Cover Page



Half Title page

Title page

Copyright page



Contributing Authors

Chapter 1: Introduction

1.1 Nomenclature of Heterocycles

1.2 Aromaticity of Heterocycles

1.3 Importance of Heterocycles in Life

1.4 Importance of Heterocycles in Drug Discovery

Part I: Five-Membered Heterocycles with one Heteroatom

Chapter 2: Pyrroles

2.1 Introduction

2.2 Reactivity of the Pyrrole Ring

2.3 Construction of the Pyrrole Ring

2.4 Palladium Chemistry of Pyrroles

2.5 Possible Liabilities of Pyrrole-Containing Drugs

2.6 Problems

2.7 References

Chapter 3: Indoles, Oxindoles, and Azaindoles

3.1 Introduction

3.2 Reactivity of the Indole Ring

3.3 Construction of Indole Rings

3.4 Oxindole-containing Drug Synthesis

3.5 Cross-coupling Reactions for Indoles

3.6 Azaindoles

3.7 Possible Liabilities of Drugs Containing 3-Methylindole

3.8 Problems

3.9 References

Chapter 4: Furans, Benzofurans, Thiophenes, and Benzothiophenes

4.1 Introduction

4.2 Furans and Benzofuran

4.3 Thiophenes and Benzothiophenes

4.4 Possible Liabilities of Furan- and Thiophene-Containing Drugs

4.5 Problems

4.6 References

Part II: Five-Membered Heterocycles with two Heteroatoms

Chapter 5: Pyrazoles, Pyrazolones, and Indazoles

5.1 Introduction

5.2 Reactivities of the Pyrazole Ring

5.3 Construction of the Pyrazole Ring

5.4 Pyrazolone-containing Drugs

5.5 Indazole-containing Drugs

5.6 Problems

5.7 References

Chapter 6: Oxazoles, Benzoxazoles, and Isoxazoles

6.1 Introduction

6.2 Construction of the Heterocyclic Ring

6.3 Reactivity

6.4 Cross-Coupling Reactions

6.5 Selected Reactions of Isoxazoles

6.6 Possible Liabilities of Oxazole-Containing Drugs

6.7 Problems

6.8. References

Chapter 7: Thiazoles and Benzothiazoles

7.1 Introduction

7.2 Reactions of the Thiazole Ring

7.3 Palladium Chemistry Undergone by Thiazoles and Benzothiazoles

7.4 Construction of the Thiazole Ring

7.5 Construction of the Benzothiazole Ring

7.6 Possible Liabilities of Drugs Containing Thiazoles and Benzothiazoles

7.7 Thiazoles and Benzothiazoles as Bioisosteres

7.8 Problems

7.9 References

Chapter 8: Imidazoles and Benzimidazoles

8.1 Introduction to Imidazole

8.2 Reactivity of the Imidazole Ring

8.3 Construction of the Imidazole Ring

8.4 Conversion of Imidazolines to Imidazoles

8.5 Possible Liabilities of Imidazole-Containing Drugs

8.6 Introduction to Benzimidazole

8.7 Synthesis of Benzimidazoles: Classical Approaches

8.8 Construction of the Benzimidazole Core Using Transition Metal-Mediated Approaches

8.9 Alternative Cyclization Approach Toward Benzimidazoles: Process Route Toward BYK405879

8.10 Problems

8.11 References

Chapter 9: Triazoles and Tetrazoles

9.1 Introduction

9.2 Reactivity of the Triazole and Tetrazole Ring

9.3 Construction of the Triazole Ring

9.4 Possible Liabilities of Triazole-Containing Drugs

9.5 Problems

9.6 References

Part III: Six-Membered Heterocycles with one Heteroatom

Chapter 10: Pyridines

10.1 Introduction

10.2 Reactivity of the Pyridine Ring

10.3 Construction of the Pyridine Ring

10.4 Problems

10.5 References

Chapter 11: Quinolines and Isoquinolines

11.1 Introduction

11.2 Reactivity of the Quinoline and Isoquinoline Ring

11.3 Construction of Quinoline Core

11.4 Construction of Isoquinoline Core

11.5 Possible Liabilities of Drugs Containing Quinoline and Isoquinoline Ring

11.6 Problems

11.7 References

Part IV: Six-Membered Heterocycles with two Heteroatoms

Chapter 12: Pyrazines and Quinoxalines

12.1 Introduction

12.2 Formation of Diazines

12.3 Reactivity of the Molecules

12.4 Coupling Reactions

12.5 Problems

12.6 References

Chapter 13: Pyrimidines

13.1 Introduction

13.2 Construction of the Pyrimidine Ring

13.3 Synthesis of Pyrimidine-Containing Drugs

13.4 Problems

13.5 References

Chapter 14: Quinazolines and Quinazolinones

14.1 Introduction

14.2 Reactions of Quinazolines and Quinazolinones

14.3 Quinazoline and Quinazolinone Synthesis

14.4 Synthesis of Quinazoline- and Quinazolinone-Containing Drugs

14.5 Problems

14.6 References


Heterocyclic Chemistry in Drug Discovery

Title Page

Dedicated To
Li Jing Ya, Li (Zhen) Cheng-Cheng, Li Chun, and Li Lei


There is a disconnection in our education of organic chemists whose inspiration is to work on drug discovery in either industry or academia. The traditional textbooks are no longer adequate in preparing our undergraduate and graduate students in entering the pharmaceutical industry. The original philosophy was that one could learn medicinal chemistry “on the job” after a strong synthetic chemistry background.

In this book, attempts have been made to fuse the two fields: heterocyclic chemistry and drug discovery. I hope it will give our undergraduate and graduate students a “jump-start” in this competitive employment market. As a matter of fact, there is no sacrificing of a solid education in “authentic” heterocyclic chemistry here. All aspects of reactions, reactivity, and mechanisms are still intact, except they are discussed in the context of medicinal chemistry and drug discovery.

