A brief overview of different methods, used for synthesize carbazoles

and it’s derivatives via first transition metal catalysed, followed By C-

N bond forming coupling reaction
A REVIEW REPORT

SUBMITTED FOR THE PARTIAL FULFILLMENT OF THE DEGREE OF

MASTER OF SCIENCE

IN

ORGANIC CHEMISTRY

Department of Chemistry
ALIAH UNIVERSITY

Submitted By:

Anis Ahmed
Roll No. CHM145020
Registration No. CHM145020 of 2014-2015

Under the Supervision of

Dr. Safiul Alam

Assistant Professor
Department of Chemistry, Aliah University
 Department of Chemistry,
Aliah University
IIA/27, New Town, Kolkata-700160, India
………………………………………………………………………………………………………………………………

Certificate

This is to certify that the Review work entitled “A brief overview of different
methods, used for synthesize carbazoles and it’s derivatives via first
transition metal catalysed, followed by C-N bond forming coupling
reaction” submitted by Anis Ahmed, Department of Chemistry, Aliah University
for the partial fulfillment of the M.Sc. degree in Chemistry, year 2019. He has done
this study under my direct supervision. Neither this project nor any part of it had
been submitted anywhere before for any degree/diploma/academic awards.

………………………………. ………………………………….
Project Supervisor Head of the Department
Dr. Safiul Alam Dr. Akhtarul Alam
 ACKNOWLEDGEMENTS

I bend over in adoration to the Almighty ALLAH whose kind blessing gave me the required
enthusiasm for completion of the work.

Every big or small is successful largely due to the effort of a number of wonderful people who
have always given their valuable advice and helping hand. I sincerely appreciate the inspiration ;
support and guidance of all those people who have been instrumental in making this project a
success.

I would like to express my sincere gratitude to my M.Sc. Project and Review work supervisor
Dr. Safiul Alam, Assistant Professor, Department of Chemistry, Aliah University for giving me
such a golden opportunity to do this project in the field of new methodology development in
organic synthesis. I am thankful to the Ph.D. scholars of the laboratory, Aminur Khan and Rejaul
Karim for their help. This opportunity helped me a lot to enhance my knowledge and practical
skill in Synthetic Organic Chemistry and Catalysis.

I would also like to thank Dr. Akhtarul Alam(HOD), and all my respected teachers in the
Department of Chemistry, Aliah University, for their valuable advices.

It is my pleasure and a very good experience working in a good research environment research
at Department of Chemistry, Aliah University, New Town campus, Kolkata-700160.

Last but not the least I place a deep sense of gratitude to my family members and my friends
who have been constant source of inspiration during the preparation of this project work.

………………………….

ANIS AHMED

CONTENTS
 1. Abstract

2. Introduction

3. Early transition metal

4. Synthetic routes
5. Therapeutic effect of Carbazoles
6. Uses
7. Conclusion

8. References

A brief overview of different methods, used for synthesize carbazoles

and it’s derivatives via first transition metal catalysed, followed by
C-N bond forming coupling reaction
 Anis Ahmed

Department of Chemistry, Aliah University, IIA/27, New Town, Kolkata 700160, India

1. ABSTRACT

A palladium catalyzed reaction sequence consisting of an intermolecular amination and an

intramolecular direct arylation enabled highly regioselective syntheses of functionalized indoles
or carbazoles and proved to be amenable to the use of inexpensive 1,2-dichloroarenes as
electrophiles. Some first transition metal was also used as catalyst. Metal like Cu was used to
prepare carbazoles. Genarally Negishi coupling, Silylative coupling, Hiyama coupling takes
place for formation of carbazoles. From various type of amine compound carbazoles with
different yield. Importance of carbazole synthesis is for having biological activities that
beneficial to human. Carbazoles inhibits DNA topoisomerase activity. It is also used for breast
cancer treatment.

Graphical Abstract:

Scheme 1

2. INTRODUCTION

The prevalence of heterocycles in medicinally important compounds continues to derive the

need for new methods for their preparation . Carbazole derivatives are known to have important
photo physical and biological properties. Carbazole A was isolated first from coal tar in 1872 by
Graebe and Glazer.

