Domino Reactions in Organic Synthesis

SYNTHESIS

A Thesis submitted to Goa University for the Award of the Degree of

D O C T O R O F P H IL O S O P H Y In

C H E M IS T R Y

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G O A U N IV E R SIT Y T A L IE G A O P L A T E A U

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CERTIFICATE

This is to certify that the w ork incorporated in this thesis entitled,

“DOM INO R E A C T IO N S IN O R G A N IC S Y N T H E S IS ” submitted by Ms.

Prachi S. T orney, has been carried out by the candidate under my supervision and the same has not been submitted elsewhere for the award o f a degree.

Goa University January 2013

Prof. Santosh G. Tilve Research Guide and Head Department o f Chemistry G oa University

Heac' Department of '

GOA UNIVEK&i

I hereby declare that the matter em bodied in this thesis entitled,

“DOMINO R E A C T IO N S IN O R G A N IC S Y N T H E S IS ” is the result o f investigation carried out by m e, in the Department o f Chemistry, Goa University, Goa-India, under the supervision o f P ro f. S. G. T ilve and it has not previously formed basis for any other titles.

In keeping with the general practice o f reporting scientific observations, due acknowledgement has been m ade wherever the work described is based on the findings o f other investigators

Goa University January 2013

Ms. Prachi S. Torney

A C K N O W L E D G E M E N T

Undertaking this Ph. D has been a truly life-changing experience for me and it would not have been possible to reach to this stage w ithout the support and guidance that I received from many people during this journey. I take this opportunity to express my deep sense of gratitude to all the people who have directly or indirectly contributed to the successful completion o f this thesis.

First and foremost, I sincerely thank my supervisor Prof. S. G. Tilve, Head, Department o f Chemistry, Goa U niversity, for giving me an opportunity to pursue my research work under his valuable guidance. The work presented in this thesis would not have been possible w ithout his able guidance, constant support, constructive criticism and painstaking efforts. I also truly appreciate the independence given by him to carry out experimental work and also the patience shown during the tim es o f my failures. I will forever be grateful to him for the very im portant role he has played in my life.

I offer my thanks to Prof. A. V. Salker (Ex-Head, Department o f Chemistry, Goa University, for providing necessary facilities for my research work. I also acknowledge DST, New Delhi, for providing financial assistance.

I express m y sincere gratitude towards my subject experts, Dr. V. S. Nadkarni and Dr. P. S. Param eswaran, for providing the much needed insight into my subject. I can never forget the pains taken by Dr. P. S. Parameswaran for recording N M R data of many of my samples. I also acknowledge Prof. B. R. Srinivasan for his expert advice and help during the X RD studies o f my samples.

My very special thanks to Prof. S. P. Kamat and Prof. V. P. Kamat for all the knowledge I gained from them during m y tenure in the university. I also thank Prof. J. B.

Fernandes, Prof. K. S. Rane, Dr. R. N. Shirsat, Dr. V. M. S. Verenkar, and Dr.

Sunder Dhuri for their encouragem ent and goodwill.

All the non-teaching staff, Departm ent o f Chemistry, Goa University have been extremely helpful and I thank them all. I also acknowledge the Librarian and staff members of Library, Goa University for their constant help.

and support during the entire period o f m y thesis work. I w ish to thank my senior group members Dr. R upesh, Dr. M ahesh, Dr. Reshma, Dr. Prakash, and Dr. Sonia for helping me to adjust in the lab during the initial stages and also for their valuable suggestions and constant encouragement. I thank Dr. R upesh for providing me with some of the required references and GCMS analysis o f my sam ples and also for the fruitful discussions. During the final days o f my experimental work, Dr. Prakash has been a great support. His suggestions and encouragem ent helped m e tremendously to give my investigation its present shape and I w ill always be grateful to him for this. I am also grateful to my present colleagues Chinm ay, Hari, Sandesh, Kashinath, Sagar, Prajesh, Durga, Mayuri, Siddhi and Dr. Nitya for warm friendship, encouragement and help in numerous ways. I specially thank the boys for spending their extra time and efforts in recording the N M R data o f my samples. I owe my thanks to Siddhi and Siddhesh for designing the cover pages o f my chapters. My friend Sandesh has been the biggest support for me dining the final stages o f this thesis. It was his encouragement and support that helped me keep going through the difficult times. I am glad to have a friend like him and I wish him the best in his life and career. 1 also cherish the friendship o f Dr. Priyanka, Dr.

Lactina, Shrikant, Dr. Puzy, M ufedah and Surekha who have always been a great support throughout m y Ph. D tenure. I also acknowledge m y other research colleagues Dr.

Savia, Dr. Sulaksha, Dr. Jose, Dr. V inod, Dr. Satish, Dr. Rohan, Dr. Rajashri, Kiran, Mira, Diptesh, D attaprasad, M ithil, M adhvi, Shambhu, Satu, Celia, Savita, and Rita for making my days enjoyable at the university.

I am greatly indebted to my parents for their unconditional love and sacrifice. They have worked very hard all their lives so as to provide me and m y brother the best possible environment. In their supportive, understanding, loving and caring ways, they always stood with us in all our pursuits. I thank them greatly for their constant support and inspiration, w ithout w hich it would not have been possible for me to be where I am today.

I also thank my little brother for alw ays being there besides me.

Above all, I thank the Almighty for giving me such a wonderful and satisfying life and for showering his kind blessings on us.

Ms. Prachi S. Torney

Page No.

General Remarks i

Definition o f Abbreviations ii

Abstract o f the Thesis vii

List of Publications viii

Chapter 1: Recent Developments o f W ittig Reaction Through Domino or Sequential Processes

1-23

Introduction 1

Sequences involving W ittig reaction - Claisen rearrangement 5 Sequences involving W ittig reaction - Cope rearrangement 10

Sequences involving W ittig - Diels - A lder reaction 11

Sequences involving oxidation - W ittig reaction 17

Chapter 2:

Domino W ittig - Diels - A lder Reactions

Section A:

Synthesis o f Furo and Pyrrolocarbazoles 24-96

Introduction 24

Review of Literature 25

Results and Discussion 33

Experimental Section 80

References 90

Section B:

Synthesis o f Heterolignans 97-145

Introduction 97

Review o f Literature 99

Results and Discussion 109

Experimental Section 136

References 144

Section C

: An Approach Towards Synthesis of Taiwanin C 146-174

Introduction 146

Review of Literature 147

Results and Discussion 158

Experimental Section 167

Spectra 169

References 173

Chapter 3: Synthetic Studies Towards Indolocarbazole Alkaloids- 175-225 Arcyriaflavin A and Staurosporinone

Introduction 175

Review of Literature 177

Results and Discussion 196

Experimental Section 209

Spectra 213

References 222

Chapter 4: Dom ino W ittig Reaction- Claisen rearrangement:

Synthesis of Ostruthin

226-248

Introduction 226

Review o f Literature 227

Results and Discussion 227

Experimental Section 237

Spectra 239

References 247

1) The compound numbers, figure num bers, scheme numbers and reference numbers given in each chapter refer to that particular chapter only.

