition-metal-free

synthesis of benzo-fused five and six-membered
heterocycles: an update
Tony Roy and Akkattu T. Biju
11.1 Introduction 355
11.2 Synthesis of five-membered heterocycles 356
11.2.1 Cycloaddition reactions 356
11.2.2 Heterocyclic construction initiated by insertion
reactions 363
11.2.3 Domino aryne routes for heterocycles synthesis 365
11.2.4 Molecular rearrangements 367
11.2.5 Multicomponent reactions 369
11.3 Synthesis of six-membered heterocycles 370
11.3.1 Cycloaddition reactions 370
11.3.2 Transition metal-catalyzed reactions 372
11.3.3 Insertion reactions 375
11.3.4 Multicomponent reactions 375
11.3.5 Molecular rearrangements 375
xii Contents

11.4 Selected examples for the synthesis of medium-sized

heterocycles 376
11.5 Concluding remarks 378
References 379

12. Multicomponent approach for the sustainable

synthesis of lawsone-based heterocycles
Ankita Chaudhary, Garima Khanna and J.M. Khurana
12.1 Introduction 383
12.2 Synthesis of lawsone-based heterocycles via
multicomponent approach 384
12.2.1 Chromenes 384
12.2.2 Phenazines 389
12.2.3 Xanthenes 394
12.2.4 Furans 397
12.2.5 Oxazines 398
12.2.6 Spiro-compounds 399
12.2.7 Quinolines 402
12.2.8 Acridines 407
12.2.9 Miscellaneous 407
12.3 Concluding remarks 411
References 411

13. Synthesis of biologically relevant heterocyclic

skeletons under solvent-free condition
Garima Tripathi, Abhijeet Kumar, Sanchayita Rajkhowa
and Vinod K. Tiwari
13.1 Introduction 421
13.2 Synthesis of nitrogen-containing heterocycles 424
13.2.1 Solvent-free synthesis of
five-membered heterocycles 424
13.2.2 Synthesis of nitrogen containing six-membered
heterocycles 437
13.3 Synthesis of biologically relevant oxygen heterocycles 443
13.3.1 Synthesis of functionalized furans 443
13.3.2 Synthesis of benzopyrans and their derivatives 445
13.3.3 Synthesis of substituted chromones under
solvent-free condition 447
13.4 Syntheses of heterocycles with two different heteroatoms 449
13.4.1 Synthesis of benzoxazoles and benzothiazoles 449
13.4.2 Synthesis of benzothiazole 449
13.5 Synthesis of larger ring size heterocycles 450
13.6 Concluding remarks 451
Acknowledgment 451
References 452
 Contents xiii

14. Ultrasound-promoted metal-catalyzed synthesis of

heterocyclic compounds of medicinal interest
Marı́a A. Schiel, Gustavo F. Silbestri, Mónica B. Alvarez
and Claudia E. Domini
14.1 Introduction 461
14.1.1 Ultrasound 462
14.1.2 Cavitation 462
14.1.3 Instrumentation 466
14.1.4 Ultrasound in organic chemistry 466
14.2 Ultrasound-promoted metal-catalyzed synthesis of
heterocycles of medicinal interest 467
14.2.1 Pyrrole and furan derivatives 467
14.2.2 Pyrazole and imidazole derivatives 469
14.2.3 Pirazolone derivatives 471
14.2.4 Pyridine and pyrimidine derivatives 472
14.2.5 Benzodiazepines 474
14.2.6 Triazole derivatives 476
14.3 Concluding remarks 488
References 488