I welcome your critique! Please send your comments to me directly:

Jack Li
June 1, 2012

Contributing Authors:

Dr. Nadia M. Ahmad
Eli Lilly and Company
Erl Wood Manor
Surrey, GU20 6PH
United Kingdom

Dr. Narendra B. Ambhaikar
Dr. Reddy’s Laboratories
Bollaram Road, Miyapur
Hyderabad-500 049
A. P., India

Professor Adam M. Azman
Department of Chemistry
Butler University
4600 Sunset Avenue
Indianapolis, IN 46208, United States

Connor W. Brown
Hamilton College
198 College Hill Road
Clinton, NY 13323, United States

Dr. Timothy T. Curran
Chemical Development
Vertex Pharmaceuticals
130 Waverly Street
Cambridge, MA 02139, United States

Professor Amy B. Dounay
Department of Chemistry and Biochemistry
Colorado College
14 East Cache La Poudre Street
Colorado Springs, CO 80903, United States

Tyler W. Farnsworth
Division of Natural Sciences and
University of South Carolina Upstate
800 University Way
Spartanburg, SC 29303, United States

Professor Micheal Fultz
Department of Chemistry
West Virginia State University
Institute, WV 25112, United States

Professor Timothy J. Hagen
Department of Chemistry and
Northern Illinois University
DeKalb, IL 60115, United States

Dr. Jie Jack Li
Medicinal Chemistry
Bristol-Myers Squibb Company
Route 206 and Province Line Road
Princeton, NJ 08540, United States

Dr. Sha Lou
Process Research and Development
Bristol-Myers Squibb Company
New Brunswick, NJ 08901, United States

Professor Richard J. Mullins
Department of Chemistry
Xavier University
3800 Victory Parkway
Cincinnati, OH 45207-4221, United States

Dr. Jennifer Xiaoxin Qiao
Medicinal Chemistry
Bristol-Myers Squibb Company
P.O. Box 5400
Princeton, NJ 08543-5400, United States

William Rollyson
Department of Chemistry
West Virginia State University
Institute, WV 25112, United States

Professor Joshua V. Ruppel
Division of Natural Sciences and Engineering
University of South Carolina Upstate
800 University Way
Spartanburg, SC 29303, United States

Professor Nicole L. Snyder
Department of Chemistry
Davidson College
Box 7120
Davidson, NC 28036, United States

Alexander D. Thompson
Hamilton College
198 College Hill Road
Clinton, NY 13323, United States

Dr. Ji Zhang
HEC R&D Center
Pharmaceutical Science
Process Research and Development
HEC-Hi-Tech Park, Dongguan
Guang Zhou, Guang-Dong Province
P. R. China

Dr. Zheng Zhang
Department of Chemistry and
Northern Illinois University
DeKalb, IL 60115, United States

Professor Alexandras L. Zografos
Department of Chemistry
Aristotle University of Thessaloniki
Thessaloniki 54124, Greece

Chapter 1


Jie Jack Li

1.1 Nomenclature of Heterocycles

What’s in a name? That which we call rose by any other name would smell as sweet. [William Shakespeare, Romeo and Juliet (II, ii, 1–2)].

Contrary to Shakespeare’s exclamation, naming heterocycles is an integral part of our learning of heterocyclic chemistry. They are the professional jargon that we routinely use to communicate with our peers.

Heterocycles, as the name suggests, are cyclic compounds containing one or more heteroatoms such as N, O, S, P, Si, B, Se, and Se. They may be further divided into aromatic heterocycles and saturated heterocycles. This book will focus largely on aromatic heterocycles. Saturated heterocycles represent a smaller portion of drugs. Another way of naming heterocycles is using the size of the heterocyclic rings. Therefore, they may be classified as three-, four-, five-, six-, and seven-membered heterocycles, and so on.

Three-membered heterocycles are important reaction intermediates in organic chemistry and in preparing medicines. But they usually do not exist in final drugs because they are reactive in physiological environments. Exceptions are found in cancer drugs such as epothilone A and mitomycin C (see Section 1.4, page 9), where their reactivities are taken advantage of for therapeutic purposes.

The most frequently encountered three-membered heterocycles are oxirane, thiirane, aziridine, and azirine.

Four-membered heterocycles include oxetane, 2H-oxete, thietane, 2H-thiete, azetidine, and azete. In the field of drug discovery, oxetanes and azetidines are more and more incorporated into drugs for modulating biological and physical properties as well as for expanding intellectual properties space.

Five- and six-membered heterocycles are of utmost importance to both life and drug discovery. The most common five-membered heterocycles with one heteroatom are pyrrole, furan, and thiophene.

Popular five-membered heterocycles with two heteroatoms include pyrazole, imidazole, oxazole, isoxazole, thiazole, and isothiazole.

All these aromatic heterocycles have their counterparts in the corresponding saturated heterocycles. Among those, pyrrolidines, tetrahydrofurans, and oxazolidines are more frequently encountered in drug discovery.

Some of the important benzene-fused five-membered heterocycles are indole, benzofuran, benzothiophene, benzimidazole, benzoxazole, and benzothiazole. The numbering of these heterocycles is shown below:

Chief among the six-membered heterocycles, pyridine and its benzene-fused derivative quinoline are most ubiquitous. Pyrazine and its benzene-fused analogue, quinoxaline, also play an important role in heterocyclic chemistry.

Their corresponding saturated derivatives often encountered in drug discovery are piperidine and piperazine.