In this review, the authors summarize different synthetic routes for the syntheses of carbazole
alkaloids and their derivatives. Moreover, a detailed coverage from year 2001-Feb 2008 of the
classical methods and the non-classical procedures for the total syntheses of the biologically
active carbazole alkaloids and their derivatives have also been reported. The nomenclature used
in this review for carbazole alkaloids is that used by Chemical Abstracts. Conventional tricyclic
ring systems are denoted by A,B and C and the numbering starts from ring A. The term
carbazole used in this review refers to a 9H-carbazole. The classification of the carbazoles is
based on the substitution pattern of ring A, although ring C may also carry various substituents.
Carbazole is an alkaloid which we need to synthesis for human beneficial issues. Like it has
some activities to stop DNA replication. Carbazoles, whether synthetic or natural, constitute an
important class of indole-containing heterocycles known for their potent antitumor activities also
for antibacterial, anti-inflammatory, psychotropic, and anti-histamine properties. Therefore
synthesis of carbazole is very Important. By intermolecular interaction of iodobenzoic acid and
aniline and then cyclisation through C-C bond forming reaction carbazole can be prepared. Or
intramolecular interaction of biphenylaniline carbazole can be synthesize. Negishi coupling,
Silylative coupling, Hiyama coupling reaction route followed for formation of carbazoles. The
cyclisation takes place using ‘early transition metal’ or ‘first transition metal’ like Copper. Some
synthetic routes are shown in the Review report. Mainly in this Review report synthesis is shown
according to seheme 1.

3. Early transition metal:

 Many compounds with early transition metals (Ti, Zr, V, Nb, Ta, Mo, W, Re…..) in low
oxidation states are known which are characterized by metal metal bond. These metals from
aggregates, called clusters, such as pairs, triangles or regular shaped polyhedral such as
tetrahedral, octahedral or polyoctahedra.

4. Synthetic routes:

Ching-Yuan li and co-workers have developed a method for new carbazole synthesis starting
from Grignard reagent. They have done a Negeshi cross-coupling with 1,2-diiodobenzene
resulting in the formation of derived polyfunctional biphenyls. They used Pd-cat as well as 1st
transition metal Zn.
Some reaction routes are shown here with yield.

Here biphenylacetanilides are coupled together to form carbazole(2). Reaction condition is Pd-
cat and Cu-cat in O2 atmosphere in toluene solvent at 120oC temperature.

Cyclisation by intramolecular C-N bond forming carbazoles synthesis are shown in the table
(1)with yield.
Table 1
From 2-chloroaniline derivaties, carbazole synthesis is also possible that is shown in the table(2).

Table 2

Carbazole can be synthesize from nitrophenyl and its derivatives. It is also shown in this table(3).
Table 3
5.Therapeutic effect of Carbazoles:

Carbazoles, whether synthetic or natural, constitute an important class of indole-containing

heterocycles known for their potent antitumor activities also for antibacterial, anti-inflammatory,
psychotropic, and anti-histamine properties.

The precise mechanism of their anti-neoplatic activity have not yet been fully explained,
however it was suggested that the prevalent mechanisms of the antitumor. Mutagenic and
cytotoxic activities is based on their intercalation into DNA and inhibition of DNA
topoisomerase.

In spite of the significant progresses in cancer prevention, early diagnosis and treatment, in the
last few decades reports on carcinoma cases have shown a drastic increase, mostly due to
changes in lifestyle and environment. Today, research studies still uncover lifestyle factors or
habits which may influence breast cancer risk but some studies evidenced changes in metabolic
biomarkers, e.g. insulin and insulinlike growth factors, and that body fatness in mid- and laterlife
may increase the risk in postmenopausal women, although these findings are not yet consistent .
The two most common types of cancer in females are represented by cervical and breast cancer,
indeed the American Cancer Society (ACS) estimates more than 12.000 new cases of diagnosed
cervical cancer in 2011, whereas breast cancer has become the most commonly diagnosed
malignant tumor in women, accounting for 24% of all female cancer and being the second most
lethal cancer among women. A major contribution to the rise of the mortality has been attributed
to the development of resistance against chemotherapeutics, for instance to cisplatin.

