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Table of Contents ix
4.6.7 Isoxazole 217
Problem 80: Formation of 5-Chloro-3-phenylbenzo[c]isoxazole 217
Problem 81: Preparation of Isoxazoles from Nitro Compounds and
Oxetanes 219
4.6.8 Thiazole 221
Problem 82: Preparation of Thiazole by Thiourea 221
Problem 83: Preparation of Thiazole from Sulfoxide During Ceftibuten
Synthesis 223
4.6.9 Pyrazole 224
Problem 84: Synthesis of Trifluoromethylpyrazoles 224
Problem 85: Preparation of Pyrazole by Sulfur Extrusion 226
Problem 86: Synthesis of
4-(3-Aminopropyl)-5-amino-1-methylpyrazole 227
4.6.10 Pyrimidine 229
Problem 87: Formation of 5-Hydroxypyrimidin-4(3H)-one by 3,3-sigma-
tropic Rearrangement 229
Problem 88: Regioselective Chlorination of
1-Methylpyrimidine-2,4,6(1H,3H,5H)-trione 231
Problem 89: An Industrial Synthesis of Orotic Acid 232
Problem 90: 2-Thioxo-2,3-dihydropyrimidin-4(1H)-one to
Pyrimidine-2,4(1H,3H)-dione 234
Problem 91: Preparation of N,N′-Dicyclohexylbarbituric Acid from DCC
and Malonic Acid 235
4.6.11 Pyrazine 237
Problem 92: Synthesis of Ethyl 3-(trifluoromethyl)
pyrazine-2-carboxylate 237
4.6.12 Triazole 239
Problem 93: Preparation of [1,2,4]Triazolo[1,5-a]pyridin-2-amine 239
4.6.13 Oxadiazole 240
Problem 94: Formation of 1,3,4-Oxadiazole 240
Problem 95: Preparation of 1,2,4-Oxadiazole 241
4.6.14 Thiadiazole 243
Problem 96: Formation of 1,2,4-Thiadiazole 243
4.6.15 Triazine 245
Problem 97: Synthesis of 1,2,3-Triazines 245
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 248
4.7.1 Indole 248
Problem 98: Formation of 2,3-Disubstituted Indole 248
Problem 99: A Novel Synthesis of Indoles by Vinyl Grignard Reagent with
Nitroarenes 250
Problem 100: Deprotection of 2-Hydroxylethyl from Indole
Derivative 252
4.7.2 Indolizine 254
Problem 101: Access to 2-Iodoindolizines via Iodine-Mediated Cyclization
of 2-pyridylallenes 254
4.7.3 Quinolone 254
Problem 102: Oxidative Rearrangement of Carboline to Quinolone 254
Table of Contentsx
4.7.4 Indazole 257
Problem 103: A Special Cadogan Reductive Cyclization-Preparation of
Indazole 257
Problem 104: Preparation of Indazoles from 2-Methylanilines 259
Problem 105: Synthesis of 7-aza-Indazoles by Diels-Alder/Retro-Diels-
Alder Cascade 260
Problem 106: Synthesis of Indazole by Davis-Beirut Reaction 262
4.7.5 Quinazoline 265
Problem 107: Synthesis of Quinazolines 265
Problem 108: Carbon Dioxide Mediated Synthesis of
Quinazoline-2,4(1H,3H)-dione 266
Problem 109: Synthesis of 3-Alkylquinazolin-4-ones Promoted by
Mukaiyama Reagent 269
Problem 110: Dimroth Rearrangement in the Preparation of Gefitinib and
Erlotinib 270
4.7.6 Thienoquinolizine 272
Problem 111: A [3+2] Cycloaddition Followed by Sulfur Extrusion 272
4.7.7 Pyridopyrimidine 273
Problem 112: An Extended Dimroth Rearrangement Catalyzed by
MeONa 273
4.7.8 Pyrrolopyrimidine 274
Problem 113: One-Pot Synthesis of 2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)
acetates 274
4.7.9 Pyrazolopyrimidine 276
Problem 114: Cyclization of Diazo Compound with Aldehyde 276
4.8 Miscellaneous 277
4.8.1 Steroid 277
Problem 115: Formation of Cyclopropane Ring in a Nucleophile
Substitution on Steroid 277
Problem 116: Preparation of 21-Hydroxypregna-4,9(11),
16-triene-3,20-dione-21-acetate 280
4.8.2 Macrolide 281
Problem 117: An Ascomycin Rearrangement 281
4.8.3 Gibberellin 283
Problem 118: An Acyloin Rearrangement in Gibberellin 283
4.8.4 Cannabicitran 284
Problem 119: Formation of Cannabicitran During the Synthesis of
Cannanbichromene 284
4.8.5 Serratezomine 287
Problem 120: Transformation of Serratinine into Serratezomine A 287
4.8.6 Vincamine 288
Problem 121: Preparation of Vincamine from Tabersonine 288
References 290
Table of Contents xi