1.2 Aromaticity of Heterocycles

The major thrust of this book is aromatic heterocycles. According to Hückel’s rule of aromaticity, a cyclic ring molecule is aromatic when the number of its π-electrons equals 4n + 2, where n is zero or any positive integer. The most common aromatic compound is benzene, which has 4 + 2 = 6 π-electrons. Pyridine, an electron-deficient aromatic heterocycle, also has 6 π-electrons. In comparison with benzene, pyridine has an additional lone pair of electrons at the nitrogen atom after it contributes a pair of two electrons to make up the 6 π-electrons for aromaticity. These lone pair electrons are responsible for much of pyridine’s unique physical and chemical properties. On the other hand, furan, an electron-excessive aromatic heterocycle also with 6 π-electrons, is different from both benzene and pyridine. The oxygen atom has two lone pairs of electrons, one of which contributes to the 6 π-electrons to achieve the aromaticity. The second pair of electrons is located in an sp2 hybrid orbital in the plane of the furan ring. Thiophene is similar to furan in its aromaticity although thiophene is more “aromatic” because the S atom is larger than the O atom.

The relative aromaticity of common heterocycles is shown below:

Pyrrole, also an aromatic heterocycle with 6 π-electrons, is probably the most unique of all among the aromatic heterocycles. Different from furan and thiophene, the nitrogen atom on the pyrrole ring only has one lone pair of electrons, which both contributed to the 6 π-electrons to achieve the aromaticity. As a consequence, although pyrrole is also an electron-excessive aromatic heterocycle, just like furan and thiophene, pyrrole has many of its own characteristics. For instance, it is probably the most reactive as a nucleophile among all aromatic heterocycles (see Chapter 2). In addition, pyrrole’s conjugation effect outweighs the nitrogen’s inductuve effect in the contributing dipole moment, with the partial positive charge resting at the nitrogen atom.

1.3 Importance of Heterocycles in Life

The importance of heterocycles in life was recognized as the nascent stage of organic chemistry two centuries ago with isolation of alkaloids such as morphine from poppy seeds, quinine from cinchona barks, and camptothecin from the Chinese joy tree. Today, heterocycles are found in numerous fields of biochemical and physiological such as photosynthesis, amino acids, DNA bases, vitamins, endogenous neurotransmitters, and so on.

To begin with, chlorophyll is porphyrin (a tetramer of pyrrole) surrounding a magnesium atom. It is the molecule that absorbs sunlight and uses its energy to synthesize carbohydrates from CO2 and water. This process, known as photosynthesis, is the basis for sustaining the life processes of all plants.

On the other hand, the heme consists of a porphyrin ring surrounding an iron atom. The ring contains a large number of conjugated double bonds, which allows the molecule to absorb light in the visible part of the spectrum. The iron atom and the attached protein chain modify the wavelength of the absorption and give hemoglobin its characteristic color.

Several amino acids, the building block of life, are made of heterocycles. Histidine has an imidazole; tryptophan has an indole; yet proline has a pyrrolidine.

Heterocycles also play an important role as endogenous neurotransmitters. Chief among them are serotonin and histamine, which are of paramount importance in modulating the body’s physiological and biochemical processes.

Melatonin regulates circadian rhythms, most noticeably sleep, whereas tryptamine is closely related to melatonin and the amino acid tryptophan.

The double helix of DNA, the code of life, comprises two base pairs: adenine/thymine (A/T) and cytosine/guanine (C/G).

By adding the ubiquitous sugar fragments, we are left with nucleic acids contaning pyrimidine bases, including cytosine, thymine, and uracil and purine bases such as adenine and guanine.

Thiazoles also play a prominent role in nature. For example, the thiazolium ring present in vitamin B1 serves as an electron sink and its coenzyme form is important for the decarboxylation of α-keto-acids. The left-hand fragment of vitamin B1 is an aminopyrimidine.

Vitamin B5 (nicotinic acid amide) and vitamin B6 (pyridoxal) are pyridine-based molecules, whereas vitamin B7 (biotin) is a bi-heterocycle fusing reduced imidazole and thiophene.

1.4 Importance of Heterocycles in Drug Discovery

It will be evident from the ensuing chapters that heterocycles play an extremely important role in drug discovery, in general, and in medicinal chemistry, in particular. Heterocycle-containing drugs are found in all therapeutic areas including cardiovascular and metabolic diseases, central nervous system (CNS), anti-cancer, anti-inflammatory, anti-ulcer, anti-infective drugs, and so on.

1.4.1 Five-Membered Heterocycles with One Heteroatom

Three-membered heterocycles are usually not fragments of drugs because they are reactive toward nucleophiles in physiological environments. Cancer drags such as epothilone and mitomycin are exceptions rather than the rules. The epothilones have shown their eminent cytotoxic activity against tumor cells, taxol-like mitose inhibition and toxicity against multiple drug-resistant tumor cell lines. On the other hand, mitomycin C is isolated from a strain of bacteria called Streptomyces lavendulae. It is a chemotherapy agent because of its anti-tumor properties. It is indicated as a useful therapeutic agent in combination with other anticancer drugs for the treatment of disseminated adenocarcinoma of the pancreas and the stomach.

Not many drugs contain four-membered heterocycles either. The best-known drug containing an azetidine-ring is Schering-Plough’s ezetimibe (Zetia). Launched in 2002 as a cholesterol absorption inhibitor, its mechanism of action is the inhibition of the Nieman–Pick C1-like 1 (NPC1L1) protein.

Just as in life, five-membered heterocycles are of utmost importance to drug discovery. The most conspicuous of all is probably atorvastatin (Lipitor), an HMG-CoA inhibitor. Another bioactive pyrrole shown below is an antipsychotic agent.

Many drugs contain the indole-ring as their core structures. Fluvastatin sodium (Lescol) is an HMG-CoA reductase inhibitor.

