Naming Reactions in

Organic Chemistry

Editor
Charanjit Kaur
Naming Reactions in Organic
Chemistry

Editor
Charanjit Kaur
Professor,
Faculty of Applied Medical Sciences,
Lovely Professional University,
Phagwara Punjab-144411 India

ISBN:978-81-974054-2-6

2024
 Table of Contents
Preface
Chapter 1
Ugi reaction............................................................................................................................................1
Pankaj Wadhwa*, Shubham Kumar, Amit Kumar
Chapter 2
Brook rearrangement..............................................................................................................................5
Pankaj Wadhwa*, Shubham Kumar, Amit Kumar
Chapter 3
Ullmann reaction....................................................................................................................................8
Gurvinder Sigh*, Charanjit Kaur, Rajesh Kumar
Chapter 4
Dieckmann reaction..........................................................................................................................11
Gurvinder Sigh*, Charanjit Kaur, Rajesh Kumar
Chapter 5
Doebner-Miller reaction.................................................................................................................13
Amit Mittal*, Anuradha Mehra
Chapter 6
Sandmeyer reaction........................................................................................................................16
Amit Mittal*, Anuradha Mehra
Chapter 7
Mitsunobu reaction.........................................................................................................................17
Banoth Karan Kumar*, Deepshika Patle
Chapter 8
Mannich reaction............................................................................................................................21
Bhupinder Kapoor*, Reena Gupta
Chapter 9.......................................................................................................................................27
Vilsmeyer-Haack reaction
Mukta Gupta*
Chapter 10....................................................................................................................................30
Sharpless asymmetric epoxidation
Mukta Gupta*
Chapter 11
Baeyer-Villiger oxidation.............................................................................................................33
 Bhupinder Kapoor*, Reena Gupta
Chapter 12
Shapiro reaction.............................................................................................................................36
Banoth Karan Kumar*, Deepshika Patle
Chapter 13
Suzuki reaction...............................................................................................................................39
Rekha Sangwan*
Chapter 14
Debus-Radziszewski imidazole synthesis..................................................................................42
Rekha Sangwan*
Chapter 15
Knorr pyrazole synthesis..............................................................................................................45
Charanjit Kaur*, Gurvinder Singh
Chapter 16
Pinner pyrimidine synthesis.........................................................................................................48
Charanjit Kaur*, Gurvinder Singh
Chapter 17
Bernthsen acridine synthesis........................................................................................................50
Salvi Sood, Gurdeep Singh*, Ritesh Patel, Mukesh Kr. Singh
Chapter 18
Combes quinoline synthesis.........................................................................................................54
Salvi Sood, Gurdeep Singh*, Ritesh Patel, Mukesh Kr. Singh
Chapter 19
Smiles rearrangement...................................................................................................................57
Anuradha Mehra*, Amit Mittal
Chapter 20
Traube purine synthesis...............................................................................................................60
Anuradha Mehra*, Amit Mittal
 Preface

Organic chemistry, often described as the chemistry of life, is a vast and intricate landscape.
At its core lies a complex web of reactions, each a unique transformation of matter. These
reactions, when understood, provide the building blocks for synthesizing an incredible array of
compounds, from pharmaceuticals to polymers. A significant subset of these reactions, known
as named reactions, have become the lexicon of organic chemists.

This book is an endeavor to illuminate this lexicon. It is a comprehensive guide to the most
important and frequently encountered named reactions in organic chemistry. Our aim is to
provide a clear, concise, and accessible resource for students, researchers, and practitioners
alike.

Each reaction is presented with a clear explanation of its mechanism, scope, limitations, and
synthetic utility. We have strived to balance depth with clarity, providing sufficient detail for
a thorough understanding without overwhelming the reader. Historical context, where relevant,
is also included to enrich the narrative and appreciate the evolution of these reactions.

We believe that a deep understanding of named reactions is essential for mastering organic
chemistry. It is our hope that this book will serve as a valuable companion on this journey.

We, are confident that this book will serve as a valuable resource for undergraduate and post
graduate students and researchers, in their exploration of the captivating world of organic
chemistry.
 Chapter 1
Ugi Reaction
Pankaj Wadhwa1*, Shubham Kumar1, Amit Kumar2
1 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab
2
Tahira Institute of Medical Sciences, GIDA, Gorakhpur, U.P
Introduction

The Ugi reaction, also known as the Ugi four-component reaction (U-4CR), is a
multicomponent reaction that forms a peptidic scaffold through the condensation of four
reactants: an aldehyde or ketone, an amine, a carboxylic acid, and an isocyanide. The reaction
was discovered by Ivar Ugi in 1959 and has since become a valuable tool in synthetic organic
chemistry due to its efficiency in constructing complex molecules in a single step [1-4].

Ugi Reaction Mechanism

The mechanism of the Ugi reaction involves the formation of the imine begins when the amine
reacts with a carbonyl compound, either an aldehyde or a ketone, resulting in the creation of
an imine, also known as a Schiff base. Following this, the imine intermediate undergoes a
reaction with an isocyanide, which leads to the generation of a nitrilium ion intermediate. Next,
the carboxylic acid deprotonates, producing a carboxylate ion that subsequently attacks the
nitrilium ion. This sequence of reactions culminates in the formation of the final product, which
is a peptidic compound known as an α-acylaminoamide [5-6].

1
Applications

1. Fentanyl, is a synthetic opioid analgesic widely used for pain relief following various
medical treatments. The novel substituted amino acid-tethered norsufentanil derivatives were
prepared using the Ugi reaction, which involved reacting carboxylic acid-tethered
norsufentanil with a range of aldehydes, amines, and isocyanides to create a diverse library of
the desired norsufentanil derivatives. The analgesic properties of these synthesized compounds
such as sufentanil, sufentanil citrate, and norsufentanil were evaluated in vivo using the tail
flick test [7].

2. Additionally, the Ugi reaction was utilized to develop a specialized library of C-capped
dipeptide efflux pump inhibitors. This involved synthesizing C-capped dipeptides BU-005
through the Ugi four-component reaction, followed by complete deprotection of Boc and DMB
groups from Ugi product using TFA. These inhibitors have significant potential as
pharmacological agents, capable of restoring the drug sensitivity of multidrug-resistant
bacterial pathogens. Specifically, C-capped dipeptides BU-005 inhibit two chloramphenicol-
specific efflux pumps in Streptomyces coelicolor, a Gram-positive bacterium related to the
human pathogen Mycobacterium tuberculosis [8].

O R
O R H
H H2N N
BocHN N TFA N
N
DMB O
DMB O

H2N
BocHN Boc and DMB C-capped dipeptides BU-005
protected compound

3. Balalaie and colleagues achieved the synthesis of pseudo-peptides featuring a quinazolinone

moiety through the Ugi-4 component reaction (U-4CR), utilizing derivatives of 3-amino-
1,2,3,4-tetrahydro-4-oxoquinazoline-2-carboxylic acid. This reaction, involving compound 5
with various aromatic aldehydes, primary amines, and isonitriles, produced the targeted
pseudo-peptides containing the quinazolinone moiety. Remarkably, the predominant

2
diastereoisomer was isolated in crystalline form, while the minor diastereoisomer remained in
ethanol solution [9].

4. A series of innovative chiral morpholin-2-one-3-carboxamide derivatives and

ketopiperazine-2-carboxamide compounds were synthesized through an asymmetric Ugi three-
component reaction, employing chiral cyclic aldimines or ketoimines. These chiral imines
exhibited excellent stereocontrol over the formation of the new chiral center in the Ugi
products, resulting in predominantly trans-isomers with high diastereoselectivity at the C-3
position in the products [10].

R3 O
O
R N R1 R2-NC TFE, r.t. N R1
+ HN
R
O X R3-COOH
R2 O X
Isocyanide
cyclic aldimines or ketoimines Carboxylic acid morpholin-2-one-3-carboxamide derivatives

In summary, the Ugi reaction is a powerful tool in organic synthesis, enabling the rapid and
efficient construction of complex molecules with a wide range of applications, particularly in
drug discovery, combinatorial chemistry, and materials science.