2) All melting points and boiling points were recorded using Thiele's tube and are uncorrected.

3) Commercial reagents were used w ithout further purification.

4) All solvents were distilled prior to use and then dried using standard procedure.

5) Petroleum ether refers to the hydrocarbon fraction collected in the boiling range 60 - 80 °C.

6) All reagents were prepared using literature methods.

7) Chromatographic purification was conducted by column chromatography using

silica gel (60 - 120 mesh size) or b y flash chrom atography using silica gel (200-400 mesh size). Chemical shifts within.square brackets give the values o f the amide torsion isomer while those in the round bracket represent the m inor isomers formed during the reactions.

8) Thin layer chrom atography (TLC) were carried out on glass plates using silica gel G and were developed in iodine.

9) The 1R spectra were recorded on Shimadzu FT-IR spectrophotometer.

10) *H NMR (400 MHz) and l3C NM R (100 MHz) spectra were recorded on a Brucker AVANCE 400 instrument and the multiplicities o f carbon signals were obtained from DEPT experiment.

11) The high resolution mass spectra (HRMS) were recorded on MicroMass ES- QTOF mass spectrometer.

DEFINITION OF ABBREVIATIONS

1) G eneral Abbreviations

g Gram/s

mg Milligram/s

mmol Millimole

mL Milliliter

m.p. Melting point

b.p. Boiling point

IMDA Intramolecular Diels-Alder

Eq. Equation/s

lit. Literature

d Day/s

h Hour/s

min Minute/s

sec Second/s

Z Zussamen (together)

E

Eentegegen (opposite)

R

Rectus

S

Sinister

Fig. Figure

cone. Concentrated

dil. Dilute

sat. Saturated

aq. Aqueous

anhyd. Anhydrous

hv

Irradiation

C

Degree Celcius

% Percentage

RT / r.t. Room tem perature

Expt. Experiment

Temp. Temperature

M W / p W Microwave

m

Meta

P

^Para

MS Molecular sieves

psi Pounds per square inch

cat. Catalytic

atm. Atmospheric

et al.

Et alia (and others)

TLC / tic Thin layer chromatography

ORTEP Oak ridge therm al ellipsoid plot

RCM Ring closure metathesis

SAR Structure activity relationship

Calcd. Calculated

2) Com pound Abbreviations

Ac Acetyl

AC2O Acetic anhydride

TBAF Tetrabutyl am m onium fluoride

Ar Aryl

Boc

tert

-Butyl carbonyl

Bn Benzyl

Bz Benzoyl

t-

Bu

tert

-Butyl

TFA Trifluoro acetic acid

TFAA Trifluoro acetic anhydride

TEA Triethyl am ine

AcOH Acetic acid

MeOH Methanol

EtOH Ethanol

m-CPBA m-Chloroperbenzoic acid

p-TsOH/

p

-TS A /7-Toluene sulfonic acid

ICZs Indolocarbazoles

DMSO Dimethyl sulfoxide

DMF N,N-Dimethylformamide

THF T etrahydrofuran

Et Ethyl

Me Methyl

LDA Lithium diisopropylamide

LAH Lithium alum inium hydride

NBS M-Bromosuccinimide

EtOAc Ethyl acetate

w-BuLi n-Butyl lithium

t-BuLi /-Butyl lithium

ECz M-Ethylcarbazole

Pd/C Palladium on activated charcoal

Ph Phenyl

PMB p-M ethoxybenzyl

PPh3 Triphenylphosphine

TBAF Tetrabutylammonium fluoride

Ms Methane sulfonyl

TMS Trimethylsilyl

TMSCN Cyanotrimethyl silane

Ts /7-Toluene sulfonyl

Py Pyridine

NMO ./V-Methyl m orpholine oxide

DM AD Dimethyl acetylene dicarboxylate

DCM Dichloromethane

DCE 1,2-Dichloroethane

PCC Pyridinium chlorochromate

DMS Dimethyl sulphate

DDQ 2,3-Dichloro-5,6-dicyanobenzoquinone

Pet ether Petroleum ether

TsCl Tosyl chloride

DABCO 1,4-Diazabicyclo[2.2.2]octane

DMAP 4-Dimethyl amino pyridine

HMPA Hexamethylphosphoramide

MCP Methylene cyclopropyl

DCC Dicyclohexyl cabodiimide

CAN Cerric ammonium nitrate

DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DMP Dess-M artin periodinane

DIBALH Diisobutyl aluminium hydride

MOM M ethoxymethyl ether

B0C2O

tert

-Butyl dicarbonate

/-PrOH Iso-propanol

TBHP

tert

-Butyl hydroperoxide

DNA Deoxyribonucleic acid

CDK Cyclin-dependant kinase

3) Spectroscopic Abbreviations

IR Infrared

Umax Frequency m axim um

cm'1 Frequency in wavenumber

u v Ultra violet

N M R Nuclear m agnetic resonance

CDCI3 Deuterated chloroform

D M SO -d6 Deuterated dimethyl sulfoxide

DEPT Distortionless Enhancement by Polarization Transfer

ppm Parts per m illion

S

Delta (Chemical shift in ppm)

MHz M egahertz

Hz Hertz

J

Coupling constant

br s Broad singlet

s Singlet

d Doublet

t Triplet

q Quartet

m Multiplet

dd Doublet o f doublet

td Triplet o f a doublet

HRMS High Resolution Mass Spectrum

M+ Molecular ion

m/z

Mass to charge ratio

Domino processes have gained paramount interest in organic synthesis as they allow access to a myriad o f complex molecules with high stereocontrol in an efficient, atom-economical manner. The thesis entitled "Domino Reactions In Organic Synthesis"

describes our efforts towards the synthesis o f some natural and non-natural potentially bioactive compounds using domino reaction sequences. It is divided into four chapters as follows:

Chapter I gives a review o f recent developments o f Wittig reaction in organic synthesis through domino or sequential processes and is centered on the use o f one-pot processes involving W ittig as the core reaction for the synthesis o f highly functionalized and biologically important compounds and also for the total synthesis o f natural products.