In addition, sumatriptan succinate (Imitrex), a serotonin receptor (5-HT1B1D) agonist, is used to treat migraines. And naratriptan (Naramig) is a “me-too,” indole-containing anti-migraine drug on the market.

Furthermore, delavirdine (Rescriptor) is a novel HIV-1 reverse transcriptase inhibitor for HIV-positive individuals and zafirlukast (Accolate) is an antiasthma drug.

Bristol-Myers Squibb’s thiophene-containing clopidogrel (Plavix) inhibits platelet aggregation induced by adenosine diphosphate (ADP), a platelet activator that is released from red blood cells, activated platelets, and damaged endothelial cells. Clopidogrel, launched in 1993, achieved great commercial success. But its mechanism of action (MOA) was not elucidated until 1999: through the antagonism of the P2Y12 purinergic receptor and prevention of binding of ADP to the P2Y12 receptor by its active metabolite. Therefore, clopidogrel is a bona fide pro-drug.

Eli Lilly’s raloxifene (Evista) is a selective estrogen receptor modulator (SERM) indicated for osteoporosis and breast cancer. Its core structure is a benzothiophene.

Thiophene seems to be very popular in Li Lilly drugs. Its dual selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for depression, duloxetine (Cymbalta), contains a thiophene. And its atypical antipsychotic drug olanzapine (Zyprexa) has a fused thiophene as its core structure.

1.4.2 Five-Memhered Heterocycles with Two Heteroatoms

Histamine-2 (H2) receptor antagonists as anti-ulcer drugs best showcased the versatility of heterocycles in drug discovery. Marketed in the United States in 1977, SmithKline & French’s cimetidine (Tagamet) became the first blockbuster drug ever in medical history in 1985. Transforming the imidazole ring into the dimethylamino-furan in combination with replacing cyanoguanidine with nitrovinyl guanidine gave rise to ranitidine (Zantac). Later on, Yamanouchi arrived at famotidine (Pepcid) using guanidinothiazople as its core structure and sulfamoyl-amidine as its side chain. All of these drugs went on to become blockbuster drugs.

Anti-inflammatory cyclooxygenase-2 (COX-2) selective inhibitor celecoxib (Celebrex) has the tri-substituted pyrazole as its core structure.

1.4.3 Six-Membered Heterocycles with One Heteroatom

As we mentioned in Section 1.2, pyridine has an additional lone pair of electrons at the nitrogen atom after it contributes a pair of two electrons to make up the 6 π-electrons for aromaticity. These lone pair electrons are responsible for much of pyridine’s unique physical and chemical properties.

One prominent example is AstraZeneca’s H+/K+-ATPase inhibitor, pyridine-containing omeprazole (Prilosec) and its enantiomerically pure follow-up esomeprazole (Nexium).

They are both pro-drugs and their MOA is through the “omeprazole cycle,” initiated by pyridine’s lone pair of electrons. In fact, pyridine’s lone pair of electrons could be viewed as the engine that propels the “omeprazole cycle.” The pyridinium sulfydryl intermediate is the actual inhibitory species.

There are quinoline-containing drugs from both nature and synthesis. Natural product drugs may be exemplified by quinine, an anti-malarial drug used for three centuries. Synthetic quinoline-containing drugs are represented by pitavastatin calcium (Livalo), Sankyo’s HMG-CoA inhibitor for lowering cholesterol.

1.4.4 Six-Membered Heterocycles with Two Heteroatoms

The best-known pyrimidine-containing drug of today is probably AstraZeneca’s rosuvastatin (Crestor) as an HMG-CoA redutase inhibitor for lowering cholesterol. By choosing a sulfonamide substituent, a unique intellectual property position was achieved.

AstraZeneca’s gefitinib (Iressa)’s core structure is a quinazoline. It is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) indicated for the treatment of cancers. Several other protein kinase inhibitors also used the quinazoline ring as their core structure. They include OSI’s erlotinib (Tarceva) and GSK’s lapatinib (Tykerb).

Sepracor’s eszopiclone (Lunesta) contains a pyrazine ring. It is a GABAA receptor agonist for the treatment of insomia.

Finally, Pfizer’s varenicline (Chantix) used a fused quinoxaline ring. It is an α4β2 nicotinic receptor partial agonist for smoking cessation.

In this section, only a small portion of marketed drugs are shown to illustrate the importance of hetereocyclic chemistry in drug discovery. Many drugs containing saturated heterocycles, heterocycles with more than two heteroatoms, and non-heterocycles. In the ensuing chapters, the most popular types of heterocycles in drug discovery are reviewed for their physical and chemical properties, their constructions in the context of medicinal chemistry, and their potential liabilities as drugs when applicable.



Chapter 2 Pyrroles

Chapter 3 Indoles, Indolines, and Azaindoles

Chapter 4 Furans, Benzofuran, Thiophenes, and Benzothiophenes

Chapter 2


Jie Jack Li

2.1 Introduction

The parent compound pyrrole is a colorless, flammable liquid with a boiling point of 131 °C. It turns to a light-amber color upon exposure to air and/or light. Pyrrole has a mild aniline-like odor.

Pyrrole, with 6 π-electrons, is an electron-excessive (also known as electron-rich) aromatic heterocycle because the electron density on each ring atoms is greater than one. Its lone pair electrons take part in the delocalization thus essential to pyrrole’s aromaticity. Pyrrole’s aromaticity is between furan and thiophene, which is in accordance with Pauling’s electronegativity for O (3.5), N (3.0), and S (2.5):

The reason why pyrrole is an electron-excessive aromatic heterocycle is because the electron density on each ring atom is greater than one. Pyrrole has a dipole moment of 1.55 D, similar to that of pyrrolidine in number although with opposite direction. (Here, the direction of the dipole moment vector is represented by an arrow and is properly defined so that the arrow is directed from the positive fractional charge to the negative fractional charge).