References

1. Janežič, D., Hodošček, M. and Ugi, I., 2002. The Simultaneous a-Addition of a Cation
and an Anion onto an Isocyanide. Internet Electron. J. Mol. Des, 1, pp.293-299.

2. Kumar, S., Mukesh, K., Harjai, K. and Singh, V., 2019. Synthesis of coumarin based
Knoevenagel-Ugi adducts by a sequential one pot five-component reaction and their
biological evaluation as anti-bacterial agents. Tetrahedron letters, 60(1), pp.8-12.

3. Passerini, M. and Simone, L., 1921. Isonitriles. I. Compound of p-isonitrileazobenzene

with acetone and acetic acid. Gazz. Chim. Ital, 51(2), pp.126-129.

3
4. Chandgude, A.L. and Dömling, A., 2016. An efficient Passerini tetrazole reaction (PT-
3CR). Green chemistry, 18(13), pp.3718-3721.

5. Ayoup, M.S., Wahby, Y., Abdel-Hamid, H., Teleb, M., Abu-Serie, M.M. and Noby, A.,
2019. Design, synthesis and biological evaluation of novel α-acyloxy carboxamides via
Passerini reaction as caspase 3/7 activators. European journal of medicinal
chemistry, 168, pp.340-356.

6. Ugi, I., Werner, B. and Dömling, A., 2003. The chemistry of isocyanides, their
multicomponent reactions and their libraries. Molecules, 8(1), pp.53-66.

7. Nami, M., Salehi, P., Dabiri, M., Bararjanian, M., Gharaghani, S., Khoramjouy, M., Al‐
Harrasi, A. and Faizi, M., 2018. Synthesis of novel norsufentanil analogs via a four‐
component Ugi reaction and in vivo, docking, and QSAR studies of their analgesic
activity. Chemical Biology & Drug Design, 91(4), pp.902-914.

8. Okandeji, B.O., Greenwald, D.M., Wroten, J. and Sello, J.K., 2011. Synthesis and
evaluation of inhibitors of bacterial drug efflux pumps of the major facilitator
superfamily. Bioorganic & medicinal chemistry, 19(24), pp.7679-7689.

9. Balalaie, S., Saeedi, S. and Ramezanpour, S., 2016. Synthesis of Pseudo‐Peptides

Containing a Quinazolinone Skeleton via Ugi Four‐Component Reaction. Helvetica
Chimica Acta, 99(2), pp.138-142.

10. Zhu, D., Xia, L., Pan, L., Li, S., Chen, R., Mou, Y. and Chen, X., 2012. An asymmetric
Ugi three-component reaction induced by chiral cyclic imines: Synthesis of morpholin–
or piperazine–keto-carboxamide derivatives. The Journal of Organic Chemistry, 77(3),
pp.1386-1395.

4
 Chapter 2

Brook Rearrangement

Pankaj Wadhwa1*, Shubham Kumar1, Amit Kumar2

1 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab

2
Tahira Institute of Medical Sciences, GIDA, Gorakhpur, U.P

Introduction

The Brook rearrangement, named after Adolphus B. Brook, involves the migration of a
substituent within a molecule, typically from one carbon atom to an adjacent carbon atom. The
[1,2]-Brook Rearrangement of α-silyl carbinols is an example, where a silyl group migrates
from carbon to oxygen in the presence of a catalytic base like Et2NH, NaH, or NaOH. This
rearrangement is intramolecular and 1,2-anionic, and similar migrations are called Brook
Rearrangements, with migratory aptitude seen across homologues. This rearrangement often
occurs under the influence of heat or other activating conditions. The Brook rearrangement is
typically observed in carbocations or in certain types of cyclic compounds where ring
expansion can occur [1-3] .

Brook Rearrangement Mechanism

The mechanism involves the formation of a cyclic pentavalent silicon species post-
deprotonation. This species undergoes ring opening, followed by rapid protonation of the
carbanion by the initial alcohol or its conjugate base, yielding the desired silyl ether [4-5].

Applications

1. Preparation of α-Hydroxy Acid Derivatives: Using CsF, α-substituted α-siloxy silanes were
carboxylated under 1 atm of CO2 via Brook rearrangement, yielding α-hydroxy acids in good
yields [6].

5
 2. 1-Siloxy-1-alkenylcopper species were generated via 1,2-Csp2-to-O silyl migration from
copper enolates of acyltriphenylsilanes. These alkenylcopper intermediates reacted with
methyl, benzyl, allylic, and tributylstannyl halides, and with aryl and alkenyl iodides in the
presence of a Pd(0) catalyst, yielding geometrically pure (Z)-enol silyl ethers [7].

3. A [1,2]-phospha-Brook rearrangement under Brønsted base catalysis efficiently

synthesizes 2,4,5-trisubstituted-3-iodofurans. This involves a formal [3 + 2] cycloaddition
of an in situ generated α-oxygenated propargyl anion to an aldehyde, followed by
intramolecular cyclization with N-iodosuccinimide. The method yields a variety of
tetrasubstituted furans [8].

4. Copper(I) tert-butoxide and allylic halides can be used to substitute the silyl group in
vinylsilanes with an allylic group. This reaction leverages a 1,3 Csp2-to-O silyl migration,
offering a valuable method to generate vinyl anion equivalents [9].

References

1. Moser, W.H., 2001. The Brook rearrangement in tandem bond formation

strategies. Tetrahedron, 57(11), pp.2065-2084.

2. Zhang, Y., Chen, J.J. and Huang, H.M., 2022. Radical Brook rearrangements: concept and
recent developments. Angewandte Chemie, 134(37), p.e202205671.

6
3. Kondoh, A. and Terada, M., 2023. [1, 2]‐Phospha‐Brook Rearrangement as Tool for
Generation of Anionic Nucleophiles in Addition Reactions under Brønsted Base
Catalysis. Asian Journal of Organic Chemistry, 12(3), p.e202300003.

4. Wilson, S.R. and Georgiadis, G.M., 1983. A homo-Brook rearrangement. The Journal of
Organic Chemistry, 48(22), pp.4143-4144.

5. Sasaki, M. and Takeda, K., 2015. Brook rearrangement. Molecular Rearrangements in

Organic Synthesis, pp.151-182.

6. Mita, T., Higuchi, Y. and Sato, Y., 2014. Carboxylation with CO2 via brook rearrangement:
preparation of α-hydroxy acid derivatives. Organic letters, 16(1), pp.14-17.

7. Tsubouchi, A., Onishi, K. and Takeda, T., 2006. Stereoselective preparation of 1-siloxy-1-
alkenylcopper species by 1, 2-Csp2-to-O silyl migration of acylsilanes. Journal of the
American Chemical Society, 128(44), pp.14268-14269.

8. Kondoh, A., Aita, K., Ishikawa, S. and Terada, M., 2020. Synthesis of tetrasubstituted furans
through one-pot formal [3+ 2] cycloaddition utilizing [1, 2]-phospha-Brook
rearrangement. Organic letters, 22(5), pp.2105-2110.

9. Tsubouchi, A., Itoh, M., Onishi, K. and Takeda, T., 2004. Copper (I) tert-Butoxide-Promoted
Allylation of β-Triphenylsilyl Allylic Alcohols via 1, 3 Csp²-to-O Silyl
Migration. Synthesis, 2004(09), pp.1504-1508.

7
 Chapter 3
Ullmann Reaction
Gurvinder Sigh1*, Charanjit Kaur1, Rajesh Kumar1
1 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab
Introduction

The Ullmann reaction (also known as Ullmann coupling) is an organic named reaction that
involves the coupling of two aryl halides in the presence of copper to yield a biaryl as the
product. Ullmann coupling reaction is named after the German chemist Fritz Ullmann [1] .

Ullmann reaction mechanism

Applications of the Ullmann Reaction

1. Synthesis of biaryls

The formation of a biaryl by the condensation of two molecules of an aryl halide in the presence
of finely divided copper is known as the Ullmann reaction [2].