15. Ultrasonication under catalyst-free condition:

an advanced synthetic technique toward the green
synthesis of bioactive heterocycles
Rajiv Karmakar and Chhanda Mukhopadhyay
15.1 Introduction 497
15.2 Ultrasound wave-assisted catalyst-free multicomponent
synthesis of N-/O-heterocycles 498
15.2.1 Crisscross cycloaddition 498
15.2.2 Condensation reactions 500
15.2.3 Spiro compounds based on isatin moieties 510
15.2.4 Synthesis of 1,2,4-oxadiazoles 514
15.2.5 Synthesis of biscoumarins 516
15.2.6 Synthesis of pyridazines 516
15.2.7 Synthesis of dithiocarbamates 517
15.2.8 Synthesis of highly substituted pyrazoles 518
15.2.9 Synthesis of tetrahydropyrazolopyridines 519
15.2.10 Synthesis of substituted thiourea 522
15.2.11 Synthesis of 6H-1-benzopyrano[4,3-b]
quinolin-6-ones 522
15.2.12 Synthesis of ketene imines 523
15.2.13 Synthesis of rhodanines 524
15.2.14 Synthesis of 2,20 -(1,4-phenylene)bis[1-acetyl-1,
2-dihydro-4H-3,1-benzoxazin-4-one] derivatives 525
15.2.15 Synthesis of N-(4-arylthiazol-2-yl)hydrazones 526
15.2.16 Synthesis of pyrazolo[3,4-b]pyridines 527
xiv Contents

15.2.17 Synthesis of benzo[c]acridin-9H-one 528

15.2.18 Synthesis of benzofurans 528
15.2.19 Synthesis of dihydropyrano[2,3-c]pyrazoles 529
15.2.20 Synthesis of pyrimidopyrans 531
15.2.21 Synthesis of 2-aminopyrano[3,2-b]pyrans 531
15.2.22 Synthesis of 2-amino-4,6-diphenylnicotinonitriles 531
15.2.23 Synthesis of pyrazoloquinazolinones 532
15.2.24 Synthesis of spiro[acenaphthylene-1,
30 -pyrrolizine/pyrrolo-thiazoline]-2-one derivatives 533
15.2.25 Synthesis of pseudopeptide containing rhodanine 534
15.2.26 Synthesis of functionalized 2-aminoselenopyridines 536
15.2.27 Synthesis of 3,4-dimethyl-2,4- dihydropyrazolo
[4,3-c][1,2]benzothiazine-5,5- dioxide 537
15.2.28 Synthesis of pyrrolidine Lobelia alkaloids analogs 537
15.2.29 Synthesis of N-acetyl-2-aryl-1, 2-dihydro-
(4H)-3,1-benzoxazin-4-ones 538
15.2.30 Synthesis of chiral 2-iminoselenazolines 538
15.2.31 Synthesis of 1-substituted 1H-1,2,3,4-tetrazoles 539
15.2.32 Synthesis of pyrazole and pyrimidine derivatives 541
15.2.33 Synthesis of substituted 1,3,4-oxadiazole derivatives 542
15.2.34 Improved synthesis of pyrazole derivatives 542
15.2.35 Synthesis of dihydrothiophenes derivatives 543
15.2.36 Synthesis of benzothiazole derivatives 544
15.3 Concluding remarks 545
References 546

16. Self-catalytic techniques for the synthesis of

biologically relevant heterocyclic scaffolds at
room temperature: a recent update
Goutam Brahmachari
16.1 Introduction 563
16.2 Self-catalytic synthetic endeavors for biologically relevant
heterocyclic scaffolds without the aid of any catalysts 565
16.2.1 Synthesis of functionalized pyrido[2,3-d:6,5-d0 ]
dipyrimidine-4,6-diones 565
16.2.2 Synthesis of functionalized 1H-benzo[6,7]chromeno
[2,3-d]pyrimidines 565
16.2.3 Synthesis of functionalized pyrano[3,2-c]
chromen-5(4H)-ones 568
16.2.4 Synthesis of structurally diverse 4H-benzo[d][1,3]
thiazines and 3,4-dihydroquinazoline-2(1H)-thiones 569
16.2.5 Synthesis of substituted 2-iminothiazolidines 569
16.2.6 Synthesis of substituted tetrahydroquinolines 571
16.2.7 Synthesis of substituted 1,2,3-triazole-fused indoles
and pyrroles 572
 Contents xv