Electron Densities of the Atoms on the Pyrrole Ring and Dipole Moments

Although the direction of pyrrolidine’s dipole moment is easily rationale by the nitrogen atom’s inductive effect, that of pyrrole’s is more nuanced. As shown in the following resonance structures:

As a consequence, pyrrole has a resonance hybrid that places the partial positive charge on the nitrogen atom and the partial negative charges on the four carbon atoms. For pyrrole, the resonance effect overpowers the inductive effect exerted by the nitrogen atom, whereas the inductive effect for furan and thiophene was a stronger force than their resonance effect.

As far as furan and thiophene are concerned, their resonance effect is not as strong as the inductive effect. Therefore, their dipole moments are in the same direction of pyrrolidine.

Geographically, the pyrrole ring is a plane pentagon, with bond angles and bond lengths almost the same as a regular pentagon:

For its 1H-NMR (Nuclear Magnetic Resonance Spectroscopy), the two β-protons (Hβ) show up at 6.32 ppm, whereas the two α-protons (Hα) show up at 6.87 ppm, further down field from the two β-protons, because of the inductive effect from the nitrogen atom. As far as the NH is concerned, its chemical shift often is affected by solvents and concentrations for the NMR- samples. The coupling constant between Hα and Hβ is 2.6 Hz, whereas the coupling constant between Hβ and Hβ is 3.4 Hz.

For the 13C-NMR spectrum, Cα is further down field with a chemical shift of 117.9 ppm again thanks to the NH’s group’s inductive effect. Cβ has a chemical shift of 108.1 ppm.

Pyrrole is possibly one of the most reactive heterocycles thanks to its lonepair electrons at the nitrogen atom. The enormous reactivity of pyrrole in electrophilic substitution reactions explains the occurrence of more than 100 naturally occurring halogenated pyrroles. Indeed, the pyrrole ring is widely distributed in nature. It occurs in both terrestrial and marine plants and animals. An illustration of the abundant complex natural pyrroles is konbu’acidin A, a sponge metabolite that inhibits cyclin-dependent kinase 4 (CDK4).

The pyrrole ring has found great use in the design and development of pharmaceuticals. Atorvastatin (Lipitor), a HMG CoA inhibitor, is the best selling drug ever. Other bioactive pyrroles shown as follows include an antipsychotic agent, a sodium-independent dopamine receptor antagonist, and a DNA cross-linking agent.

However, pyrroles are most frequently found in analgesic and anti-inflammatory drugs. Tolmetin and zomepirac were the first pyrrole-acetic acids to be used as nonsteroidal anti-inflammatory drugs (NSAIDs). Ketorolac (Toradol for inflammatory indications and Acular for ophthalmic indications), also an analgesic and anti-inflammatory, was discovered by Syntex. It was one of the top 100 selling drags during its heydays during the 1980s. Pyrrolnitrin is an antifungal and an antibiotic.

2.2 Reactivity of the Pyrrole Ring

2.2.1 Protonation

The pyrrole nitrogen atom (pKa = −3.80)1 is only weakly basic, pyrrole loses its aromaticity when protonated because the lone pair electrons are involved in the aromatic sextet. When treated with strong acid such as sulfuric acid, the protonation does not occur at the nitrogen atom, but most of the protonation takes place at C2 (80%) and 20% of the protonation takes place at C3 (20%).

2.2.2 C2 Electrophilic Substitution

Pyrrole’s lone pair of electrons is the engine that propels many of its unique reactivities. Contrary to the indole where C3 electrophilic substitution takes place predominantly, when treated with an electrophile (E), the lone pair of electrons pushes the pyrrole ring to attack the electrophile at its C2 position. Therefore, C2-electrophilic substitution is the most fertile ground with regard to pyrrole’s reactivities. Nonetheless, C3 electrophilic substitution and poly-substitution still take place from time to time, often with concurrent C2-electrophilic substitution.

Here is why the pyrrole ring prefers C2-electrophilic substitution. First of all, N1-electrophilic substitution is not favored because the positive charge would be localized on the nitrogen atom. On the other hand, C2-electrophilic substitution is favored over the C3-electrophilic substitution because the intermediate for the C2 substitution is more delocalized than that of the C3 substitution. This preference of more delocalization is reflected by the protonation as well. As shown in the previous section, 80% of the protonation occurs on the C2 position.

C2-electrophilic substitution predominates:

C3-electrophilic substitution is less preferred:


The aforementioned regioisomer formation is showcased by bromination of pyrroles. The C2(α)-bromination is prevalent for bromination of the 1N-Boc protected pyrrole.2

There are exceptions to the rule. For instance, when there is a bulky group on the nitrogen such as triisopropylsilyl group (TIPS), bromination occurs predominantly on the C3 (β) position instead of on the C2 (α) position.3

Bromination on both α- and β-positions is also possible4:

Depending on the reaction conditions, 1-methylpyrrole can be brominated at C2 with NBS (N-bromosuccinate) to give 2-bromo-1-methylpyrrole or at C3 with NBS and catalytic PBr3 to give 3-bromo-1-methylpyrrole. Both reactions are essentially quantitative, but both bromides decompose on silica gel.5

Methyl-protected bipyrrole was chlorinated at both C2 positions on treatment with NCS (N-chlorosuccinate) in excellent yield.6

Mannich reaction

For the Mannich reaction with pyrrole, the substitution occurs predominantly at the C2 position as well.7

Pyrrole Mannich bases have been transformed into the tertiary ammonium salt as a good leaving group. Therefore, treatment of the quaternary ammonium salt with sodium sulfinate to give the corresponding sulfonyl pyrrole, which in turn, could undergo another Mannich reaction to synthesize sulfonyl pyrrole Mannich bases as germicides.8