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or
Side Products 305
5.1 Formation of Noncyclic Alkane and Derivatives 306
5.1.1 Alcohol 306
Problem 122: An Unexpected Impurity from a Grignard Reaction 306
Problem 123: Formation of a Dimer Impurity in the Development of
Delafloxacin 308
Problem 124: Formation of an Amidino-Diol Side Product 310
5.1.2 Amine 312
Problem 125: Formation of Ketoamine During Semmler–Wolff
Aromatization 312
Problem 126: Formation of an Aniline Impurity by Smiles
Rearrangement 314
5.2 Formation of Cyclic Alkane and Derivatives 316
5.2.1 Cyclopropane 316
Problem 127: Formation of a Cyclopropane Impurity 316
5.3 Formation of Aromatic Compounds 318
5.3.1 Benzene 318
Problem 128: Formation of an Undesired Substituted Benzene Side
Product 318
5.4 Formation of Nonaromatic Heterocycles 320
5.4.1 Aziridine 320
Problem 129: Formation of an Aziridine-a Neighboring Group
Participated Cyclization 320
5.4.2 Pyrrolidine 323
Problem 130: Formation of Ring-contracted Side Product During
Fluorination 323
5.4.3 Piperidine 326
Problem 131: An Unusual DAST-Mediated Rearrangement 326
5.4.4 Tetrahydropyrazine 329
Problem 132: Formation of an Unexpected Tetrahydropyrazine
Product 329
5.4.5 Tetrahydropyrimidine 332
Problem 133: Formation of Impurities During a CDI-promoted
Cyclization 332
5.4.6 Oxazepane 334
Problem 134: An Unusual Stevens Rearrangement Catalyzed by
Acid 334
5.4.7 Tetrahydroquinoline 336
Problem 135: Formation of Unexpected Tetrahydrobenzoquinoline Side
Product in a Hydrogenation 336
Table of Contentsxii
5.5 Formation of Monocyclic Aromatic Heterocycles 338
5.5.1 Pyrrole 338
Problem 136: Formation of an Amino Pyrrole Impurity 338
5.5.2 Pyridine 341
Problem 137: Pyridyl Walks to Hydroxyl from Sulfone During an
Alkylation 341
5.5.3 Pyrazole 343
Problem 138: Ring Expansion by [3 + 2] Cycloaddition During the
Synthesis of Pyrazoles 343
5.5.4 Oxazole 346
Problem 139: Formation of 2-(2,6-difluorophenyl)-4-(p-tolyl)oxazole as an
impurity 346
Problem 140: Formation of an Oxazoline Impurity in the Synthesis of a
M1 Agonist 349
5.5.5 Triazole 351
Problem 141: Formation of Dimethylcarbamoyl-OBt in a HBTU-promoted
Amide Preparation 351
5.5.6 Tetrazole 353
Problem 142: Formation of a Tetrazole Impurity Caused by Acetone 353
5.5.7 Diazepine 355
Problem 143: Accidental Discovery of Librium 355
5.6 Formation of Bicyclic Aromatic Heterocycles 356
5.6.1 Benzofuran 356
Problem 144: Formation of Two Benzofuran Side Products During the
Synthesis of Morin 356
5.6.2 Benzoxazolinone 361
Problem 145: Formation of Undesired Benzoxazolinone from
N,2-Dihydroxybenzamide 361
5.6.3 Quinoline 363
Problem 146: Formation of Quinoline-4-carboxylic Acids by Pfitzinger
Reaction Conditions 363
Problem 147: Formation of a Tricyclic Impurity During Alkylation of
8-hydroxyquinoline 365
5.6.4 Naphthyridine 368
Problem 148: Unexpected Formation of a
Dibenzo[c,f]-2,7-naphthyridine-3,6-diamine 368
5.6.5 Pteridine 370
Problem 149: Formation of Two Pteridine Impurities During a Synthesis
of Dexrazoxane 370
5.7 Miscellaneous 372
5.7.1 Steroid 372
Problem 150: Formation of Impurity F of Clobetasol Propionate 372
Problem 151: Formation of a 24-Methylene Steroidal Impurity 373
Table of Contents xiii
5.7.2 Terramycin 375
Problem 152: An Unusual Reaction of Terramycin with Methyl
Iodide 375
5.7.3 Cephem 376
Problem 153: Degradation of Cephem Intermediate 376
References 378
Index 383
If you read a book or article and find yourself agreeing with every single point
without a single question or doubt, it might indicate that you’re not thinking criti-
cally and you have been brain washed. True growth comes from recognizing what
you don’t know—without acknowledging your own ignorance, progress becomes
impossible.