2. Synthesis of diaryl amines

8
An aryl amine and aryl halide are refluxed in the presence of anhydrous potassium
carbonate and copper powder[3]

3. Synthesis of diarylether

A phenolic compound and aryl halide are refluxed in presence of potassium carbonate and
copper[4]. This reaction is further employed for the synthesis of thyroxin

4. Carbazole synthesis

Banwell and team develop the synthesis of carbazole via Pd(O)-mediated Ullmann cross-
coupling of o-halonitrobenzene and with arrange of α-halo enones followed by reductive
cyclization [5].

References

1. Wit, B., 2016. On-surface Genesis of Complex Molecular Architectures Based on Polycyclic
Aromatic Compounds. The University of Liverpool (United Kingdom).

9
2. Hassan, J., Sévignon, M., Gozzi, C., Schulz, E. and Lemaire, M., 2002. Aryl− aryl bond
formation one century after the discovery of the Ullmann reaction. Chemical
reviews, 102(5), pp.1359-1470.
3. Ruchi, R., Avidha, K. and Nidhi, S., 2017. An overview of Ullmann reaction, its importance
and applications in synthesis of dibenzopyranones. Int. J. Sci. Eng. Res, 8, pp.1479-1496.
4. Giri, R., Brusoe, A., Troshin, K., Wang, J.Y., Font, M. and Hartwig, J.F., 2018. Mechanism
of the Ullmann biaryl ether synthesis catalyzed by complexes of anionic ligands: Evidence
for the reaction of iodoarenes with ligated anionic CuI intermediates. Journal of the
American Chemical Society, 140(2), pp.793-806.
5. Preston, R.W., Tucker, S.H. and Cameron, J.M., 1942. 90. The Graebe–Ullmann synthesis
of carbazole derivatives. Preparation and synthesis of 1-nitrocarbazole. Journal of the
Chemical Society (Resumed), pp.500-504.

10
 Chapter 4
Dieckmann Reaction/Condensation
Gurvinder Sigh1*, Charanjit Kaur1, Rajesh Kumar1
1 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab
Introduction

Dieckmann condensation was reported by Dieckmann, is an intramolecular di-

ester condensation reaction, in which dicarboxylic acid with α-hydrogen is cyclized to β-
ketonic ester in the presence of base, mostly develops 5- or 6-membered cyclic β-keto esters
[1].

Dieckmann reaction mechanism [2].

Applications

1. One-Pot Synthesis of Tetronic Acids from Esters [3]

11
2. Construction of Polycyclic β-Ketoesters Using a Homoconjugate Addition/
Decarboxylative Dieckmann Annulation Strategy [4].

O O
OCH3 N(C2H5)3, MgBr2 COOC2H5
COOC2H5

COOC2H5

References

1. Wagay, S.A., Rather, I.A. and Ali, R., 2023. Unraveling the potential role of green
chemistry in carrying out typical condensation reactions of organic chemistry.
In Nanoparticles in Green Organic Synthesis (pp. 317-349). Elsevier.
2. Ho, J.Z., Mohareb, R.M., Ahn, J.H., Sim, T.B. and Rapoport, H., 2003. Enantiospecific
synthesis of carbapentostatins. The Journal of Organic Chemistry, 68(1), pp.109-114.
3. Mallinger, A., Le Gall, T. and Mioskowski, C., 2008. One-pot synthesis of tetronic acids
from esters. Synlett, 2008(03), pp.386-388.
4. Chen, Z., Hong, A.Y. and Linghu, X., 2018. Construction of polycyclic β-ketoesters
using a homoconjugate addition/decarboxylative Dieckmann annulation strategy. The
Journal of Organic Chemistry, 83(11), pp.6225-6234.

12
 Chapter 5

Doebner-Miller Reaction

Amit Mittal1*, Anuradha Mehra1

1 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab

Introduction

The Doebner-Miller reaction is the acid-catalyzed aerobic reaction between anilines and α, β-
unsaturated carbonyl compounds yielding quinolines. The reaction is named after Oscar
Döbner and Wilhelm von Miller who first described it in 1881.

R3 R7
R1 R3 H O R2 R6
Acid, [O]
R2 H + R7 R5
R6 R2 N R5
R4 NH2 R4
 -unsaturated
Substututed Anilines carbonyl compounds Subsitituted Quinoline

Doebner-Miller Reaction Mechanism

13
Applications

1. Synthesis of Methyl 6,8 bis(tert-butoxycarbonyl) amino)-2-oxo-1,2-dihydropyrrolo [4,3,2-

de]quinoline-4-carboxylate [2]

2. Synthesis of Trimethyl 5-methoxy-1H-pyrrolo[2,3-f] quinoline 2,7,9-tricarboxylate [2]

3. Synthesis of 4,9-dimethoxy-8-methyl-2-phenylthio[5,4-g]quinoline [3]

References

1. Doebner, O. and v. Miller, W., 1883. Ueber chinaldinbasen. Berichte der deutschen
chemischen Gesellschaft, 16(2), pp.2464-2472.

14
2. Yamashkin, S.A. and Oreshkina, E.A., 2006. Traditional and modern approaches to the
synthesis of quinoline systems by the Skraup and Doebner-Miller methods. Chemistry
of Heterocyclic Compounds, 42, pp.701-718.

3. Corey, E.J. and Tramontano, A., 1981. Total synthesis of the quinonoid alcohol
dehydrogenase coenzyme (1) of methylotrophic bacteria. Journal of the American
Chemical Society, 103(18), pp.5599-5600.

15
 Chapter 6

Sandmeyer Reaction
Amit Mittal1*, Anuradha Mehra1
1 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab
Introduction

The Sandmeyer reaction is an organic reaction used to convert an aryl diazonium salt to an aryl
halide using a copper(I) halide catalyst. [1,2]

Applications:

1. Synthesis of 1–(tert-butyl)-2-Phenyldisulfane [1]

2. Synthesis of Diphenyl phenylphosphonate [2]

References

1. Chen, S., Cao, S., Liu, C., Wang, B., Ren, X., Huang, H., Peng, Z. and Wang, X., 2021.
Sandmeyer-type reductive disulfuration of anilines. Organic Letters, 23(19), pp.7428-
7433.

2. Wang, S., Qiu, D., Mo, F., Zhang, Y. and Wang, J., 2016. Metal-free aromatic carbon–
phosphorus bond formation via a Sandmeyer-type reaction. The Journal of Organic
Chemistry, 81(23), pp.11603-11611

16
 Chapter 7
Mitsunobu reaction
Banoth Karan Kumar*1, Deepshika Patle1
School of Pharmaceutical sciences, Lovely Professional University, Punjab.
1. Introduction
Oyo Mitsunobu (1934–2003) was the one who made the discovery. The Mitsunobu reaction is
a widely used and versatile method for the dehydrative oxidation-reduction condensation of an
acid/pronucleophile with a primary or secondary alcohol. This process utilizes a reducing
phosphine reagent along with an oxidizing azo reagent. This reaction is highly advantageous
as it exhibits a remarkable level of selectivity when it comes to stereoisomerism. Additionally,
it usually leads to the inversion of the stereochemical configuration of the starting alcohol.
Furthermore, a diverse array of functional groups can be synthesized by employing different
compounds, including carboxylic acids, phenols, imides, sulphonamides, and others, as the
acid/pronucleophile in this reaction [1,2].
A typical process involves dissolving the triphenylphosphine, carboxylic acid, and alcohol in
tetrahydrofuran (THF) or a suitable solvent (such diethyl ether). The next step is to use an ice
bath to bring the mixture down to 0 °C. The next step is to gradually add the diethyl
azodicarboxylate (DEAD) solution to the THF, and then stir the mixture at room temperature
for many hours. This process produces esters [3]

2. Early investigations

In 1967, Professor Oyo Mitsunobu introduced his renowned reaction, which is now widely
recognized. However, this new reaction was clearly influenced by Mitsunobu. A student under
Prof. Teruaki Mukaiyama, had the opportunity to observe the synthesis of allyl phenyl ether.
This involved the reaction of phenol with allyl diethyl phosphite and DEAD. Additionally, It
was exposed to the cutting-edge research conducted by the Mukaiyama group on oxidation-
reduction condensation reactions.