A similar strategy was employed in preparing a pilot scale of FR143187, a novel nonpeptide angiotensin II receptor antagonist for the treatment of hypertension.9 At first, acid-catalyzed cyclization of ethyl 4-aminobenzoate with dialkoxytetrahydrofuran formed the N-aryl pyrrole. The reaction is sometimes known as the Clauson–Kaas pyrrole synthesis. Next, the Mannich base was prepared quantitatively by the treatment of the N-phenylpyrrole with paraformaldehyde and dimethylamine hydrochloride. The procedure was superior to the original standard Mannich conditions using 37% aqueous formaldehyde (47% yield) in EtOH. The quaternary ammonium salt was formed in 93% yield by mixing the Mannich base with methyl iodide in EtOAc. The reaction was carried out in a 125-kg scale. Reduction of the quaternary ammonium salt was achieved using borane•pyridine complex in 1,3-dimethylimidazolinone (DMI). The resulting methylpyrrole was then transformed into FR143187 in additional 7 steps.

The Mannich reaction between 2-phenylpyrroles and phenylpiperazines provided Mannich bases as a new class of potential antipsychotics. They served as conformationally restricted benzamide analogues.10

Pyrrole Mannich bases have been prepared as potential antipsychotic agents that do not have the extrapyramidal side effects (EPS). In one case, N-methylpyrrole was amidomethylated with 1-(hydroxymethyl)azepan-2-one, which was assembled by condensation between the seven-membered lactam and formaldehyde.11,12 The amidomethylated N-methylpyrrole then underwent the Mannich reaction with arylpiperazine and formaldehyde in the presence of trifluoroacetic acid (TFA). The pyrrole Mannich bases synthesized in this manner exhibited a high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these arylpiperazines interact weakly with dopamine D-1 and D-2 receptors, they were reasonably potent in an in vivo model in the rat CAR (conditioned avoidance responding), an indication of potent antipsychotic activity.

Outside the CNS (central nervous system), pyrrole Mannich bases have found utility in other therapeutic areas as well. The Mannich reaction between iminoibitol and 9-deazahypoxanthine took place at the C3 position to provide an N-pyrrolylmethyl substituted iminoribitol as an inhibitor of a purine-specific nucleoside hydrolase.13 In terms of regiochemistry, this particular Mannich reaction of 9-deazahypoxanthine behaved similarly to indole rather than to pyrrole. The resulting Mannich bases are potential treatment for parasitic infections.

C-10 pyrrole Mannich bases of artemisinin have been accessed as potential anti-malarial agents.14 Treatment of dihydroartemisinin with N-methylpyrrole in the presence of a Lewis acid gave rise to the C-10 pyrrole analogue. The subsequent Mannich reaction used preformed Eschenmoser’s salt to afford the dimethylaminopyrrole, which was an anti-malarial with enhanced water solubility.

Vilsmeier–Haack reaction

The Vilsmeier–Haack reagent, a chloroiminium salt, is a weak electrophile. Therefore, the Vilsmeier–Haack reaction works better with electron-rich carbocycles and heterocycles. Since pyrrole is very electron-rich, the Vilsmeier–Haack reaction readily takes place. Formylation of methyl pyrrole-2-carboxylate was achieved using the Vilsmeier–Haack reaction.15 The mechanism is shown below. The resulting methyl 5-formylpyrrole-2-carboxylate, in turn, was converted into nonpeptidic analogues of neurotesin(8–13), which are potential treatment for neuropsychiatric diseases such as schizophrenia and Parkinson’s disease.

Oxidative coupling

An exciting new development of oxidative cyclization of pyrroles emerged from Baran’s Laboratories at Scripps Research Institute. Building on their success with the oxidative cyclization of indoles,16 Baran et al. expanded the methodology to pyrroles.17

Applying the strategy of direct coupling of pyrroles with carbonyl compounds, Baran et al. developed a short enantioselective synthesis of (S)-ketorolac, Syntex’s analgesic and anti-inflammatory agent.17 The antipode of ketorolac is more potent and causes fewer side effects.

2.2.3 C3 Electrophilic Substitution

In the last section, we saw many C2 halogenations. Depending on the substrates, C3 electrophilic substitutions do occur although often accompanying the C2 electrophilic substitutions. The C3 electrophilic substitutions generally take place more sluggishly and often at lower yields, although this is not always the case.

Various iodinated pyrroles have been prepared by direct iodination or via initial thallation. For example, 3-iodo-N-TIPS-pyrrole is prepared in 83% yield from N-TIPS-pyrrole.18 And 3,4-diiodo-2-formyl-1-methylpyrrole is available in 54% yield via a bis-thallation reaction.19 Although N-protected 2-lithiopyrroles are readily generated and many types are known, these intermediates have not generally been employed to synthesize halogenated pyrroles.

As in the example shown below, the Vilsmeier–Haack reaction was performed on 2-benzoyl-1-methyl-1H-pyrrole to afford the C2 formylation product in 44% yield and the C3 ketone affords the C2 formylation product in 44% yield in 56% yield.20 The two pyrrolyl aldehydes, in turn, were converted into the corresponding hydroxamates, which are a new class of histone deacetylase (HDAC) inhibitors.

A similar tactic was employed in transforming methyl pyrrole-2-carboxylate into hepatitis C virus (HCV) helicase inhibitors.21

When C3 is the only position open, the C3 electrophilic substitutions obviously occur exclusively. The following Vilsmeier–Haack reaction was applied to the synthesis of a novel class of glycine site antagonists of the ionotropic N-methyl-D-aspartate (NMDA) glutamatergic receptor.22

A Friedel–Crafts acylation of 2-(1-methyl-1H-pyrrol-2-yl)acetonitrile with benzoyl chloride gave the C3 substitution product in 21% yield, whereas the C2 substitution product was obtained in 25% yield.23 The C2 adduct, in turn, was hydrolyzed to the corresponding acid, which is a potent anti-inflammatory agent and was active in the in vivo animal models.