16.2.8 Synthesis of substituted isoxazolidine-cis-fused

phosphadihydrocoumarins 573
16.2.9 Synthesis of 5-substituted indole chromeno[2,3-b]
pyridines 573
16.2.10 Synthesis of substituted 2-amino-4H-pyran-3,
5-dicarbonitrile derivatives 574
16.2.11 Synthesis of substituted 5,6,11,11b-tetrahydro-1
H-indolizino[8,7-b]indol-1-one derivatives 574
16.2.12 Synthesis of diversely functionalized 4-hydroxy-
3-pyrazolylcoumarins 575
16.3 Concluding remarks 576
Acknowledgment 577
References 578

Index 589
List of contributors

Mónica B. Alvarez Departamento de Quı́mica, Instituto de Quı́mica del Sur

(INQUISUR), Sección Quı́mica Analı́tica, Universidad Nacional del Sur, Bahı́a
Blanca, Argentina
Beeraiah Baire Department of Chemistry, Indian Institute of Technology Madras,
Chennai, India
Debasish Bandyopadhyay Department of Chemistry, The University of Texas Rio
Grande Valley, Edinburg, TX, United States; School of Earth, Environmental, and
Marine Sciences (SEEMS), The University of Texas Rio Grande Valley,
Edinburg, TX, United States
Bimal Krishna Banik Community Health Systems of South Texas, Edinburg, TX,
United States; Department of Mathematics and Natural Sciences, College of
Sciences and Human Studies, Deanship of Research, Prince Mohammad Bin Fahd
University, Al Khobar, Kingdom of Saudi Arabia
Basudeb Basu Department of Chemistry, North Bengal University, Darjeeling,
India; Department of Chemistry, Raiganj University, Raiganj, India
Akkattu T. Biju Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
Goutam Brahmachari Laboratory of Natural Products & Organic Synthesis,
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan,
India
Ankita Chaudhary Department of Chemistry, Maitreyi College, Bapu Dham
Complex, Chanakyapuri, New Delhi, India
Prasun Choudhury Department of Chemistry, North Bengal University, Darjeeling,
India
Anton V. Dolzhenko School of Pharmacy, Monash University Malaysia, Selangor,
Malaysia; School of Pharmacy and Biomedical Sciences, Curtin Health
Innovation Research Institute, Curtin University, Perth, WA, Australia
Claudia E. Domini Departamento de Quı́mica, Instituto de Quı́mica del Sur
(INQUISUR), Sección Quı́mica Analı́tica, Universidad Nacional del Sur, Bahı́a
Blanca, Argentina
Andrea Fiorati Department of Chemistry, Materials, and Chemical Engineering
“G. Natta,” Politecnico di Milano, Milan, Italy
Cristian Gambarotti Department of Chemistry, Materials, and Chemical
Engineering “G. Natta,” Politecnico di Milano, Milan, Italy