When applying for a position as a synthetic chemist or medicinal chemist, you
can expect to be questioned about reaction mechanisms during the interview pro-
cess. These mechanistic problems are typically not taken directly from textbooks
but are often drawn from the interviewer’s own research experiences. This was cer-
tainly the case for me when I interviewed for such roles in pharmaceutical com-
panies after completing my postdoctoral research. A solid understanding of organic
reaction mechanisms is a fundamental skill for any synthetic organic chemist. It is
essential not only for designing synthesis routes and experimental procedures but
also for troubleshooting and resolving synthetic challenges effectively.
The fundamental reactions and named reactions in organic chemistry, along with
their mechanisms, have been extensively covered in numerous textbooks and mono-
graphs. These mechanisms are also readily accessible through online platforms such
as Wikipedia, Google, the Organic Chemistry Portal, and YouTube videos. However,
when it comes to specific reactions in published synthetic routes, their mechanisms
are not always straightforward to identify or comprehend. This often depends on
the chemist’s knowledge and experience. In many instances, understanding the
mechanisms behind the formation of unexpected products, side products, or even
impurities can significantly aid chemists in addressing challenges in their research.
With these points in mind, this book compiles a selection of intriguing and chal-
lenging mechanism problems in organic reactions, particularly within the realm of
medicinal chemistry, drawing from my experience and the literature I have studied.
Many of the reactions featured in this book are key steps in the synthesis of target
compounds, while others involve the formation of side products, unexpected prod-
ucts, or impurities. I have made an effort to avoid including examples that have
already been covered in other books. The primary goal of this book is to assist
organic chemists, professionals, and students in deepening their understanding of
reaction mechanisms. For mechanisms reported in the literature, I have redrawn
them in a more accessible format to enhance clarity for readers. Additionally, I have
offered my own perspectives on certain mechanisms that I find questionable in the
Preface
Prefacexvi
literature. For reactions, particularly those described in patents, where mechanisms
are not provided, I have proposed mechanistic explanations based on my under-
standing. I strongly encourage readers to attempt drawing their own mechanisms
before consulting my proposed answers.
Certainly, whether derived from the literature or proposed by me, the mechanisms
should not be considered the only possible explanations or the “definitive answers.”
You are encouraged to develop your own mechanisms, provided they offer a reason-
able and logical explanation for the reaction.
Needless to say, this book is not an encyclopedia and it does not aim to cover all
reaction mechanisms in organic synthesis. For example, some common, hotly cited,
or frontier organic reactions, such as transition metal catalyzed coupling, catalytic
asymmetric reactions, photo-promoted reactions, and electrochemical reactions,
are barely included.
I would like to extend my appreciation to the original publishers for experimental
procedures for granting permission to use in this book. The publishers include the
American Chemical Society, Elsevier, the Royal Society of Chemistry, John Wiley &
Sons, Springer Nature, the American Association for the Advancement of Science,
and Oxford University Press. I would like to thank all inventors for patent literatures
cited in this book.
Errors occasionally creep into any book, so it should not be surprising if you find
mistakes in this one. If you do find any, feel free to discuss them with me. I would
welcome any comments from readers, especially those suggestions that would make
the book of greater value to the reader.
I would like to express my sincere gratitude to my mentors, students, and col-
leagues throughout my university studies, teaching, research, and career in the
pharmaceutical industry.
I deeply appreciate Wiley editors Dr. Anne Brennführer, Priyadarshini Natarajan
and Haridharini Velayoudame for helping me turning my ideas into this book.
Finally, I wish to thank my family members for their continual support and
understanding.