17
In the original publication, named “Preparation of Esters of Carboxylic and Phosphoric Acid
via Quaternary Phosphonium Salts” the first reaction described involved the combination of n-
valeric acid with allyl diethyl phosphite and DEAD, resulting in the formation of allyl valerate
and diethyl N-(diethyl)phosphoryl hydrazo dicarboxylate [4].

These reactions involved the combination of benzoic acid and alcohols, using DEAD and TPP
as catalysts. The outcome was the successful formation of the corresponding esters (Scheme
2). with high yields[5][6].

18
 3. Reaction mechanism

A betaine is formed from TPP and DEAD. This betaine reacts with an alcohol to yield an anion
and a phosphonium. An anion is generated by proton abstraction by the anion from acid. This
anion attacks the phosphonium to give the desired inversion product.
4. Applications
This reaction is used to synthesize colchicine, quinine, morphine, sarain, eudistomin, stigma
tellin, strychnine, nupharamine, and oseltamivir [7].

19
References
1. But, T.Y.S. and Toy, P.H., 2006. Organocatalytic mitsunobu reactions. Journal of the
American Chemical Society, 128(30), pp.9636-9637.

2. But, T.Y.S. and Toy, P.H., 2007. The Mitsunobu reaction: origin, mechanism, improvements,
and applications. Chemistry–An Asian Journal, 2(11), pp.1340-1355.

3. Hirose, D., Gazvoda, M., Košmrlj, J. and Taniguchi, T., 2018. Systematic Evaluation of 2-
Arylazocarboxylates and 2-Arylazocarboxamides as Mitsunobu Reagents. The Journal of
Organic Chemistry, 83(8), pp.4712-4729.

4. Mitsunobu, O., 1981. The use of diethyl azodicarboxylate and triphenylphosphine in

synthesis and transformation of natural products. Synthesis, 1981(01), pp.1-28.

5. Mitsunobu, O. and Yamada, M., 1967. Preparation of esters of carboxylic and phosphoric
acid via quaternary phosphonium salts. Bulletin of the Chemical Society of Japan, 40(10),
pp.2380-2382.

6. Swamy, K.K., Kumar, N.B., Balaraman, E. and Kumar, K.P., 2009. Mitsunobu and related
reactions: advances and applications. Chemical reviews, 109(6), pp.2551-2651.

7. Van Veen, B.C., Wales, S.M. and Clayden, J., 2021. N-Methyl Allylic Amines from Allylic
Alcohols by Mitsunobu Substitution Using N-Boc Ethyl Oxamate. The Journal of Organic
Chemistry, 86(12), pp.8538-8543.

20
 Chapter 8
Mannich Reaction
Bhupinder Kapoor1*, Reena Gupta1
1
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
Introduction

In Mannich reaction, formaldehyde (or sometimes other aldehyde) is condensed with ammonia
(in the form of its salt e.g. hydrochloride which acts as a catalyst) and a compound containing
active hydrogen. Initially ammonia adds into formaldehyde to form methanolamine which then
undergoes nucleophilic substitution to give Mannich base.

Instead of ammonia, the reaction can be carried out with salts of primary or secondary amine
or amides; and the products obtained is substituted on the nitrogen with R, R2 or RCO-
respectively. Arylamines do not normally give this reaction [1].

Active hydrogen containing compounds may be aldehydes, ketones, acids, esters, nitriles, nitro,
phenols, picoline or acetylene.

Mannich reaction can be acid catalyzed or base catalyzed [2].

(a) Mechanism of base catalyzed reaction

21
(b) Mechanism of acid catalyzed reaction

Mannich base can further react in three different ways:

1. If it is a primary or secondary amine, it may condense with one or two additional molecules
of aldehydes and hydrogen containing active compounds e.g.

2. If the active hydrogen containing compound has two or three active hydrogens, the Mannich
base may condense with or mor two additional molecules of aldehydes and ammonia.

22
3. Mannich base can even condense with excess of formaldehyde

Examples of other active hydrogen containing compounds are:

23
Applications

Mannich base can be used as an intermediate in many synthetic reactions:

1. Synthesis of α,β-unsaturated carbonyl compounds [3].

These compounds can be generated from carbonyl compounds either by heating or

hydrogenation of Mannich base.

O
in g R NH2 +
O heat R
R , -unsaturated
N R carbonyl compound
H H2 ,
Ni O
R NH2 +
R

dehydrogenation

R
, -unsaturated
carbonyl compound

Elimination reaction undergoes readily because a double bond is generated in conjugation with
second double bond.

2. Synthesis of higher analogues of α,β-unsaturated ketones [4].

3. Synthesis of heteroauxin and tryptophan [5].

Mannich reaction can also be employed in the synthesis of gramine, starting from indole, which
is further used in the synthesis of heteroauxin and tryptophan.

24
(a) Synthesis of heteroauxin

(b) Synthesis of tryptophan

4. Synthesis of alkaloids [6].

The use of aldehydes rather than formaldehyde can lead to the formation of alkaloids e.g. a
mixture of succinaldehyde, methylamine and acetone will lead to the formation of tropinone
which is further used in synthesizing alkaloids.

25
References

1. Thompson, B.B., 1968. The Mannich reaction. Mechanistic and technological

considerations. Journal of pharmaceutical sciences, 57(5), pp.715-733.

2. Nobles, W.L. and Potti, N.D., 1968. Studies on the Mechanism of the Mannich
Reaction. Journal of Pharmaceutical Sciences, 57(7), pp.1097-1103.

3. Zhang, S., Neumann, H. and Beller, M., 2020. Synthesis of α, β-unsaturated carbonyl
compounds by carbonylation reactions. Chemical Society Reviews, 49(10), pp.3187-3210.

4. Pu, M.X., Guo, H.Y., Quan, Z.S., Li, X. and Shen, Q.K., 2023. Application of the Mannich
reaction in the structural modification of natural products. Journal of Enzyme Inhibition and
Medicinal Chemistry, 38(1), p.2235095.

5. Snyder, H.R. and Smith, C.W., 1944. A convenient synthesis of dl-tryptophan. Journal of the
American Chemical Society, 66(3), pp.350-351.

6. van Rootselaar, S., Peterse, E., Blanco‐Ania, D. and Rutjes, F.P., 2023. Stereoselective
Mannich reactions in the synthesis of enantiopure piperidine alkaloids and
derivatives. European Journal of Organic Chemistry, 26(22), p.e202300053.

26
 Chapter 9
VILSMEIER HAACK REACTION
Mukta Gupta*
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab
Introduction

The Vilsmeier Haack reaction, also known as Vilsmeier reaction represents a typical example
of classical electrophilic aromatic substitution reaction involving formylation of electron rich
arenes or heteroarenes with the help of Vilsmeier reagent (Phosphorous oxychloride and DMF)
to produce corresponding iminium species along with aromatic aldehyde/ketone [1-3].

Reaction Mechanism

Applications

1. Haack reaction of carbonyl compounds: Reaction of carbonyl compounds having two

adjacent ionizable carbons with Vilsmeier reagent affords pyrones, whereas if intermediate
iminium ion is further treated with ammonium acetate, it results in synthesis of pyridine
[1].

2. Synthesis of 2-formylimidazole derivatives: The reaction involves quenching of N-

(Benzoyloxy) imidazole with electrophilic species and DMF to yield formyl imidazole.

27
 3. Synthesis of diformylbenzodipyrrole compounds: Vilsmeier reaction has been
successively employed in synthesis of diformylbenzodipyrrole by formylation of
benzodipyrrole [4].

4. Annulation of pentacyclic steroidal pyrimidines: Two step reaction is involved to

couple steroidal nucleus with pyridine from anticipated ketone [5].

5. Synthesis of chromone nucleus: Vilsmeier reagent is used to the efficient synthesis of

different types of flavonoids with excellent yield in short time duration [6].