xvii
xviii List of contributors

Soniya Gandhi Department of Chemistry, Indian Institute of Technology Madras,

Chennai, India
Ramesh Gardas Department of Chemistry, Indian Institute of Technology Madras,
Chennai, India
Rajiv Karmakar Department of Chemistry, University of Calcutta, Kolkata, India;
Department of Chemistry, Dum Dum Motijheel College, West Bengal State
University, Kolkata, India
György Keglevich Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest, Hungary
Garima Khanna Department of Chemistry, University of Delhi, New Delhi, India
J.M. Khurana Department of Chemistry, University of Delhi, New Delhi, India
Abhijeet Kumar Department of Chemistry, School of Physical Sciences, Mahatma
Gandhi Central University, Motihari, India
Rakesh Kumar Laboratory of Organic Chemistry, Department of Chemistry, Central
University of Punjab, Bathinda, India
Felicia Phei Lin Lim School of Pharmacy, Monash University Malaysia, Selangor,
Malaysia
Pintu Maity School of Chemical Sciences, Indian Association for the Cultivation of
Science, Jadavpur, Kolkata, India
Davor Margetić Laboratory for Physical-Organic Chemistry, Division of Organic
Chemistry and Biochemistry, Ruðer Bošković Institute, Zagreb, Croatia
Lucio Melone Department of Chemistry, Materials, and Chemical Engineering
“G. Natta,” Politecnico di Milano, Milan, Italy
Nirmalya Mukherjee School of Chemical Sciences, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata, India
Chhanda Mukhopadhyay Department of Chemistry, University of Calcutta,
Kolkata, India
Nadia Pastori Department of Chemistry, Materials, and Chemical Engineering
“G. Natta,” Politecnico di Milano, Milan, Italy
Carlo Punta Department of Chemistry, Materials, and Chemical Engineering
“G. Natta,” Politecnico di Milano, Milan, Italy
Giuseppina Raffaini Department of Chemistry, Materials, and Chemical
Engineering “G. Natta,” Politecnico di Milano, Milan, Italy
Sanchayita Rajkhowa Department of Chemistry, Gauhati University, Guwahati,
India
Brindaban C. Ranu School of Chemical Sciences, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata, India
Tony Roy Department of Organic Chemistry, Indian Institute of Science, Bangalore,
India
 List of contributors xix

Marı́a A. Schiel Departamento de Quı́mica, Instituto de Quı́mica del Sur

(INQUISUR), Sección Quı́mica Orgánica, Universidad Nacional del Sur, Bahı́a
Blanca, Argentina
Gustavo F. Silbestri Departamento de Quı́mica, Instituto de Quı́mica del Sur
(INQUISUR), Sección Quı́mica Orgánica, Universidad Nacional del Sur, Bahı́a
Blanca, Argentina
Arun Kumar Sinha Medicinal & Process Chemistry Division, CSIR-Central Drug
Research Institute, Lucknow, India
Vinod K. Tiwari Department of Chemistry, Institute of Sciences, Banaras Hindu
University, Varanasi, India
Garima Tripathi Department of Chemistry, T. N. B. College, TMBU, Bhagalpur,
India
Ada Truscello Department of Chemistry, Materials, and Chemical Engineering
“G. Natta,” Politecnico di Milano, Milan, Italy
Editor

Born on April 14, 1969 in Barala, a village in the

district of Murshidabad (West Bengal, India),
Goutam Brahmachari had his early education from
his native place. He received his high school degree
in scientific studies in 1986 at Barala R. D. Sen High
School under the West Bengal Council of Higher
Secondary Education (WBCHSE). Then he moved to
Visva-Bharati (a Central University founded by
Rabindranath Tagore at Santiniketan, West Bengal,
India) to study chemistry at the undergraduate level.
After graduating from this University in 1990, he
then completed his masters in 1992 with a specialization in organic chemis-
try. Thereafter, receiving his Ph.D. in 1997 in chemistry from the same
University, he joined his alma mater the very next year and currently holds
the position of a full professor of chemistry since 2011. The research inter-
ests of Prof. Brahmachari’s group include green chemistry, organic synthesis,
and the medicinal chemistry of natural and natural product inspired syn-
thetic molecules. With more than 22 years of experience in both teaching
and research, he has produced over 200 scientific publications including
original research papers, review articles, books, and invited book chapters in
the field of natural products and green chemistry. He has already authored/
edited 25 books published by internationally reputed major publishing
houses, namely Elsevier Science (The Netherlands), Academic Press
(Oxford), Wiley-VCH (Germany), Alpha Science International (Oxford), De
Gruyter (Germany), World Scientific (Singapore), CRC Press (Taylor &
Francis Group, USA), Royal Society of Chemistry (Cambridge), and so on.
Prof. Brahmachari serves as a life member for the Indian Association for the
Cultivation of Science (IACS), Indian Science Congress Association (ISCA),
Kolkata, and Chemical Research Society of India (CRSI), Bangalore. He has
also been serving as an associate editor for Current Green Chemistry, and as
an editorial board member for several other journals.
Prof. Brahmachari serves as the Series Editor of Elsevier Book Series
“Natural Product Drug Discovery.” He is a Fellow of the Royal Society of
Chemistry, a Who’s Who in the World Listee, and also a recipient of