Many strategies have been accomplished with the hope to diminish the incidence and mortality
rates, such as the reduction of hormone replacement therapy , a better prevention and improved
early detection and treatment. Even though encouraging advances have been made in diagnosis
and clinical practice, a trend towards a multifaceted therapeutic approach, which targets
pathways promoting or sustaining cancer cell growth and invasion with a minimal effect on
normal cells, has been recorded . One of the most widely used strategies in breast cancer therapy
has been the induction of the programmed cell death, namely apoptosis, in tumor cells but,
beside, several pathways are potential targets for cancer treatments. Amongst them, pathways
involved in cell cycle regulation, angiogenesis, in maintaining the cellular redox state or even
those triggered by membrane and nuclear receptors are also considered clinically useful . Great
advances have been made in the diagnosis, prevention and treatment of the estrogen receptor
(ER) positive breast cancer and, most recently, several breast cancer trials targeting the human
epidermal growth factor receptor 2 (HER2) have demonstrated their clinical efficacy.
Nevertheless, the identification and development of effective, safe and selective therapies for the
treatment of the so called triple negative breast cancers (TNBC), which lack of ER, progesterone
receptor (PR), and HER2, still remains challenging.

6. USE:

The precise mechanisms of their anti-neoplastic activity have not yet been fully explained,
however it was suggested that the prevalent mechanisms of the antitumor, mutagenic and
cytotoxic activities is based on their intercalation into DNA and inhibition of DNA-
topoisomerase II activity . Amongst these, carbazole sulfonamides represent a novel promising
class of antimitotic agents with clinical development potential. In particular, a novel synthetic
tubulin ligand with small molecular weight and a tricyclic planar structure, has been used
successfully in vitro against MCF-7 breast cancer cells and human hepatocellular carcinoma
SMMC-7721 cells, that is IG-105 (N-(2,6- dimethoxypyridin-3-yl)-9-methylcarbazole-3-
sulfonamide) (1), synthesized by Wang et al..

6. CONCLUSION

Carbazoles are naturally occurring organic compound that can be also synthesize in
laboratory as mentioned. The necessity of synthesis of carbazole is for its activities towards
cancer and tumor cell. Carbazoles are soluble at room temperature in all the common organic
solvents. The absorption spectra of carbazole show high energy forbidden Sn-S2. To fulfill the
needs of carbazoles, it is very important to synthesize in lab. As I have shown it can be
synthesize from biphenylaniline, 2-chlorobiphenyl, nitro-biphenyl etc compound by 1st transition
metal catalysed C-N bond forming cyclisation reaction. Negeshi cross-coupling, Hiyama
coupling etc are applicable for the synthetic route of carbazoles.

5. REFERENCES

[1] C. Graebe and C. Glazer, Ber. Dtsch. Chem. Ges.,5, 12 (1872). 2518 Yaqub et al.

[2] C.Y. Liu and P. Knochel, Org. Lett., 7, 2543 (2005)

[3] R.B. Bedford and S.J. Cazin, Chem. Commun., 2310 (2002).

[4] R.B. Bedford and S.J. Cazin, Chem. Commun., 1540 (2001).

[5] M. Rawat and W.D. Wullf, Org. Lett., 6, 329 (2004)

[6] A. Aygun and U.J. Pindur, Heterocyl. Chem., 40, 411 (2003).

[7] J. Jiricek and S. Blechert, J. Am. Chem. Soc., 126, 3534 (2004).

[8] M. Tumor, J. Med. Chem., 47 1609 (2004)

[9] Z. Li and J. Li, Huaxue Shiji, 23, 188 (2001)

[10] G.H. Kirsch, Curr. Org. Chem., 5, 507 (2001)