2.2.4 Metalation

The NH pyrrole proton is acidic with a pKa of 17.5. As a consequence, bases such as NaH, Grignard reagents, n-BuLi, and NaOEt readily deprotonate pyrrole. For instance, alkylation of 4-nitro-pyrrole-2-ester was achieved by treatment of the pyrrole with sodium ethoxide in the presence of cyclopropylmethyl bromide.24 The resulting alkylated pyrrole was converted to pyrrole tetraamides, which are minor groove DNA binders and serve as potent antibacterial agents.

2.3 Construction of the Pyrrole Ring

2.3.1 Knorr Pyrrole Synthesis

The Knorr pyrrole synthesis involves the reaction between an α-amino ketone and a second carbonyl compound, having a reactive α-methylene group, to give a pyrrole.25 The amine is often generated in situ by reduction of an oximino group.

The mechanism of the original Knorr pyrrole synthesis entails in situ reduction of the oxime moiety to an amine, condensation with the second carbonyl compound, and cyclization with loss of a second molecule of water to give a pyrrole.25 Several studies have demonstrated that different pathways and pyrrole products obtain depending on the substrates.

The Knorr pyrrole synthesis was applied to make butyrophenone analogues of molindone, a typical anti-psychotic first marketed in the United States in 1974. The Knorr condensation of 2-hydroxyimino-3-pentanone with 1,3-cyclohexadione in 70% acetic acid in the presence of zinc powder at reflux afforded the dihydroindolone,26 which was transformed into QF-0400B in six additional steps. QF-0400B had similar affinities for D1, D2, and 5-HT2A receptors to those of molindone.

The same tactic was employed to prepare new cyclic butyrophenone derivatives in the indole series as potential atypical anti-psychotics. The Knorr pyrrole synthesis provided a simple and practical access of 6-aminomethyltetrahydroindol-4-ones and their affinities for D2, and 5-HT2A receptors were evaluated for their potential as atypical anti-psychotics. As shown below, the Knorr condensation between 2-isonitroso-3-pentanone with hydroxylmethyl alcohol, as a masked cyclohexadione, in 70% acetic acid in the presence of zinc powder at reflux gave a mixture of two tetrahydroindole-4-ones.27 The acetate was easily converted into the corresponding alcohol on treatment with 10% ethanolic potassium hydroxide.

A modified Knorr pyrrole synthesis was key to a practical synthesis of the potent δ-opioid agonist SB-342219 by GSK.28 SB-342219 is a selective δ-opioid agonist undergoing preclinical evaluation for the potential treatment of neuropathetic pain. The medicinal chemistry route used the conventional Knorr pyrrole synthesis. Condensation of the ketone with α-aminoketone, which was generated in situ by reduction of the requisite phenylhydrazone using zinc, gave the desired pyrrole in 63% yield.

The conventional Knorr pyrrole synthesis delivered SB-342219 on a small scale for medicinal chemistry. Nonetheless, use of metallic zinc could be problematic for scale-up. Therefore, Carey et al. devised a modified Knorr pyrrole synthesis where they use an amine instead of the phenylhydrazone, thus avoiding the use of zinc metal.28 Therefore, the condensation between the ketone and the aminoketone in the presence of NaOAc and HOAc gave the desired pyrrole in 68% yield, which was easily converted into SB-342219 in two additional steps.

2.3.2 Paal-Knorr Pyrrole Synthesis

Discovered more than a century ago, the Paal–Knorr pyrrole synthesis is similar to the Knorr synthesis. It is the intermolecular condensation of a primary amine (or ammonia) with a 1,4-diketone (or 1,4-dialdehyde) to give pyrroles.25

L-167307 is an orally bioavailable inhibitor of p38 kinase. In vivo, it reduces secondary paw swelling in the rat adjuvant arthritis model with an ID50 of 7.4 mg/kg/day. Triarylpyrrole L-167307 was assembled using the Paal–Knorr pyrrole synthesis of a 1,4-diketone and ammonium acetate.29

Celecoxib (Celebrex) is a selective cyclooxygenase-2 (COX-2) inhibitor prescribed as a nonsteroidal anti-inflammatory drug (NSAID). The Paal–Knorr cyclization was the crucial step in preparing tri-substituted keto-pyrroles as COX-2 inhibitors. Here, the tri-ketone substrates were prepared in situ from phenacyl bromide and 1,3-diketone.30

The Paal–Knorr cyclization was employed to produce highly aryl-substituted pyrrole carboxylates as useful medicinal chemistry leads.31 Therefore, 1,4-diketone-2,3-diester was assembled from an SN2 displacement of ethyl 2-bromoacetoacetate with the anion of the ketoester. Condensation with an aniline then provided a library of fully substituted pyrroles.

When Paal and Knorr discovered the pyrrole synthesis more than a century ago, they had no idea that the reaction bearing their names would have contributed greatly to the manufacture of atorvastatin (Lipitor). Indeed, synthesis of Lipitor is probably the tour de force for the Paal–Knorr pyrrole synthesis.

After more than one year’s exploration, the carefully controlled conditions were worked out to prepare penta-substituted pyrrole in 43% yield.32 The conditions entailed the condensation of the diketone with the diethyl acetal of 3-amino-propanal in the presence of 1 equivalent of pivalic acid. It was also significant that it was demonstrated that a totally convergent synthesis was possible. With this result in hand, it became possible to envision a route in which a fully elaborated side chain could be combined with the appropriate 1,4-diketone to assemble the entire molecule into one operation.