References

1. Thomas, A.D. and Asokan, C.V., 2004. Vilsmeier–Haack reactions of carbonyl compounds:
synthesis of substituted pyrones and pyridines. Tetrahedron, 60(23), pp.5069-5076.
2. Kumar, R.N., Suresh, T. and Mohan, P.S., 2003. Vilsmeier-Haack reaction on quinaldines.
3. Alunni, S., Linda, P., Marino, G., Santini, S. and Savelli, G., 1972. The mechanism of the
Vilsmeier–Haack reaction. Part II. A kinetic study of the formylation of thiophen derivatives

28
 with dimethylformamide and phosphorus oxychloride or carbonyl chloride in 1, 2-
dichloroethane. Journal of the Chemical Society, Perkin Transactions 2, (14), pp.2070-
2073.
4. Graham, A. & Robinson, M. 2008. Tricyclic Systems: Central Carbocyclic Ring with Fused
Five-membered Rings. In: Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V. & Taylor, R.
J. K. (eds.) Comprehensive Heterocyclic Chemistry III. Oxford: Elsevier.
5. Monier, M., El-Mekabaty, A., Abdel-Latif, D., Doğru Mert, B. & Elattar, K. M. 2020.
Heterocyclic steroids: Efficient routes for annulation of pentacyclic steroidal pyrimidines.
Steroids, 154, 108548.
6. Yadav, S. K. 2014. Process for the preparation of chromones, isoflavones and
homoisoflavones using Vilsmeier reagent generated from phthaloyl dichloride and DMF.
International Journal of Organic Chemistry, 4, 236.

29
 Chapter 10
SHARPLESS ASYMMETRICAL EPOXIDATION
Mukta Gupta*
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab
Introduction

The Sharpless epoxidation is an asymmetrical method of producing enatio-enriched epoxide

i.e. stereoselective isomer from a allylic alcohol by controlling facial selectivity of the reaction.
The reaction was discovered by Karl Barry Sharpless and converts 10 and 20 alcohols to 2,3
epoxy alcohol, however the selectivity depends upon type of catalyst [1-3].

Reaction Mechanism

30
Applications

1. Synthesis of natural products: Sharpless epoxidation has been successfully employed

in synthesis of various natural products including alkaloids such as muscarinic, tropane,
indole, sesquiterpenes and polyketide. The preparation of venustatriol is represented
below [4,5].

2. Synthesis of carbohydrates: Racemic diols can be converted erythro epoxide and E-diol
which upon chromatographic separation yields carbohydrates [6].
OH OH
OH O
+
(+) (-)
Racemate

HO
HO OH H3O+
H3O+ HO
O3
HO O3 O
O O O HO O
Me2S
OH Me2S O
OH
(+)-D-Olivose
(+)-D-Digitoxose

3. Preparation of flavoring agent: The quality and intensity of odorants is generally

influenced by their stereochemistry. Sharpless asymmetrical epoxidation, one of the
most common enatioselective epoxidation reaction is also involved in preparation of
different flavoring agents which are in food and drug industries. The preparation of
optically active 3-methylthio hexanal using allyl alcohol is an example in this case [7].

31
 OH
Sharpless AE O O
OH + OH

Multiple steps
CH3SK
Swern Oxidation

SCH3O
SCH3O
H
H
3-Methythiohexanal

References

1. Ager, D. 2012. 9.6 Industrial Applications of Asymmetric Oxidations. In: Carreira, E. M. &
Yamamoto, H. (eds.) Comprehensive Chirality. Amsterdam: Elsevier.
2. Mdluli, V. & Lehnherr, D. 2024. 9.10 - Industrial Applications of Asymmetric Oxidations.
In: Cossy, J. (ed.) Comprehensive Chirality (Second Edition). Oxford: Academic Press
3. Paralkar, P. S., Shinkar, D. M. & Saudagar, R. B. 2016. Sharpless Asymmetrical Epoxidation:
An Overview. Asian Journal of Research in Chemistry, 9, 281-289.
4. Mushtaq, A., Zahoor, A. F., Bilal, M., Hussain, S. M., Irfan, M., Akhtar, R., Irfan, A.,
Kotwica-Mojzych, K. & Mojzych, M. 2023. Sharpless Asymmetric Dihydroxylation: An
Impressive Gadget for the Synthesis of Natural Products: A Review. Molecules, 28, 2722.
5. Corey, E. J. & HA, D. C. 1988. Total synthesis of venustatriol. Tetrahedron Letters, 29, 3171-
3174.
6. Vogel, P. & Robina, I. 2007. 1.13-Synthesis of Monosaccharides and Analogs. In:
Kamerling, H. (ed.) Comprehensive Glycoscience. Oxford: Elsevier.

7. Tian, H. Y., Sun, B. G., Tang, L. W. & YE, H. L. 2011. Application of Sharpless asymmetric
epoxidation on the preparation of the optically active flavours 3‐methylthiohexanal and 5
(6)‐butyl‐1, 4‐dioxan‐2‐one. Flavour and fragrance journal, 26, 65-69.

32
 Chapter 11
Baeyer Villiger Oxidation
Bhupinder Kapoor1*, Reena Gupta1
1
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
Introduction

Oxidative cleavage of carbon-carbon bond adjacent to a carbonyl group in the presence of acid
catalysts, that leads to the formation of esters or lactones from ketones and cyclic ketones
respectively is called Baeyer-Villiger Oxidation. The reaction can be accomplished using
hydrogen peroxide or various peracids such as peroxybenzoic acid, peroxyacetic acid, 3-
chloroperoxybenzoic acid (m-chloroperoxybenzoic acid), peroxytrifluoroacetic acid or other
peroxy compounds [1].

The most preferable peracid is peroxy-trifluoroacetic acid, due to high yields. However, it is
often necessary to add a buffer, such as disodium phosphate, to prevent transesterification of
the product with trifluoroacetic acid that is also formed during the reaction.

Reaction Mechanism

Applications

The Baeyer–Villiger oxidation reaction is useful for the following studies:

33
1. Synthesis of lactones from mesomeric cyclohexanones [2].

OH R
OH
R S
HO S R
O O
S
O O
O
3S, 4S, 5R 3R, 4R, 5S

2. Synthesis of 3-hydroxyindole-2-carboxylates [3].

3. Synthesis of dibenzo-18-crown-6, dibenzo-21-crown-7, and dihydroxydibenzo-18-crown-

64

4. One-pot chemoenzymatic synthesis of -butyrolactones5

References

1. Yaremenko, I.A., Vil, V.A., Demchuk, D.V. and Terent’ev, A.O., 2016. Rearrangements of
organic peroxides and related processes. Beilstein journal of organic chemistry, 12(1),
pp.1647-1748.

34
2. Taschner, M.J. and Black, D.J., 1988. The enzymatic Baeyer-Villiger oxidation:
enantioselective synthesis of lactones from mesomeric cyclohexanones. Journal of the
American Chemical Society, 110(20), pp.6892-6893.

3. Hickman, Z.L., Sturino, C.F. and Lachance, N., 2000. A concise synthesis of 3-
hydroxyindole-2-carboxylates by a modified Baeyer–Villiger oxidation. Tetrahedron
Letters, 41(43), pp.8217-8220.

4. Utekar, D.R. and Saman, S.D., 2014. Application of Bayer-Villiger Reaction to the Synthesis
of Dibenzo-18-crown-6, Dibenzo-21-crown-7 and Dihydroxydibenzo-18-crown-

6. 대한화학회지, 58(2), pp.193-197.

5. González-Martínez, D., Rodríguez-Mata, M., Méndez-Sánchez, D., Gotor, V. and Gotor-

Fernández, V., 2015. Lactonization reactions through hydrolase-catalyzed peracid formation.
Use of lipases for chemoenzymatic Baeyer–Villiger oxidations of cyclobutanones. Journal of
Molecular Catalysis B: Enzymatic, 114, pp.31-36.

35
 Chapter 12
Shapiro reaction
Deepshikha Patle1*, Banoth Karan Kumar1
1
School of Pharmaceutical sciences, Lovely Professional University, Punjab.
Introduction

This Reaction is a modification of the BSR (Bamford Stevens Reaction) which involve addition
of a base tosyl hydrazones to produce alkenes. Shapiro reaction required two equivalents of an
organo-lithium molecules. It is also defines as synthesis of alkenes via organolithium mediated
decomposition of aryl sulfonyl hydrazones of aldehydes and ketones [1,2]. This reactions is
convenient, economic and simple approach for converting arene sulfonyl hydrazone of ketones
to different olefinic molecules with the formation of vinyl lithium intermediate. This reaction
required high amount of base >3 equi. to achieve better conversion into the final product i.e.
alkenyl lithium derivatives; a modified sulfonyl hydrazone releasing group such as 2,4,6-
triisopropylbenzenesulfonyl (Trisyl) is further added to minimize the amount of alkyl lithium
reagents used in the reactions [3,4].