Other reactions forming a parts o f these domino sequences are Diels-Alder reaction, Claisen rearrangements and oxidation reactions. The m ajor exploits in this area o f research for last decade are highlighted in this chapter.

Chapter II describes our work in domino Wittig- Diels- Alder reaction sequences and is further divided into three sections. Section A presents our efforts towards the synthesis o f som e furo- and pyrrolocarbazoles. Regioisomeric carbazole lactones and lactams have been synthesized from indole carboxaldehydes using a domino Wittig- Diels- Alder reaction sequence. In Section B, this domino sequence has been extended for the synthesis o f a series o f some indole based heterolignans in good yield. These compounds are structurally sim ilar to a highly potent heterolignan azatoxin and are thus expected to possess some interesting biological activities. Section C o f this chapter deals with our approach towards the synthesis o f aryl naphthalene lignans. Using this domino sequence we have successfully achieved the tricyclic framework o f justicidin E.

Chapter III presents our synthetic studies towards indolocarbazole alkaloids arcyriaflavin A and staurosporinone. The strategy employs a one pot oxidation-Wittig reaction, an iodine catalysed dom ino electrocyclisation-aromatisation, and a nitrene insertion reaction as the key steps. The total synthesis o f arcyriaflavin A and a fonnal synthesis o f staurosporinone have been achieved. The key intermediate o f this strategy also gives an access to the pentacyclic fram ew ork o f calothrixin B.

Chapter IV describes our efforts towards the synthesis o f a 6-geranyl-7- hydroxycoumarin- ostruthin. A formal synthesis o f this molecule has been described using a domino W ittig reaction- Claisen rearrangement sequence.

LIST OF PUBLICATIONS

1) Torney, P. S.; Patre R. E.; Tilve, S. G. A Rapid Assembly o f Furo[3,4-h]- and Pyrrolo[3,4-Z>]carbazolones by Domino Wittig Diels-Alder Reaction. Synlett, 2011(5): 639-642.

2) Parvatkar, P. T.; Torney, P. S.; Tilve, S. G. Recent Developments o f Wittig Reaction in Organic Synthesis through Tandem or Sequential Processes. Curr. Org.

Synth. 2011 {Review Article Accepted).

3) Torney, P. S.; Patre R. E.; Tilve, S. G. Synthesis o f Heterolignans using a domino Wittig-Diels A lder reaction sequence . {communicated).

4) Torney, P. S.; Tilve, S. G. Synthesis o f indolocarbazole alkaloids Arcyriaflavin A and Staurosporinone using dominop sequences. (communicated).

5) Torney, P. S.; Naik, M. N,; Tilve, S. G. Synthesis o f methoxymethyl ether of Ostruthin using a domino W ittig reaction- Claisen rearrangement sequence.

{manuscript under preparation).

CONFERENCE PUBLICATIONS

Oral Presentation:

1) Paper entitled “Domino reactions in Organic Synthesis" presented at National Organic Sym posium Trust, J-N O ST 2011, USER, Mohali.

Poster Presentation:

1) Paper entitled “ Synthesis o f Heterolignans using a domino Wittig-Diels Alder reaction sequence " presented at RTOS 2011, Bhartidasan University, Trichi.

2) Paper entitled “Rapid assembly o f Furo and Pyrrolocarbazoles using a domino Wittig-Diels A lder reaction sequence." presented at Royal Society o f Chemistry- West India Section 2010, Goa University, Goa.

vin

Recent Developments o f Wittig Reaction in

Organic Synthesis through Domino or

Sequential Processes

R E C E N T D E V E L O PM E N T S O F W ITTIG R EA C T IO N IN O RG ANIC SY NTH ESIS TH R O U G H D O M IN O OR SE Q U E N T IA L PR O CESSES

Synthetic organic chemistry is a creative field o f limitless scope, and has developed in a fascinating w ay over the past so many decades. Several highly selective procedures have been developed which allow the preparation o f complex molecules with excellent regio-, chemo-, diastereo-, and enantioselectivity. However, despite o f its great success and importance to the society, the current image o f organic synthesis has deteriorated predominantly because o f the environmental and the economical issues. Today, the major problems in a chemical production are handling o f the wastes, search for environmentally tolerable procedures, preservation o f resources and increase in efficiency.

To overcome the drawbacks involved in conventional multistep syntheses, a new trend of carrying out multiple reactions in a single operation came into existence a few decades ago. This m ethod o f synthesizing compounds was called as the one-pot, tandem or cascade reactions. Unlike the traditional linear and stepwise processes in which isolation and purification o f key intermediates often lead to reduced yields, these reactions offered preparatively sim ple and elegant solutions to complex synthetic problems in an ecologically and economically favorable way. A more specific term for such reaction sequences called as the domino reactions was later given by Prof. L. F. Teitze,1 which he defined as a process involving two or more bond form ing transformations (usually C-C bonds) which take place under the same reaction conditions without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence o f the functionality form ed in the previous step.

Thus, a prerequisite for an ideally proceeding dom ino transformation is that the reactivity pattern o f all participating components has to be such that, each building block gets involved in a reaction only when it is supposed to do so. These reactions proceed in a well-ordered m anner as the respective constellation o f functional groups required for a certain step is generated only in the preceding one. This makes the use o f protecting groups dispensable and waste-generating work-up and purification o f stable as well as unstable intermediates obsolete. The usefulness o f a domino reaction is correlated firstly to the number o f bonds which are formed in one sequence- called as the bond-forming efficiency (or bond-forming economy), secondly, the increase in structural complexity (structure economy) and thirdly to its suitability for a general application.

Domino processes have gained paramount interest in organic synthesis as they allow access to a myriad o f complex molecules with high stereocontrol in an efficient, atom-economical manner. They possess many practical advantages in addition to their undeniable esthetic appeal. Well designed and executed domino sequences often provide effective solutions to challenging problems and in certain cases only the simplest of conditions and reagents are required. A number of reviews2 covering many such domino methodologies are available in the literature which demonstrates the enormous power of these processes in organic synthesis.