xxi
xxii Editor

Academic Brilliance Award 2015 (Excellence in Research), Dr. Kalam Best

Teaching Faculty Award (2017), INSA (Indian National Science Academy)
Teachers Award (2019), and CRSI (Chemical Research Society of India)
Bronze Medal (2021) for his contributions of research in chemistry. Prof.
Brahmachari has been featured in the recently published World Ranking-
2020 of the Top 2% Scientists (Organic Chemistry Category).
Foreword

As I sit and write this foreword, I am minded that as a global community of

scientists and engineers, we are all experiencing relative levels of isolation
and change associated with the passing of the global pandemic of 2019 20.
The multiple impacts of COVID-19 are clear to us all, on a human level
many of our communities and families have been touched. . . changed! At
the same time as living through the COVID-19 pandemic, there are two other
enormous challenges facing us that we should not overlook. Our crippled
economy and the looming catastrophe, that is climate change.
Climate change was (and is) the biggest single threat to us all, but one
that we have been reluctant to face. Despite the warnings from eminent
scientists, environmentalists and a growing youth movement stirred into
action by Greta Thunberg, it has taken the unforeseen events of a global pan-
demic to forcibly impact our carbon emissions. As a global community, we
have recorded a significant reduction in our carbon emissions and air quality
measurements, particularly near large centers of population and dense indus-
trialization indicate a significant improvement in air quality, with demonstra-
ble reductions in air particulate matter and environmentally damaging gases
including NOx. It is not hard to see that, as we exit the restrictions of the
pandemic, this is a moment of opportunity. COVID-19 has forced a pause,
across the globe, but what will happen when it is time to press play again?
The worry is that the need to rebuild our economy will cause businesses
across the world to “put-aside” any gains they had made in the sustainability
arena before this crisis, for the chance to rebuild rapidly to help achieve a
new economic stability. As scientists and engineers, we can influence the
decisions made at production, it is incumbent upon us to deliver synthetic
methods that will enable the more efficient preparation of target molecules
for the industry.
Our laboratories will inevitably be the birthplace of new molecules that
deliver desired impacts resulting from their properties, perhaps as pharma-
ceuticals, agrochemicals, or polymers without many of the detrimental
impacts associated with the production methods of the past. As a community,
we must look forward and make plans for smarter synthesis and cleaner pro-
duction, this edited volume, which is focused on the sustainable preparation
of heterocyclic systems, is an excellent example of knowledge creation dur-
ing this most difficult time. Heterocycles are ubiquitous in medicines,

xxiii
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Longstreet, General, 168
Lookout Mountain, 173
Losantiville, 124
Louisville, 117, 127
Lulbegrud creek, 151
Luray, 131, 132
Lyell, Sir Charles, cited, 126

McClellan, General, 132

Mail, first, received at Utica, 24
Mail bags, race of the, 109
Mail coaches, 94
Manhattan island, 14, 15
Marble, 104, 168, 171
Maryland, 86
Memphis, 172
Middlesboro, 153
Milestone on Braddock’s road, 90
Missionary Ridge, 173
Mobile, 174
Mohawk valley, 16–19, 31, 42, 59
Monongahela river, 93, 96, 111
Morris, Gouverneur, 42
Mount Vernon, 41, 86
Nash, Oliver, 163
Nashborough (Nashville), 163, 171, 173
National Road, the, 91, 93, 96, 123
New Amsterdam, 14
New Jersey, Scotch-Irish in, 66
New Netherlands, 14
New river (Great Kanawha), 134
New York Central Railway, 20, 30, 58, 60, 62
New York City, 2, 7, 14
New York state, 27;
well adapted for canal, 44
Newburg, N.Y., 60
Noah’s Ark, 49
Nolichucky river, 159
Norfolk and Western Railway, 133
North Adams, Mass., 5
North American Review, 102
North Carolina, 137, 146
North-German Lloyd line, 108