Formation of Tosyl Hydrazone:

Reaction mechanism: Deprotonation of Tosyl hydrazone with a strong base to form

Hydrazone aza enolate. Elimination of aryl sulfinate gives an unstable anion. Loss of Nitrogen
leads to vinyl anion.[5]

36
Applications
The Shapiro reaction provides convenient method for preparing numerous olefinic compounds
from ketones and aldehydes via sulfonyl hydrazones. [6]
1. It is used to produce olefins and determine the absolute configuration of Phytoalexins a class
of natural products in phytocassane group. The end product generated is (-) Phytocassane D,
from (R) Wieland Miescher ketone. (-) Phytocassane is a tricyclic ketone utilised in shapiro
reaction to yield the cyclic alkene product.[7]

2. Acetal-protected ketone reacted with tosyl hydrazide to yield tosyl hydrazone intermediate
which is further involved in reaction with n-BuLi in the presence of TMEDA, to produce cyclic
alkene with 82% yield [8].

3. Allylic alcohols can also be produced by Subsequent treatment of hydrazones with n-

butyllithium in the presence of acrolein in 82 to 97% yields.[9]

37
References:

1. Uyanik, M. and Ishihara, K., 2014. Functional Group Transformations via Carbonyl
Derivatives. Compr Org Synth Second Ed. 2014;6:573-597.

2. Li, J.J. and Li, J.J., 2014. Shapiro reaction. Name Reactions: A Collection of Detailed
Mechanisms and Synthetic Applications Fifth Edition, pp.544-545.

3. Shapiro, R.H., Lipton, M.F., Kolonko, K.J., Buswell, R.L. and Capuano, L.A., 1975.
Tosylhydrazones and alkyllithium reagents: More on the regiospecificity of the reaction
and the trapping of three intermediates. Tetrahedron Letters, 16(22-23), pp.1811-1814.

4. Adlington, R.M. and Barrett, A.G., 1983. Recent applications of the Shapiro
reaction. Accounts of Chemical Research, 16(2), pp.55-59.

5. Funes-Ardoiz, I., Losantos, R. and Sampedro, D., 2015. On the mechanism of the
Shapiro reaction: understanding the regioselectivity. RSC Advances, 5(47), pp.37292-
37297.

6. Salamon-Krokosz, K., Koroniak, H. and Koroniak-Szejn, K., 2023. Shapiro and

Bamford-Stevens reactions–revisited. Arkivoc, (part v), pp.0-0.

7. Sharma, P.C., Sharma, D., Sharma, A., Saini, N., Goyal, R., Ola, M., Chawla, R. and
Thakur, V.K., 2020. Hydrazone comprising compounds as promising anti-infective
agents: Chemistry and structure-property relationship. Materials Today Chemistry, 18,
p.100349.

8. Deimling, M., Zens, A., Park, N., Hess, C., Klenk, S., Dilruba, Z., Baro, A. and Laschat,
S., 2021. Adventures and Detours in the Synthesis of Hydropentalenes. Synlett, 32(02),
pp.119-139.

9. Teramoto, H., Yamauchi, T., Sasaki, S. and Higashiyama, K., 2016. Development of κ
opioid receptor agonists by focusing on phenyl substituents of 4-dimethylamino-3-
phenylpiperidine derivatives: Structure–activity relationship study of matrine type
alkaloids. Chemical and Pharmaceutical Bulletin, 64(5), pp.420-431.

38
 Chapter 13
The Suzuki coupling
Rekha Sangwan*
School of Pharmaceutical sciences, Lovely Professional University, Punjab.
Introduction

The Suzuki coupling is an organic named reaction first reported by Akira Suzuki in 1979 that
couples an aryl, benzyl, or vinyl halide with an organoborane in a basic solution. The reaction
basically use a palladium complex catalyst for coupling [1].

Suzuki Reaction Mechanism

39
Applications

1. Synthesis of caparratriene

The Suzuki coupling has been applied on a citronellal derivative for the synthesis of
caparratriene, a natural product that is active against leukemia [2].

2. Synthesis of cyclic compound

An acrylaldehyde and aryl boronic are refluxed in the presence of anhydrous cesium
carbonate and palladium catalyst [3].

3. Synthesis of aza heterocyclic compounds

The β-brominated dehydroamino acid were reacted with 2-aminophenyl pinacolboronate and
resulted with heterocyclic compound tandem one-pot Suzuki cross-coupling and followed by
lactamization [4].

40
References

1. Takale, B.S., Kong, F.Y. and Thakore, R.R., 2022. Recent Applications of Pd-Catalyzed
Suzuki–Miyaura and Buchwald–Hartwig Couplings in Pharmaceutical Process
Chemistry. Organics, 3(1), pp.1-21.
2. Vyvyan, J.R., Peterson, E.A. and Stephan, M.L., 1999. An expedient total synthesis of
(±)-caparratriene. Tetrahedron letters, 40(27), pp.4947-4949.
3. Paul, S., Gorai, T., Koley, A. and Ray, J.K., 2011. A simple route to 9-fluorenylidenes
by domino Suzuki/Heck coupling reactions. Tetrahedron letters, 52(31), pp.4051-4055.
4. Queiroz, M.J.R., Abreu, A.S., Calhelha, R.C., Carvalho, M.S.D. and Ferreira, P.M.,
2008. New strategies for the synthesis of heteroannulated 2-pyridinones, substituted 2-
quinolinones and coumarins from dehydroamino acid derivatives. Tetrahedron, 64(22),
pp.5139-5146.

41
 Chapter 14
Debus-Radziszewski imidazole synthesis
Rekha Sangwan*
School of Pharmaceutical sciences, Lovely Professional University, Punjab.
Introduction
The Debus–Radziszewski imidazole synthesis is an examle of multi-component reaction. It
used for the synthesis of imidazoles from a 1,2-dicarbonyl, an aldehyde, and ammonia or a
primary amine [1].
Stage I: The dicarbonyl and ammonia condense to give a diimine

Stage II: Then the diimine condenses with the aldehyde and gives imidazole

Debus–Radziszewski imidazole Reaction Mechanism

Applications

1. One pot synthesis of polyimidazolium polymers

Imidazolium-type polymers can be easily synthesized from Debus–Radziszewski reactions of

pyruvaldehyde, formaldehyde, and diamines in aqueous acetic acid solution [2].

42
2. Synthesis of siloxane-based main-chain poly ionic liquid

Glyoxal and formaldehyde were used as carbonyl compounds forming a polymer backbone
containing 1,3-disubstituted imidazolium moieties separated by dimethylsiloxane oligomer
spacers [3].

3. Synthesis of phenanthro [9,10-d]imidazole derivatives

Phenanthro[9,10-d]imidazole derivatives can be synthesized which showed

electroluminescence response and emission of light [4].

43
References

1. A Hernandez Munoz, J., J Junior, J. and Martins da Silva, F., 2014. Radziszewski reaction:
an elegant, easy, simple and efficient method to synthesise imidazoles. Current Organic
Synthesis, 11(6), pp.824-834.

2. Grygiel, K., Kirchhecker, S., Gong, J., Antonietti, M., Esposito, D. and Yuan, J., 2017. Main‐
chain polyimidazolium polymers by one‐pot synthesis and application as nitrogen‐doped
carbon precursors. Macromolecular Chemistry and Physics, 218(18), p.1600586.

3. Reiter, M., Khorsand Kheirabad, A., Unterlass, M.M. and Yuan, J., 2021. Siloxane-Based
Main-Chain Poly (ionic liquid) s via a Debus–Radziszewski Reaction. ACS Polymers Au, 2(2),
pp.80-87.