Historical Background:

In nature domino reactions are a rather common phenomenon, however its direct comparison to the reactions in a flask is not possible m ainly because o f the involvement of multienzymes w hich can allow the catalysis o f different steps. A beautiful example in this respect is the biosynthesis o f steroids from squalene epoxide (Fig. 1) which is transformed highly selectively into lanosterol with the formation o f four C-C bonds and six stereogenic centers.3

Chapter I

Classification o f Dom ino Reactions:

In the last few years there has been an explosion in the development o f new domino reaction sequences. Clearly m any o f these reactions do not meet the strict definition as that given by Prof. L. F. Teitze. Hence, a clear classification o f the different types o f domino reactions was introduced which not only allowed a better understanding o f the different types o f domino reactions but also facilitated the invention o f new ones.

According to the mechanism o f the first step, one could distinguish between a cationic, anionic, radical, pericyclic, photochemical and transition metal induced transformation which could be combined with reactions o f the described type in a second, a third or even a fourth step.

A domino sequence having a combination o f reactions o f the same mechanism is called

homo-domino reactions

, whereas a sequence o f reactions with different mechanisms is called

hetero-domino reactions

(Table 1). It is understandable that homo­

domino reactions such as cationic-cationic ( la /2a), anionic-anionic (lb /2b), radical-radical (lc /2c), pericyclic-perieyclic (ld /2d) and transition metal induced reactions (lf /2f) are found in literature m ore frequently, but there are also very powerful hetero-domino reactions such as the anionic-peri cyclic (lb /2d) sequence or even the anionic-pericyclic- pericyclic (la/2d/3d) sequence which have been investigated.

1st Step 2nd Step 3rd Step

la cationic 2a cationic 3a cationic

lb anionic 2b anionic 3b anionic

lc radical 2c radical 3c radical

Id pericyclic 2d pericyclic 3d pericyclic

le carbenoid 2e carbenoid 3e carbenoid

If transition metal induced

2f transition metal induced 3f transition metal induced

lg photochemical 2g photochemical 3g photochemical

lh oxidation/reduction 2h oxidation/reduction 3h oxidation/reduction

3 ( P a g e

For our research work we were interested in employing Wittig reaction in domino sequence with pericyclic reactions for the synthesis o f some natural and non-natural compounds. The W ittig reaction5 is one o f the most effective synthetic methods for the introduction o f a carbon-carbon double bond and the versatility o f this reaction is demonstrated by its extensive use in the synthesis o f natural products.6 In its simplest fonn it involves the reaction o f a phosphorane (ylide) with either an aldehyde or a ketone, yielding an alkene and phosphine oxide as products (Scheme 2).

Rh

R3p= <

r2

ylene form

+ ^{V R 1 R 4}

r3p^ ( +

R 2 R 5

ylide form

Scheme 2

R 1 R 4

) = ( +

r

3

p

=

o

R 2 R 5

In the past decade tremendous developm ent in domino or sequential processes with the Wittig reaction has taken place for the construction o f several important compounds ranging from sim ple acyclic or cyclic compounds to complex polycyclic compounds. This review is centered on the use o f one-pot processes involving Wittig as the core reaction for the synthesis o f highly functionalized and biologically important compounds and also for the total synthesis o f natural products. In this review, we have covered the domino or sequential processes involving reactions like oxidation and pericyclic reactions with the carbon-carbon double bond forming W ittig reaction. All these reactions were carried out in one-pot wherein either the Wittig reaction is followed b y other reactions or the other reactions are follow ed by the W ittig reaction in a domino or sequential fashion. These multistep, one-pot reactions are accompanied by dram atic increase in molecular complexity and im pressive selectivity and also lead to reduction in the amount of byproducts, solvents, eluents, time and energy, thereby contributing to the protection o f the environment. The applications o f these one-pot reactions for the synthesis o f highly functionalized, biologically active com pounds and natural products for the last ten years (from 2000 to O ctober 2011) are highlighed.

A] Sequences involving W ittig reaction and Pericyclic Reactions:

Schobert and Gordon8 in 2002 have reviewed the domino Wittig-pericyclic reactions for the synthesis o f bioactive heterocycles. The examples described therein are not included in the present review.

Chapter I

a) Wittig reaction -Claisen rearrangement:

The Claisen rearrangement is the first example o f [3,3]-sigmatropic rearrangement which allows the conversion o f an easily accessible carbon-hetero atom bond into a new carbon-carbon bond, making this rearrangement a versatile method for the construction of complex molecules. The Claisen rearrangement is an atom economic process and it can be carried out under mild conditions in a chemo-, regio- and/or stereoselective manner to furnish useful polyfunctional molecules.

Using tandem Wittig-Claisen rearrangement, several simple and complex oxygen- containing heterocycles have been prepared including some naturally occurring bioactive compounds.

Mali and co-workers9 reported a novel and general route for the synthesis o f some naturally occurring 6-prenyl coumarins and their analogues using a tandem W ittig reaction and Claisen rearrangem ent sequence (Scheme 3).

When 4-methoxy-2-prenyloxybenzaldehyde and phosphorane was refluxed in

N,N-

dimethyl aniline for 6h under N2 atmosphere, the 6-prenyl -3-substituted coumarins were obtained in 47-67% yield

via

Wittig reaction followed by Claisen rearrangement. However when R=H, 3-prenyl-7-methoxycoumarin was obtained in 7% yield in addition to 6- prenyl-7-methoxycoumarin.

Similarly compounds 6 & 7 (Figure 2) were prepared from corresponding starting materials.

5 | P a g e

M e O ^ L , ° OMe MeO

r V r ° X X _"R

6 OMe

R = H, Me R = H, Me, CH2CH=CH2, CH2Ph 7

Fig. 2

Some o f these coumarins were then transformed into linear dihydropyrano- coumarins by sim ple heating with pyridine hydrochloride under inert atmosphere (Scheme 4).

The synthesis o f naturally occurring diprenylated coumarins gravelliferone 8, balsamiferone 9, 6,8-diprenylumbelliferone 10 and demethylsuberosin 11 were achieved in our laboratory10

via

a cascade W ittig reaction-double Claisen and Cope rearrangement approach (Scheme 5).

Schem e 5

2,4-Diprenyloxybenzaldehyde when treated with phosphorane in refluxing diphenyl ether, a sequential W ittig reaction and tw o consecutive Claisen and multiple Cope rearrangements took place in one pot to afford gravelliferone 8, balsamiferone 9, 6,8-

Chapter I

diprenylumbelliferone 10 and demethylsuberosin 11 in 10, 5, 15 and 20% yield respectively along with other two coumarin derivatives 12 & 13.