Ocmulgee river, 179

Ogden, Utah, 109
Ohio Company, 88
Ohio country, French in, 89
Ohio river, 76, 98, 111, 123, 127, 152
Oil City, 120
Omaha, 109
Oneida Indians, 17
Oneida Carrying Place, 22
Onondaga salt, 27, 113
Ontario, lake, 18, 22, 33
Oriskany, 29, 30, 35
Oswego, 32
Oswego river, 22
Otsego lake, 98
Oyster industry, 104

“Packers,” 72
Packets, 50
Parton, James, cited, 120
Penn, William, 66
Pennsylvania, settlement of, 66
Pennsylvania Railroad, 77–85
“Pennsylvania Dutch,” 66
Pennsylvania canal, 74
Phelps, Abner, 9
Philadelphia, 41, 63
Pike, Pittsburg, 72;
Frederick, 93
Pineville gap, 143, 147
Pittsburg, 64, 71, 75, 83, 107, 156;
description of, 111, 115, 120, 122;
pike, 72
Pittsfield, Mass., 5
Point Pleasant, 155
Portage Railway, Allegheny, 75, 76, 80
Post, John, 23, 24
Potomac Company, 99
Potomac river, 86, 106
Powell, Ambrose, 142
Powell’s river, 134, 142
Prairies in Kentucky, 152
Princeton College, 66
Providence, R.I., 4
Puncheon floors, 140

Queen City, the, 124

Queenstown, 110
Quincy, Mass., 53

Railways:
through the Berkshires, 9, 10;
from Albany to Schenectady, 9, 53;
early, 53, 56;
opposition to, 55;
growth of, 60, 109, 181;
West Shore, 59;
Erie, 60;
New York Central, 20, 30, 58, 60, 62;
Wabash, 102;
Baltimore and Ohio, 99, 101, 102, 110;
Southern Pacific, 109;
Union Pacific, 109;
Lake Shore, 110;
Norfolk and Western, 133;
Southern, 134, 170
Reading, Pa., 79
Red Star line, 108
Redstone, 117
Richardson, Judge John, 46
Rivers important in a country’s growth, 5–7, 16, 17, 24, 26, 31, 41,
122, 126, 133
Roads, in New England, 4, 6, 7;
stage, 64;
development of, 72;
indifference to, 87;
national interest in, 92;
Braddock’s, 90;
Cumberland, 93;
 Frederick, 93;
National, 91, 93, 96;
Wilderness (Boone’s trail, Kentucky road, Virginia road, Caintuck
Hog road), 127, 149
Roanoke, 134
Robertson, James, goes to Watauga, 137;
pacifies the Indians, 139;
helps protect the new settlement, 155;
founds Nashborough, 163;
trusted by the people, 164;
portrait, 164;
ability, 172
Rochester, N.Y., 25, 52
Rochester, Colonel, 26, 41, 61, 132
“Rolling roads,” 88
Rome, 22, 46, 61
Roosevelt, Theodore, cited, 137, 140, 160
Ross’s Landing, 174