4. Kula, S., Szlapa-Kula, A., Kotowicz, S., Filapek, M., Bujak, K., Siwy, M., Janeczek, H.,
Maćkowski, S. and Schab-Balcerzak, E., 2018. Phenanthro [9, 10-d] imidazole with thiophene
rings toward OLEDs application. Dyes and Pigments, 159, pp.646-654.

44
 Chapter 15
Knorr pyrazole synthesis
Charanjit Kaur1*, Gurvinder Singh1
1
School of Pharmaceutical sciences, Lovely Professional University, Punjab.
Introduction

The Knorr pyrazole synthesis is used to synthesise pyrazole derivatives by reacting hydrazine
or its derivatives with a 1,3-dicarbonyl compound in the presence of an acid catalyst. The
carbonyl group attacked determine the type of pyrazole derivative [1].

R1 R1
O O N N
H Cat. acid N N
N and/or
R1 NH2 R2 R4 R2 R4 R4 R2
R3 R3
R3

Reaction Mechanism

H
H O
H H
H2O H O
O O O
O O H O R4 H O R4
R2 R4 R2 R2
R2 R4 R1HN NH2 R3 R1HN NH R3
R3
R3
H
N
R1 NH2

H2O

R1 H R2 O
N N H R1 H R2 O
H
O N N OH N R4
R2 H N R4
R4 R4 N R3
R3 R2 N R3 H R1
H R1
R3

H2O

H3O R1
R1
N N
N N
R2 R4
R2 R4
R3 H R3

45
Applications

1. Synthesis of metamizole [2]

2. Synthesis of antipyrine [2]

O
O O
ether, 2hrs N
NH2 N
O N DMSO/NaOH
H
ethyl acetoacetate
Phenyl hydrazine Antipyrine

46
3. Synthesis of celecoxib [3]

O O
O Reflux H2NO2S
NaOCH3 CF3
CF3COOC2H5 NH2
-C2H5OH N
H
ethyl 4-hydrazineylbenzenesulfonamide
4-Methylaceophenone trifluoroacetate

Reflux
C2H5OH

H2NO2S

N N
CF3

Celecoxib

References

1. Li, J.J., 2006. Knorr pyrazole synthesis. Name Reactions: A Collection of Detailed Reaction
Mechanisms, pp.331-334.

2. Vardanyan, R. and Hruby, V., 2006. Synthesis of essential drugs. Elsevier.

3. Dadiboyena, S. and T Hamme II, A., 2012. Synthesis of celecoxib and structural analogs-a
review. Current Organic Chemistry, 16(11), pp.1390-1407.

47
 Chapter 16
Pinner pyrimidine synthesis
Charanjit Kaur*, Gurvinder Singh
School of Pharmaceutical sciences, Lovely Professional University, Punjab.
Introduction

This reaction is used to synthesise pyrimidine or its derivatives by condensing amidines with
1,3-dicarbonyl derivatives in acidic or basic pH [1].

O O NH K2CO3/H2O
. HCl N N
rt
NH2
pentane-2,4-dione acetimidamide
2,4,6-trimethylpyrimidine
hydrogen chloride

Reaction Mechanism

Applications

1. Synthesis of sulphamerazine [2]

2. Synthesis of trimethoprim [2]

48
References

1. Li, J.J. ed., 2004. Name reactions in heterocyclic chemistry. John Wiley & Sons.

2. Vardanyan, R. and Hruby, V., 2006. Synthesis of essential drugs. Elsevier.

49
 Chapter 17
BERNTHSEN ACRIDINE REACTION
Salvi Sood1, Gurdeep Singh1*, Ritesh Patel2, Mukesh Kr. Singh3
1
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab-144411
2
Indore Institute of Pharmacy, Indore, Madhya Pradesh-453331
3
School of Pharmaceutical Sciences, IFTM University, Moradabad, Uttar Pradesh-244102
Introduction

The Bernthsen reaction is reported by Bernthsen in 1884 for the synthesis of 9-substiuted
acridine by condensing diphenylamine with organic acids or anhydrides using anhydrous zinc
chloride at high temperature. [1] .

Bernthsen Acridine Reaction Mechanism

Applications

1. Synthesis of m-amsacrine (Anticancer)

In the synthesis of m-amsacrine, 4-nitro-m-aniside undergo sufonation with methanesulfonyl

chloride resulting for the formation of a sulfonyl amide which in the presence of with Fe and

50
HCl hydrogenated to form N-(4-amino-3-methoxyphenyl) methane sulfonamide. After that
treatment with 9-chloroacridine yielded m-amsacrine [2].

2. Synthesis of Tacrine (Alzheimer disease)

2-bromoaromatic aldehydes/ketones with sodium azide and acetyl acetone afforded the desired
product 3-acetyl-2- methylquinoline in 50% in the presence of inexpensive CuSO4-Dglucose
catalyst systems in green water-ethanol solvent. [3]

3. Synthesis of Proflavin (Anticancer)

The amino group in substituted acridine in the presence of thiophosgene was changed into an
isothiocyanate group, which was subsequently treated with a 1° amine to create the
intermediate.. Methyl 2-bromoacetate was applied to the molecule to produce thiazolidinone-
based acridine [4].

51
 3. Acriflavin synthesis (Anticancer)

Imidazolidinone proflavine's structural framework was ultimately generated via

cyclization with ethyl glycinate after desulfonation with HgO [5].

References

1. Das, S. and Thakur, A.J., 2011. A green development of Bernthsen 9-substituted acridine
synthesis in the absence of solvent catalyzed by p-toluenesulphonic acid (p-TSA). Green
Chemistry Letters and Reviews, 4(2), pp.131-135.
2. Vardanyan, R. and Hruby, V., 2006. Synthesis of essential drugs. Elsevier.
3. Anand, N., Chanda, T., Koley, S., Chowdhury, S. and Singh, M.S., 2015. CuSO 4–d-glucose,
an inexpensive and eco-efficient catalytic system: direct access to diverse quinolines
through modified Friedländer approach involving SN Ar/reduction/annulation cascade in
one pot. RSC Advances, 5(10), pp.7654-7660.

52
4. Liu, L.F., 1989. DNA topoisomerase poisons as antitumor drugs. Annual review of
biochemistry, 58(1), pp.351-375.
5. Janovec, L., Kožurková, M., Sabolová, D., Ungvarský, J., Paulíková, H., Plšíková, J.,
Vantová, Z. and Imrich, J., 2011. Cytotoxic 3, 6-bis ((imidazolidinone) imino) acridines:
synthesis, DNA binding and molecular modeling. Bioorganic & medicinal chemistry, 19(5),
pp.1790-1801.

53
 Chapter 18
COMBES QUINOLINE SYNTHESIS
Riya Anand1, Gurdeep Singh1*, Ritesh Patel2, Mukesh Kr. Singh3
1
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab-144411
2
Indore Institute of Pharmacy, Indore, Madhya Pradesh-453331
3
School of Pharmaceutical Sciences, IFTM University, Moradabad, Uttar Pradesh-244102

Introduction

Combes quinoline synthesis was initially described by Combes in 1888. Quinolés are created
via condensation of primary aromatic amines with acetoacetone or other β-diketones, then
cyclization in sulfuric acid-containing environments [1].

Combes quinoline Reaction Mechanism [2].

Applications [3]

1. Important drugs containing quinoline scaffold

54
2. Antimalarial Agents

Various quinoline derivatives as new antimalarial agents has been synthesised by this method
using aniline and ethylacetoacetate to produce 3-methyl-4-hydroxy quinoline [4].

3. Agrochemicals
Some quinoline derivatives act as fungicides, protecting crops from fungal diseases [5].

55
 3. Materials Science
Quinolines can find use in dyes and as flavoring agents.