The above work was later extended for the synthesis o f naturally occurring prenyl coumarins - balsamiferone 9 and cedrelopsin11. Balsamiferone is formed by tandem Wittig reaction, Claisen-Cope rearrangement, deprenylation and lactonization sequence

ai

(Scheme 6) w hile the synthesis,cedrelopsin is accomplished using tandem W ittig reaction, deprenylation, intramolecular prenylation and cyclization approach (Scheme 7).

Schobert and Jagusch12 reported a domino addition-W ittig olefination-Claisen rearrangement reaction under m icrow ave irradiation to give the functionalized resin-bound tetronates 14 (Schem e 8).

The tandem addition-intram olecular Wittig alkenation reaction o f immobilized hydroxyesters w ith cumulated ylide under microwave irradiation in presence o f catalytic amount o f benzoic acid afforded the respective compounds 14. The methodology could be useful to prepare the libraries o f potentially bioactive heterocycles.

RamaRao

et al.

have developed a microwave assisted tandem intramolecular Wittig reaction-Claisen rearrangement sequence for the synthesis o f fluoro substituted 3- cyano-2-methyl benzo[6]furans and ethyl 2-methylbenzo[&]furan-3-carboxylates in a single step from the corresponding [(aryloxyacetyl)/(cyano)- methylene]triphenylphosphorane and [(aryloxyacetyl)(ethoxycarbonyl)-methylene]- triphenylphosphorane, respectively (Schem e 9).

Chapter I

[(Aryloxyacetyl/cyano)(ethoxycarbonyl)methylene]triphenylphosphoranes were prepared in good yields by the transylidation reaction o f the [(cyano)methylene]triphenylphosphoranes with aryloxyacetyl chlorides. These phosphoranes on irradiation with microwaves for 6-8 mins resulted in the exclusive formation o f 2-methylbenzo[&]furan derivatives 15 in 32-62% yields. The formation of 15 is seen as a result o f tandem intramolecular Wittig, Claisen rearrangement reactions followed by ring closure o f the allenyl phenol intermediate. The reaction was studied for different substituents on the aryl m oiety and gave exclusively only one regioisomer in almost all cases.

However, when methyl substituent is present at the C-3 position, it favours the rearrangement to its

ortho

position resulting in the formation o f 3-cyano-2,4- dimethylbenzofuran 16 (Scheme 10).

Scheme 10

The sam e gro u p14 then extended the above work for the synthesis o f benzofurans by employing transylidation reaction w ith aryloxypropanoyl chloride (Scheme 11).

Scheme 11

R1 = H, Cl, F

R2 = H, Cl

Z = CN, COOEt

The oxy ylides thus formed, on controlled microwave irradiation for 6-8 mins, underwent a tandem intramolecular Wittig-Claisen rearrangement reaction and intramolecular cyclization to give fluoro containing 3-cyano/ethoxycarbonyl-2-ethylbenzo[6]furans in good yields.

b) Wittig reaction-Cope rearrangement:

Kawasaki and co-workers15 demonstrated the domino Wittig olefination and reverse aromatic Cope rearrangement to give a-allyl-3-indole acetate derivatives 19 in good yields (Scheme 12).

When 2-allylindolin-3-one 17 was treated with the phosphonium ylide in refluxing toluene, the W ittig olefination followed by the reverse aromatic Cope rearrangement o f the resultant intermediate 82 took place to give the corresponding compounds 19 in good yields.

Likewise, the treatment o f 2-(l,l-dim ethylallyl)indoline-3-one 20 with ylides afforded the products 21 in moderate to good yields (Scheme 13).

Tang

et al

. 16 explored a tandem Wittig reaction-C ope rearrangement of methylenecyclopropyl (MCP) aldehydes 23 with cinnamyltriphenylphosphonium bromide

Chapter I

22 at room temperature in presence o f «-BuLi to give the functionalized cyclopentene derivatives 24 in one-pot (Scheme 14).

The reaction works well with the M CP aldehydes having both electron-withdrawing as well as electron-donating groups on benzene ring to furnish the corresponding cyclopentene derivatives 24 in 55 - 77% yields indicating the broad substrate generality of this reaction.

3) Wittig- Diels-Alder reaction:

The D iels-A lder cycloaddition remains the most powerful and efficient synthetic tool for accessing highly functionalized carbocycles, possibly generating upto four stereogenic centers in one operation. Diels-Alder reaction opened up new vistas in the field o f synthetic organic chemistry and established itself as an indispensable synthetic tool. The Diels-Alder reaction is amenable to catalysis including the enantioselective variety and can be conducted in the intramolecular mode. The intramolecular Diels-Alder (1MDA) cycloaddition has been extensively used for assembly o f complex molecular architectures o f designed or m aterial products origin.

Tandem W ittig-intram olecular Diels-Alder reaction have been widely used for the synthesis o f highly functionalized and important compounds in enantiomerically pure fonn which are briefly discussed in this section.

Jarosz and Skora17 prepared highly oxygenated decalines in enantiomerically pure form

via

tandem W ittig-Diels-Alder reactions from the sugar-derived dieno-phosphoranes and sugar aldehydes (Scheme 15).

11 |P a g e

Reaction o f 25 with sugar aldehyde 26 under high pressure (10 kBar) afforded the product 28in 50% yield

via

intermediate 27.

Likewise, other decaline derivatives 29 - 32 (Figure 3) were prepared from respective sugar aldehydes and sugar-derived dieno-phosphoranes.

Fig. 3

Wu

et al

. 18 presented a m icrow ave assisted tandem W ittig-Diels-Alder reaction protocol for the synthesis o f hexahydroisobenzofuran-l-one derivatives (Scheme 16).

Chapter I

Scheme 16

When a-bromoacetate o f dienyl alcohols and a-oxoaldehydes were heated at 180°C in microwave reactor in presence o f PPh3 and 2,6-lutidine in a closed vial for 30 minutes, the corresponding products were obtained in 68 - 80% yield. The cascade reactions that took place during this process are alkylation o f PPI13 with the bromides, deprotonation o f the resultant phosphonium salts with 2,6-lutidine, olefination o f the ylides with the a- oxoaldehydes and finally the IMDA cyclization.

The sam e group19 later employed the above protocol for the synthesis of hexahydroisochrom en-l-ones (Scheme 17).

Schem e 17

In our laboratory20 the tandem W ittig-IMDA reaction has been used for the synthesis o f AB ring systems o f tricyclic framework o f furanosesquiterpines (Scheme 18).