Tongshuang Li
Hayward, CA, USA
June 2025
Preface xvii
《付梓感怀》
菊花绽放深秋, 红梅香自苦寒。蒙父母言行教诲, 得各任恩师真传。集平生经历见
闻, 受中西思想浇灌。融古今圣贤智慧, 于个人粗浅拙见。出首部学术专著, 甘愿
做引玉之砖。意启迪同辈后生, 续科学创造新篇。限本人才疏学浅, 有错误纰漏难
免。望各位专家学者, 不吝啬斧正纠偏！
《Reflections Upon My Manuscript’s Publication》
Chrysanthemums bloom proud in autumn’s snow,
Plum fragrance crystallizes winter’s blow.
Nurtured by parental virtues stern and bright,
Humbled beneath mentors’ scholarly light.
Ten thousand miles of wisdom fill my gaze,
East-West philosophies through my brush convey.
A hundred schools’ essence within me flows,
Lone quill stirs waves where silent paper glows.
May this crude work spark jade-carved replies,
To nurture magnolia beneath new skies.
Let younger waves surge where old currents crest,
Fresh voices shake academia’s hallowed nest.
Though keenly aware my borrowed insights show,
Joy finds me when errors meet your chisel’s glow.
3CL protease 3-chymotrypsin-like protease
5-HT 5-hydroxytryptamine or serotonin
5-HT4 5-hydroxytryptamine receptor 4
ABN 2-aminobenzonitrile
ACC inhibitor acetyl-CoA carboxylase inhibitor
AD Alzheimer’s disease
ADC antibody–drug conjugate
ADME absorption, distribution, metabolism, and excretion
AI artificial intelligence
AIDS acquired immunodeficiency syndrome
ALK anaplastic lymphoma kinase
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ANRORC addition of the nucleophile, ring opening, and ring closure
APIs active pharmaceutical ingredients
ATC apricitabine
ATPase adenosine 5′-triphosphatase
ATR ataxia telangiectasia and Rad3-related
AUC area under the plasma drug concentration–time curve
BACE beta-amyloid cleaving enzyme
BCC basal-cell carcinoma
BLA biologic license application
BMS Bristol–Myers Squibb Company
Boc tert-butoxycarbonyl or tert-butyloxycarbonyl
BPR back-pressure regulator
brsm based on recovered starting material
BSA N,O-bis-(trimethylsilyl)acetamide
BTK Bruton’s tyrosine kinase
BTP 2-bromo-3,3,3-trifluoroprop-1-ene
BTPP tert-butylimino-tri(pyrrolidino)phosphorane
Bus tert-butylsulfonyl
CB1 cannabinoid receptor 1
CBC cannanbichromene
CBTC cannabicitran
Cbz benzyl carbamate
Abbreviations
Abbreviationsxx
Cbz-Cl benzyl chloroformate
CCR5 cysteine-cysteine chemokine receptor 5
CD45 lymphocyte common antigen, a protein tyrosine phosphatase
CDI carbonyldiimidazole
CFTR cystic fibrosis transmembrane conductance regulator
cGMP cyclic guanosine monophosphate-specific phosphodiesterase
Chk checkpoint kinase
CMBP cyanomethylenetributylphosphorane
CMC chemistry, manufacturing, and controls
CNS central nervous system
COVID-19 coronavirus disease 2019
COX cyclooxygenase
CRF1 corticotropin-releasing factor receptor 1
CRO contract research organization
CuAAC Cu(I)-catalyzed azide-alkyne cycloaddition
CXCR4 C-X-C chemokine receptor type 4
CYP1A2 cytochrome P450 1A2
CYP2B6 cytochrome P450 2B6
CYP2C19 cytochrome P450 2C19
CYP2C9 cytochrome P450 2C9
CYP3A cytochrome P450, family 3, subfamily A
DABCO 1,4-diazabicyclo[2.2.2]octane
DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N′-dicyclohexylcarbodiimide
DCHU N,N′-dicyclohexyl urea
DCM dichloromethane
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DEAD diethyl azodicarboxylate
DCE dichloroethane
DED dry eye disease
Deoxo-Flour bis(2-methoxyethyl)aminosulfur trifluoride
DEPT distortionless enhancement by polarization transfer
DGAT-1 diacyl glycerolacyl transferase-1
DHA dihydroartemisinin
DI deionized
DIAD diisopropyl azodicarboxylate
DIHD diisopropyl hydrazine-1,2-dicarboxylate
DIPA diisopropylamine
DIPEA N,N-diisopropylethylamine
DMA dimethylacetamide
DMAD dimethyl acetylenedicarboxylate
DMAP 4-dimethylaminopyridine
DMB 2,4-dimethoxybenzyl
DMBNH2 2,4-dimethoxybenzylamine
DMF dimethylformamide