References

1. Alyamkina, E.A., Yamashkin, S.A., Artayeva, N.N. and Yurovskaya, M.A., 2010. Using of
4-amino-2-phenylindoles in the synthesis of pyrroloquinolines by the combes
reaction. Moscow University Chemistry Bulletin, 65, pp.335-340.
2. Jiang, B. and Si, Y.G., 2002. Zn (II)-mediated alkynylation− cyclization of o-trifluoroacetyl
anilines: one-pot synthesis of 4-trifluoromethyl-substituted quinoline derivatives. The
Journal of Organic Chemistry, 67(26), pp.9449-9451.
3. Yadav, P. and Shah, K., 2021. Quinolines, a perpetual, multipurpose scaffold in medicinal
chemistry. Bioorganic Chemistry, 109, p.104639.
4. Price, C.C. and Roberts, R.M., 1946. The synthesis of 4-hydroxyquinolines. 1 I. Through
ethoxymethylenemalonic ester. Journal of the American Chemical Society, 68(7), pp.1204-
1208.
5. Liu, X.H., Fang, Y.M., Xie, F., Zhang, R.R., Shen, Z.H., Tan, C.X., Weng, J.Q., Xu, T.M.
and Huang, H.Y., 2017. Synthesis and in vivo fungicidal activity of some new quinoline
derivatives against rice blast. Pest management science, 73(9), pp.1900-1907.

56
 Chapter 19
Smiles Rearrangement
Anuradha Mehra1*, Amit Mittal1
1
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab
Introduction

The Smiles rearrangement is a fundamental organic reaction through which, an aromatic ring
can transfer a leaving group intramolecularly by an anionic nucleophile. It is known as Smiles
rearrangement, which was first reported by Samuel Smiles in 1930. It is an intramolecular
nucleophilic aromatic substitution reaction in which a nucleophile within a molecule displaces
a leaving group on an aromatic ring, typically facilitated by an ortho or para electron-
withdrawing group relative to the leaving group, resulting in the formation of a new aromatic
product [1].

The substituent X in the Smiles rearrangement is either a sulfone, sulfide, ether or another
group which can leave the aromatic ring as negatively charged species. The functional group
Y at the chain end acts as an excellent nucleophile e.g. alcohol, amine or thiol. For example,
when referencing groups such as SO2NH2, SH, SO2NHR, NHR, OH, OR and NH2 nucleophile
Y is usually represented by conjugate base in Smiles rearrangement process [2].

There is evidence that having a moderate electron-withdrawing group on the aromatic ring at
the ortho position, like chloro or alkoxide, can increase the speed of Smiles rearrangement. On
the other hand, steric hindrance from an attachment in a precise location in an aromatic nucleus
may also promote such a reorganization. Furthermore, several studies have demonstrated that
solvents including THF affect and improve reaction rates. Different ethers and modified
reaction conditions have been extensively used to alter Smiles rearrangements [3].

57
Smiles Rearrangement Reaction Mechanism

X = O, Y = N

After losing a proton, the terminal amine group becomes a nucleophile and attacks a carbon on
the aromatic ring, leading to the detachment of the ether oxygen from the ring [4].

Applications

1. Synthesis of Indole Derivatives [5]

2. Synthesis of Coumarin derivatives [6]

3. Synthesis of trifluoromethylated oxadiazole derivatives [7]

58
References.

1. Hu, Y., Hervieu, C., Merino, E. and Nevado, C., 2024. Asymmetric, Remote C (sp3)−
H Arylation via Sulfinyl‐Smiles Rearrangement. Angewandte Chemie International
Edition, 63(17), p.e202319158.
2. Shen, D., Li, L., Ren, T., Chen, K., Zhang, X., Zhang, H., Zhang, S., Gong, P., Zhang,
F. and Chao, M., 2024. Radical-Smiles Rearrangement by a Vitamin B2-Derived
Photocatalyst in Water. The Journal of Organic Chemistry.
3. Shen, D., Li, L., Ren, T., Chen, K., Zhang, X., Zhang, H., Zhang, S., Gong, P., Zhang,
F. and Chao, M., 2024. Radical-Smiles Rearrangement by a Vitamin B2-Derived
Photocatalyst in Water. The Journal of Organic Chemistry.
4. Abrams, R., Jesani, M.H., Browning, A. and Clayden, J., 2021. Triarylmethanes and
their Medium‐Ring Analogues by Unactivated Truce–Smiles Rearrangement of
Benzanilides. Angewandte Chemie, 133(20), pp.11372-11377.
5. Yasui, K., Kamitani, M., Fujimoto, H. and Tobisu, M., 2021. N-Heterocyclic carbene-
catalyzed truce–smiles rearrangement of N-arylacrylamides via the cleavage of
unactivated C (aryl)–N bonds. Organic Letters, 23(5), pp.1572-1576.
6. Hu, Y., Wang, Z., Luo, H., Jin, H., Liu, Y. and Zhou, B., 2021. NHC-catalyzed Truce–
Smiles rearrangement of N-aryl methacrylamides for the synthesis of trans-cinnamides.
Organic & Biomolecular Chemistry, 19(17), pp.3834-3837.
7. Zhou, L., Liu, X., Lu, H., Deng, G., Liang, Y., Yang, Y. and Li, J.H., 2021. Copper-
catalyzed [3+ 2]/[3+ 2] carboannulation of dienynes and arylsulfonyl chlorides enabled
by Smiles rearrangement: access to cyclopenta [a] indene-fused quinolinones. Organic
Chemistry Frontiers, 8(18), pp.5092-5097.

59
 Chapter 20
Traube purine synthesis
Anuradha Mehra1*, Amit Mittal1
1
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab

Introduction

Traube purine synthesis is a chemical reaction used to synthesize purine derivatives, starting
from pyrimidine derivatives [1]. Named after Wilhelm Traube, who developed the method in
the early 20th century, this synthesis is a crucial route to constructing the purine ring system,
which is foundational to various biomolecules, including DNA and RNA [2]. It is a method for
synthesizing purine derivatives by reacting 4,5-diaminopyrimidines with formic acid or
formamide, resulting in the formation of the fused bicyclic purine ring system [3, 4].

Reaction Mechanism

60
Applications

1. Synthesis of Mercaptopurine (Anticancer Agent) [5]

2. Synthesis of Theophylline (used to treat asthma, bronchitis, emphysema) [6]

3. Synthesis of Thioguanine (to treat leukemia) [6]

61
 4. Synthesis of Acyclovir (Antiviral Agent) [7]

5. Synthesis of Azathioprine (Immunosuppressant) [8]

References.

1. Villegas, A., Satheeshkumar, R., Ballesteros‐Casallas, A., Paulino, M., Castro, A.,
Espinosa‐Bustos, C. and Salas, C.O., 2022. Convergent synthesis, drug target
prediction, and docking studies of new 2, 6, 9‐trisubstituted purine derivatives. Journal
of Heterocyclic Chemistry, 59(1), pp.97-111.
2. Goldman, L., Marsico, J. and Gazzola, A., 1956. Communications-A New Synthesis of
Purines. The Journal of Organic Chemistry, 21(5), pp.599-600.
3. Neymash, A.O., Ulomsky, E.N., Fedotov, V.V., Aminov, S.V., Lyapustin, D.N.,
Gorbunov, E.B., Ishimnikov, V.A., Slepukhin, P.A. and Rusinov, V.L., 2023.
Reconstructive Methodology in the Synthesis of 2-Aminopurine. Molecules, 29(1),
pp.134.
4. Zelli, R., Zeinyeh, W., Haudecoeur, R., Alliot, J., Boucherle, B., Callebaut, I. and
Décout, J.L., 2017. A one-pot synthesis of highly functionalized purines. Organic
letters, 19(23), pp.6360-6363.

62
5. Richter, E., Loeffler, J.E. and Taylor, E.C., 1960. Studies in Purine Chemistry. VIII. A
Convenient Synthesis of Hypoxanthines and Adenines1, 2. Journal of the American
Chemical Society, 82(12), pp.3144-3146.
6. Legraverend, M., 2008. Recent advances in the synthesis of purine derivatives and their
precursors. Tetrahedron, 64(37), pp.8585-8603.
7. Benkirane, S., Misbahi, H., Boudkhili, M., Rodi, Y.K., Sebbar, N.K. and Essassi, E.M.,
2023. Synthetic Routes and Pharmacological Activities of Purine Derivatives: A
Review. Current Organic Chemistry, 27(19), pp.1683-1696.
8. Debnath, P., 2023. Recent developments towards the synthesis of pyrimidopyrimidine
and purine derivatives. ChemistrySelect, 8(26), pp.e202300998.

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