3-Furaldehyde 33 and phosphorane when refluxed in diphenyl ether, Wittig and intramolecular Diels-A lder reaction took place in one-pot to afford. a diastereomeric mixture o f tricyclic y-lactones/lactams 34 & 34 ’ in 60 and 80% yield respectively. Under identical reaction condition, 2-furaldehyde 35 on treatment with phosphorane, furnished a mixture lactones 36 & 36 ’, regioisomeric to 34 & 34’.

The above work was later extended for the synthesis o f regioisomeric carbazole lactones and lactam s21 starting from indole carboxaldehydes 37 & 38 (Scheme 19). -

Aldehydes when treated with phosphoranes in refluxing diphenyl ether, tetrahydrocarbazole lactones / lactams were obtained

via

tandem Wittig-IMDA reaction in 59 - 61% yield. These compounds w ere then oxidized to the corresponding carbazole lactones / lactams using DDQ (Discussed

vide infra

in Chapter 2- Section A).

Chapter I

Harris and Graham22 reported an efficient oxidation-Wittig olefination-Diels-Alder multicomponent reaction sequence to yield the corresponding cycloadducts (Scheme 20).

a-Hydroxyketones 39, ylides and oxidant were refluxed in toluene for 6 hours in presence o f 2,3-dimethyl-1,3-butadiene to obtain the eyeloadducts 40 in high isolated yields. Under the reaction conditions, 39 underwent oxidation and then W ittig olefination to generate the dienophile which on [4+2] cycloaddition gave the products 40.

Hilt and Hengst23 developed a concise method for the synthesis o f substituted stilbenes and styrenes 41 from propargylic phosphonium salts, 1,3-dienes and aldehydes using Diels-Alder/W ittig reaction/DDQ oxidation sequence (Scheme 21)

Scheme 21

The reaction works well with arom atic aldehydes having both electron-donating as well as electron-withdrawing groups and also with aliphatic aldehydes to give the corresponding products in moderate to excellent yield.

Similarly, the compounds 42-45 (Figure 4) were prepared from corresponding starting materials.

An enantioselective total synthesis o f (+)-vigulariol and (-)-sclerophytin A were reported by C rim m ins and co-workers24 b y utilizing W ittig/IM DA reaction as the key steps (Scheme 22).

Schem e 22

Chapter I

(+)-Vigulariol 47 was prepared in 15 steps while (-)-sclerophytin A 48 in 16 steps from common intermediate 46. The main reaction involved was the tandem Wittig/intramolecular Diels-Alder (IMDA) cycloaddition to form the hydroisobenzofuran core, basic structural m o tif o f the natural products 47 and 48.

B] Sequences involving Oxidation —W ittig reactions:

The utility o f the Wittig reaction is limited when applied to carbonyl compounds, particularly aldehydes that are difficult to isolate due to their instability, toxicity or volatility. The application o f tandem oxidation-W ittig olefination circumvents these shortcomings and a wide range o f oxidizing agents have been employed [Mn02, PCC, barium permanganate, Dess-Martin periodinane (DMP), tetrapropyl ammonium perruthenate (TPAP), ortAo-iodobenzoic acid] to give the olefination product in one-pot, which shows great utility in organic synthesis.

a) MnCh oxidation - W ittig reaction:

Taylor's group at University o f Y ork has extensively developed tandem oxidative processes (TOP) in organic synthesis. These tandem oxidation processes have been reviewed by them in 2005 and those examples are excluded in the present review.

Phillips

et al.26'27

have described the desymmetrization o f diols by a tandem oxidation-Wittig olefination reaction using M n02 as oxidant (Scheme 23)

HO ( )n OH n = 0, 1,2 or 3

M nO 2

H O ^ R

v x - W / C O O E t ()n ^

or R

P h 3P = C R C O O E t 52 - 7 9 %

E tO O C ^ ^ i ^ C O O E t

R = H, Me (When n = 0)

Schem e 23

When n=0, directly the dienyl diesters w ere obtained by double oxidation-double Wittig reactions in one-pot. However, when n > 1, the a,|3-unsaturated hydroxyl esters were formed in 52 - 79% yields regardless o f the quantity o f oxidant used. a,P-Unsaturated hydroxy esters are versatile intermediates in a number o f natural product synthesis.

A wide range o f functionalized dienes 49 have been prepared by MnC>2 mediated one-pot oxidation-consecutive W ittig reaction sequence (Scheme 24) by Lang and Taylor28.

The same strategy was extended for benzylic alcohols and related systems to give the desired dienes 50 (Figure 5) in moderate to good yields.

0

R 50

X = CH o r N

R = 4 -N O 2 , 2 -N O 2, 4-CO O M e, H Fig. 5

2 9 *

Taylor and co-workers have also described a one-pot process for the preparation o f (±)-diethyl trans-(£’,fi)-cyclopropane-1,2-acrylate 51 using MnCh oxidation-stabilized phosphorane olefination protocol (Schem e 25).

M n 0 2

. LAH, TH F A P h ,P = C H C O O E t

HO. J - A .. .OH

E tO O C x<%:;^ ~ ^ < ^ C O O E t 51

EtOOC C O O E t reflux, 2h then r.t., 18h

C H C I3, reflux 18h, 7 5 %

Scheme 25

(Z)-a-Iodo- a,j3-unsaturated esters 52 have been prepared by Karama 30

via

sequential halogenation o f ylide, oxidation o f alcohols and Wittig reaction in one-pot (Scheme 26) using ultrasound technique.

Chapter I

ph3p= \ + RCHpOH

CO O Et

NIS, Mn02 CH2CI2 23 - 86% m

COOEt (Z : E = 88 : 1 2 - 1 0 0 :0 )

52

R = Ph, P hC H =C H ,2-furyl, CH3C H 2CH=CH,Ph— = C , H3C H 2C ^ C , n-hexane Scheme 26

b) PCC oxidation — W ittig reaction:

In our laboratory,31'35 the tandem PCC oxidation-W ittig reaction (Scheme 27) has been developed and extensively used for the synthesis o f -

i) Highly functionalized a,P-unsaturated compounds 53 ii) A BT-418 54 and (£)-4-oxonon-2-enoic acid 55 iii) Streptomyces lactones 56

iv)

a

-(Alkylidine)-5,5-dimethyl-5-lactones 57 v) (5)-Pyrrolam A 58

vi) (-)-& (+)-Tedanalactam 59 & 59 ’.

Scheme 27

c) Oxidation-W ittig reaction using other oxidizing agents:

The synthesis o f a functionalized spiropiperidine 60 is reported by Edwards

et al.36 via

one pot Swem oxidation-W ittig olefination and tandem RCM as the key steps (Scheme 28).