When the fully functionalized, stereochemically pure side chain and the fully substituted diketone were treated under very carefully defined conditions (1 equiv. pivalic acid, 1:4:1 toluene/heptanes/THF), a 75% yield of the penta-substitued pyrrole was obtained.33 Deprotection and formation of the hemi-calcium salt produced stereochemically pure atorvastatin calcium in a convergent, high-yielding, and commercially viable manner.

2.3.3 Hantzsch Pyrrole Synthesis

The Hantzsch pyrrole synthesis is the condensation of β-ketoesters with primary amines (or ammonia) and α-haloketones to give substituted pyrroles.

It is possible that the mechanism of the Hantzsch pyrrole synthesis commenced with the condensation between the amine and the ketoester. The resulting imine then undergoes an SN2 replacement reaction with the α-haloketone via the intermediacy of an enamine. The adduct as an enamine ketone then undergoes an intramolecular C–N bond formation to deliver the final pyrrole after extrusion of a molecule of water.

The Hantzsch pyrrole synthesis was employed to prepare pyrrole-2-acetic acids as anti-inflammatory agents.23b A transient precipitate of a white crystalline solid was formed when diethyl acetone-dicarboxylate was mixed with aqueous methylamine. After chloroacetone was added rapidly with cooling before the disappearance of the precipitate, a good yield of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate was produced. Further functional group transformations then produced pyrrole-2-acetic acids as anti-inflammatory agents.

A variant of the Hantzsch pyrrole synthesis was applied to prepare LY231514 (Alimta), an antifolate as a potential anti-cancer drug.33 As is typical of the Hantzsch pyrrole synthesis, the Feist–Benary reaction is frequently the competing pathway to afford the corresponding furan. As shown below, condensation of 2,6-diaminopyrimidin-4(3H)-one with α-chloro-ketone gave rise to a 1:1 mixture of the corresponding furan and pyrrole in 40% yield each. It is interesting that when α-bromo-ketone was used in place of the α-chloro-ketone, no Feist-Benary reaction was observed to give the furan, and only the pyrrole was isolated.34

2.3.4 Barton–Zard Reaction

The Barton–Zard reaction refers to the base-induced reaction of nitroalkenes with alkyl α-isocyanoacetates to afford pyrroles.35 Solvents used are THF or alcohols (or mixtures), and the reaction often proceeds at room temperature. The Barton–Zard pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMIC and to the Montforts pyrrole synthesis that uses α,β-unsaturated sulfones and alkyl α-isocyanoacetates. An alternative to the use of the reactive nitroalkenes is their in situ generation from β-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation.

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus, base-induced formation of enolate is followed by Michael addition to the nitroalkene and cyclization of nitronate to furnish the nitroisocyanide after protonation. Loss of nitrous acid (HNO2) and aromatization then affords the pyrrole ester.

The Barton–Zard reaction found its application in the synthesis of LY2059346, a positive allosteric modulator of the α-amino-3-hydroxyl-L-aspartate (AMPA) receptor as a potential treatment of neurological and psychiatric disorders.36

2.4 Palladium Chemistry of Pyrroles

A series of novel 2,5-bis(guanidino-aryl)-1-methyl-1H-pyrroles was synthesized starting from 1-methyl-1H-pyrrole employing the Stille coupling as the key operation.37 The bis-stannylpyrrole was obtained from 1-methylpyrrole via 2,5-dilithiation. Subsequent Stille coupling afforded di(nitrophenyl)-pyrrole, which was used to craft novel diguanidine antifungal agents. The derivative shown below was found to be equipotent or more potent than fluconazole against most of the tested fungus strains.

The stannylpyrrole aldehyde shown below underwent the Stille coupling with the aldehyde group unmolested. The Stille coupling between stannylpyrrole aldehyde and acid chloride was used to synthesize the sponge metabolite mycalazol 11 and related compounds, which have activity against the P388 murine leukemia cell line.38

The Suzuki coupling of a bis-pyrrolo-2-triflate with pyrrolo-2-boronic acid afforded a triple pyrrole such as prodigiosin. Although the mechanism is unknown at the moment, prodigiosins and copper prodigiosins cleave double-strand DNA and show promise in cancer treatment.39

2.5 Possible Liabilities of Pyrrole-Containing Drugs

Because the pyrrole ring is extremely electron-rich, pyrrole-containing drugs are easily oxidized by cytochrome P-450 (CYP-450) enzymes in the liver. The resulting metabolic oxidation products are prone to nucleophilic replacement by physiological nucleophiles such as the thiol group. The consequence is toxicities such as agranulocytosis, hepatotoxicity, and so on. An anti-hypertensive agent, mopidralazine (MDL-899), was extensively investigated with regard to the metabolic oxidation of its pyrrole ring in rats and dogs.40–42 Isolation and characterization of mopidralazine’s metabolites led to the hypothesis that the biotransformations of pyrrole may involve the introduction of molecular oxygen into the pyrrole ring. The intermediacy of 1,2-dioxetane explains that an oxidative cleavage of the pyrrole ring could provide all metabolites identified.

As one could imagine, the highly reactive intermediates from pyrrole could wreak havoc in the physiological system. Nucleophiles such as the thiol group could induce toxicities. As a result, the development of mopidralazine was subsequently discontinued.

Similar oxidative metabolism was observed for premazepam, an antianxiety drug, in the rat and the dog43; prinomide, an anti-inflammatory agent, in six species of laboratory animals44; and pyrrolnitrin, an anti-fungal agent, in rats.45

Nonetheless, if one assumes that all pyrrole-containing drugs are toxic, we would have missed atorvastatin (Lipitor). Atorvastatin is remarkably safe barring the mechanism-based safety concerns such as rhabdomyolysis that are associated with all HMG-CoA inhibitors.46,47para