Sails on cars, 105

St. Clair, General, 124
St. Leger, General, 33, 61
Salt, 27, 61, 113
Samp mortars, 21
San Francisco, 109
Saratoga, 38
Schenectady, 19, 42, 47, 61
“Schonowe,” 19
Schuyler, Fort (Utica), 23
Schuyler, Han Yost, 37
Schuylerville, 38
Scotch-Irish, 66, 136
Seneca river, 24
Seneca lake, 25
Settlement:
in New England, 4;
in New York, 14, 24;
in Pennsylvania, 66;
in the Ohio country, 117;
in Tennessee, 135, 170;
in Kentucky, 148
Sevier, John, goes to Watauga, 138;
fights on the frontier, 155;
plans to attack Ferguson, 160;
returns home, 162;
portrait, 162;
monument to, 165;
other honors, 166;
on the Tennessee river, 172
Shelby, Isaac, 155, 159, 165
Shelbyville, 165
Shenandoah valley, 88, 107, 130, 132
Sheridan, 133
Shippensburg, Pa., 71
Shreve, Captain, 117
Slate, 104
“Smoky City, The,” 120
South Mountain, Pa., 132
Southern Pacific Railway, 22
Southern Railway, 134, 170
Speed of early trains, 105
Spotswood, Alexander, 129
Springfield, Mass., 6, 10
Stanwix, Fort, 22, 23, 34, 37, 61, 149
Stark, General, 38
Staunton, Va., 135
Steamboats, 118
Stephenson, George, 53
Stillwater, 38
Susquehanna valley, 26, 41, 46, 104
Swift Run Gap, 130
Sycamore Shoals, 160
Sydney, Australia, 109
Syracuse, 27, 52, 57, 61

Tarleton, Colonel, 159

Teamsters of early days, 64, 69
Tennessee, 134, 154, 164, 172;
University of, 170
Tennessee river, 134, 142, 163, 167, 172, 174
Ticonderoga, 32, 37, 38
Tidewater country, 87, 130
Timber, 104, 180
Toll houses, 68, 87
Toll rates, 94
Tom Thumb, 106
Trails, old, 4, 6, 17, 19, 22, 25, 28, 72
Tramways in England, 54
Transylvania Company, 148
Travel, early, 5, 22, 56, 64, 91
Trow Plat, 23
Trunk line, 57
“Tubal Cain of Virginia,” 129
Tudor, Frederick, 4
Twentieth Century Limited, 56

Union Pacific Railroad, 109

University of Tennessee, 170
Utica, 21, 23, 37, 57, 61

Valley of east Tennessee, 135;

of Virginia, 132
Valley, the Great, 71, 130, 132, 134, 136, 139
Valleys as natural roads, 5–7, 16, 17, 22, 24, 26, 31, 41, 126, 133,
142, 152, 156
Van Curler, Arent, 17, 19, 57, 61
Vanderbilt, Cornelius, 58
Ventura, the, 109
Vincennes, Ind., 158
Virginia, 129, 154;
valley of, 132

Wabash Railway Company, 102

Wabash river, 158
Walker, Dr. Thomas, 142
Ward, Nancy, 139
Washington, D.C., 91, 93, 94
Washington, George, 41, 60, 86, 112, 133;
part taken by, in road making, 88–92, 98
Washington, Lawrence, 89
Watauga Settlement, 135–141, 144, 146, 159
Waterford, 47
West, the, 40, 60
Westfield valley, 6
West Shore Railway, 59
Wheeling, 94, 107, 122
White, Hugh, 21
Whitesboro, 21
Wilderness Road, 127, 149
Willett, Captain Marinus, 35
William and Mary College, 142
Wills creek, 89, 102
Wills mountain, 93
Winchester, Va., 132, 135
Windmills, Dutch, 15
Wood creek, 22, 42

Yadkin valley, North Carolina, 146

 Transcriber’s Notes
Punctuation, hyphenation, and spelling were made
consistent when a predominant preference was found in the
original book; otherwise they were not changed.
Simple typographical errors were corrected; unbalanced
quotation marks were remedied when the change was
obvious, and otherwise left unbalanced.
Illustrations in this eBook have been positioned between
paragraphs and outside quotations. In versions of this eBook
that support hyperlinks, the page references in the List of
Illustrations lead to the corresponding illustrations.
Portions of the captions of some illustrations were taken
from the List of Illustrations.
The images have not been descreened because doing so
lost too much detail.
The index was not checked for proper alphabetization or
correct page references.
Page 18: The pronunciation mark above the first “o” in “ĭr-
ṓ-kwoi´” was an inverted “T”, which was only visually
approximated here.
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