Scheme 28

Martin and co-workers37 designed a convenient one-pot oxidation-W ittig olefination protocol using SCb.pyridine complex as an oxidizing agent for the.chemoselective C2- homologation o f carbohydrate-derived glycols (Scheme 29).

Statement of Objectives:

The specific objective o f this w ork was to develop domino reaction sequences by combining W ittig reaction with Diels-Alder reaction, Sigmatropic rearrangements, and electrocyclisation reaction for the synthesis of-

a) Carbazole lactones and lactams b) Lignans and Heterolignans

c) Indolocarbazole alkaloids- Staurosporinone and Arcyriaflavin A d) Geranylated coumarin.

Chapter I

References:

1) a) Tietze, L. F.; Beifuss, U. Angwe. Chem. Int. Ed. Engl. 1993, 3 2 ,131.

b) Tietze, L. F. Chem. Rev. 1996, 96, 115.

c) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.

2) a) Waldmann, H. Domino Reactions in organic Synthesis, Highlight II, ed. H.

Waldmann, 1995, VCH, Weinheim, pp. 193.

b) Ho, T. L. Tandem Reactions in Organic Synthesis, Wiely-Interscience, New York, 1997.

c) Padwa, A. Pure Appl. Chem.

2004,

76, 1933.

d) Rejzek, M.; Stockmann, R. A.; Van Maarseeven, J. H.; Hughes, D. L. Chem.

Commum. 2005, 4661.

e) Pellissier, H. Tetrahedron, 2006, 62, 1619.

f) Pellissier, H. Tetrahedron, 2006, 62, 2143.

g) Padwa, A.; Bur, S. K. Tetrahedron, 2007, 63,5341.

h) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem. Int. Ed., 2007, 46, 1570.

i) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev.,2009, 38, 2993.

3) a) Corey, E. J.; Russey, W.E.; Oritz de Montellano, P. R. J. Am. Chem. Soc. 1966, 88, 4750.

b) Corey, E. J.; Virgil, S. C.

J.

Am. Chem. Soc. 1991, 113,4025.

c) Corey, E. J.; Virgil, S. C.; Sarshar, S.

J.

Am. Chem. Soc. 1 9 9 1 ,113,8171.

d) Corey, E. J.; Virgil, S. C.; Sarshar, S.

J.

Am. Chem. Soc. 1 9 9 2 ,114, 1524.

4) a) Mannich, Arch. Pharm. 1917, 255.

b) F. F. Blicke, Org. React. 1 9 4 2 ,1,303.

c) Tramontini, M. Synthesis 1973, 703.

d) Gevorgyan, G. A.; Agababyan, A. G.; Mndzhoyan, O. L. Russ: Chem. Rev. 1984, 53, 561.

e) Trmontini, M.; Angiolini, L.

Tetrahedron

1990,

46,

1791.

f) Leete, E. Planta Med. 1990, 56, 339.

5) Maryanoff, B. E.; Reitz, A. B. Chem. Rev., 1989, 89, 863-927.

6) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs Annalen, 1997, 1283- 1301.

7) Parvatkar, P. T.; Tom ey, P. S.; Tilve, S. G. Current Organic Synthesis, 2012, 9,.

21 |P a g e

8) Schobert, R.; Gordon, G. J. Curr. Org. Chem.,2002, 6, 1181.

9) Mali, R. S.; Joshi, P. P.; Sandhu, P. K.; Manekar-Tilve, A. J. Chem. Soc., Perkin Trans.

7,2002,371.

10) Patre, R. E.; Shet, J. B.; Parameswaran, P. S.; Tilve, S. G. Tetrahedron Lett., 2009, 50, 6488.

11) Patre, R. E.; Parameswaran, P. S.; Tilve, S. G. Arkivoc, 2011, 9, 68. 12) Schobert, R.; Jagusch, C. Tetrahedron Lett., 2003, 44, 6449.

13) RamaRao, V. V. V. N. S.; Venkat Reddy, G.; Maitraie, D.; Ravikanth, S.; Yadla, R.; Narsaiah, B.; Shanthan Rao, P. Tetrahedron, 2004, 60, 12231.

14) RamaRao, V. V. V. N. S.; Venkat Reddy, G.; Yadla, R.; Narsaiah, B.; Shanthan Rao, P.

Arkivoc,

2005, 3,211.

15) Kawasaki, T.; Nonaka, Y.; W atanabe, K.; Ogawa, A.; Higuchi, K.; Terashima, R.;

Masuda, K.; Sakam oto, M. J. Org. Chem., 2001, 66, 1200.

16) Tang, X.-Y.; W ei, Y.; Shi, M. Eur. J. Org. Chem., 2010, 6038.

17) Jarosz, S.; Skora, S. Tetrahedron: Asymmetry, 2 0 0 0 ,11, 1433.

18) Wui J.; Sun, L.; Dai, W.-M. Tetrahedron, 2006, 62, 8360.

19) Wu, J.; Sun, L.; Dai, W.-M. Tetrahedron, 2011, 67, 179.

20) Patre, R. E.; Gawas, S.; Sen, S.; Parameswaran, P. S.; Tilve, S. G. Tetrahedron Lett., 2007, 48,3517.

21) Tomey, P. S.; Patre, R. E.; Tilve, S. G. Synlett,2011, 639.

22) Haris, G. H.; G raham , A. E. Tetrahedron Lett.,2010, 51, 6890.

23) Hilt, G.; H engst, C. J. Org. Chem., 2007, 72, 7337.

24) Crimmins, M. T.; Stauffer, C. S.; M ans, M. C. Org. Lett., 2 0 1 1 ,13,4890.

25) Taylor, R. J. K.; Reid, M.; Foot, J.; Rew, S. A. Acc. Chem. Res., 2005, 38, 851.

26) Phillips, D. J.; Pillinger, K. S.; Li, W .; Taylor, A. E.; Graham, A. E. Chem. Commun., 2006, 2280.

27) Phillips, D. J.; Pillinger, K. S.; Li, W.; Taylor, A. E.; Graham, A. E. Tetrahedron, 2007,63, 10528.

28) Lang, S.; Taylor, R. J. K. Tetrahedron Lett., 2006, 47, 5489.

29) Taylor, R. J. K.; Campbell, L.; M cA llister, G. D. Org. Synth., 2008, 85, 15.

30) Karama, U. Synth. Commun., 2010, 40,3447.

31) Shet, J.; Desai, V.; Tilve, S.

Synthesis,

2004, 1859.

32) Amonkar, C. P.; Tilve, S. G.; Parameswaran, P. S. 2005, 2341.

Chapter I

33) Parsekar, S. B.; Amonkar, C. P., Nadkam i, V. S.; Tilve, S. G. Indian J. Chem. Sect B, 2009, 48B, 1333.

34) Majik, M. S.; Shet, J.; Tilve, S. G.; Parameswaran, P. S. Synthesis 2007, 663.

35) Majik, M. S.; Parameswaran, P. S.; Tilve, S. G.J. Org. Chem., 2009, 74, 6378.

36) Edwards, A. S.; Wybrow, R. A. J.; Johnstone, C.; Adams, H.; Harrity, J. P. A. Chem.

Commun.,2002, 1542.

37) Pinacho Crisostomo, F. R.; Carrillo, R.; Martin, T.; Garcia-Tellado, F.; Martin, V. S.J. Org. Chem., 2005, 70, 10099.

D O M IN O W ITTIG - D IE L S- A LD ER REA C TIO N Section A: Synthesis o f furo and pyrrolocarbazoles Introduction:

Condensed heterocyclic compounds are playing increasingly important roles as synthetic building blocks and pharmacophores.1 Carbazoles (diphenylenimine) constitute an important and grow ing class o f such heteroaromatic compounds displaying a wide variety o f biological activities. First isolation o f the parent compound 9//-carbazole 1 (Fig I) was reported by Graebe and Glaser2 in 1872, which was obtained from the anthracene fraction o f coal tar distillate (it is currently produced commercially from this source and crude oil on the scale o f thousands o f tons per annum). N inety years later, in 1965, Chakraborty et al? described the isolation and antibiotic properties o f murrayanine from Murraya koenigii Spreng also known as the curry-leaf tree in India. This was the first report o f isolation o f a naturally occurring carhazole alkaloid. Since then, a wide variety of biologically active carhazole alkaloids have been isolated from different plant sources.

Most o f the carhazole alkaloids have been isolated from the taxonomically related higher plants o f the genus Murraya, Glycosmis, and Clausena from the family Rutaceae.

The genus Murraya represents the richest source o f carhazole alkaloids from terrestrial plants. In addition, a few bacterial strains belonging to Streptomyces sp are also known to produce these com pounds. Additional natural sources for carhazole alkaloids are, the blue- green algae Hyella caespitosa, Aspergillus species, Actinomadura species, and the Didemnum granulatum. Several working hypotheses have been proposed to account for the biogenesis o f carhazole alkaloids.4

Carbazoles form the core structures o f numerous biologically active compounds.4 Both, natural and synthetic carbazoles display a wide range o f biological activities which includes inhibition o f CDK-5, antitumor, psychotropic, anti-inflammatory, antimicrobial,

24 | P a g e

antihistaminic, antibiotic, antioxidative activities.5 In addition to this, the [

b

] annelated carbazole derivatives are o f interest because o f their DNA interacting properties.6 Fused carbazoles are found in several highly potent natural products like ellipticine (tumor therapy), vinemine

{Alzheimer

disease) and in large group o f secale alkaloids. Compounds such as carvedilol8 and carazolol9 were identified for their potential as multiple-action antihypertensive drugs. It was later realized that their therapeutic value might derive from the properties o f the 4-alkoxycarbazole cores that act as potent antioxidants against radical-induced lipid oxidation. Subsequently, new molecules with a 4-alkoxycarbazole core have been developed for the treatment o f obesity and type II diabetes.10

In addition to their use in medicinal chemistry, carbazoles have attracted increasing attention from the com m unity o f m aterial scientists owing to their potential in photophysical and optoelectronic applications.11 Polyvinyl carbazole (PVK) has been extensively investigated for its use in photorefractive materials and xerography, while

N-

ethylcarbazole (ECz) was recognized as an effective charge-transporting functional plasticizer for PVK and other doped polym ers.12 In the past decade, carbazole compounds were intensively investigated for the developm ent o f optoelectronic applications such as polymeric light-em itting diodes (PLED )12a,c’13 and organic light-emitting devices (OLED).14-16 In particular, it was found that certain carbazole oligomers led to a family of host materials that w ere suitable for the electrophosphorescence o f blue lights,14’15 a critical component for the fabrication o f commercial OLED displays.

The intriguing structural features, promising pharmacological activities and photophysical properties o f these compounds have led to an enormous development in carbazole chemistry w hich is emphasized b y the large num ber o f monographs, accounts, and reviews.16-49. The preparation o f new and various substituted derivatives is still a highly pursued objective.

Literature Methods:

Over the last few decades, a wide range o f substituted carbazoles have been prepared by different approaches, like reductive cyclization o f 2-nitrobiphenyls50 and Pd- catalyzed diarylamines,51 cyclization o f 2-arylacetanilides,52 oxidative cyclization o f 3-(30- alkenyl)indoles,53 or double N-arylation o f prim ary amines.54 However, among the large number o f methods available, those involving Diels-Alder reactions deserve special

Chapter Ila

mention. Some selected methods for the synthesis o f functionalised carbazoles wherein Diels-Alder cycloaddition reaction is used as the key step are described below.

Backvall and Plobeck have reported55 the synthesis o f the antitumor alkaloids ellipticine and olivacine, starting from indole. The cycloaddition o f 3-(phenylsulphonyl)- 2,4-hexadiene or 2-(phenylsulponyl)-l,2-pentadiene with the magnesium salt o f indole followed by M ichael addition o f lithium salt o f acrylonitrile, desulfonylation and aromatisation afforded the carbazole. Subsequent Bischler-Napieralski cyclisation and aromatization afforded ellipticine and olivacine (Scheme 1).

Schem e 1

In Scheme 2, Diels-Alder reaction o f substituted 2-vinylindoles with carbodienophiles in the synthesis o f tetrahydrocarbazoles described by Blechert and W irth56 is shown.

26 | P a g e

Pindur’s group57 has described the synthesis o f 2-vinylindole and its Diels-Alder reactions with C -dienophiles to form carbazole derivatives (Scheme 3).

Noland

et al.58

have synthesized tetrahydrocarbazoles by using indole, ketone or aldehyde, and m aleim ide w ith acid catalyst in one pot (Scheme 4).

Schem e 4

Chataigner

et al 59

have developed a synthesis o f tetrahydrocarbazoles using [4+2]

cycloaddition reaction un d er high pressure conditions or a combination o f Lewis acid catalyst (Scheme 5). U nder the reaction conditions employed, indole with an electron withdrawing substituent at 3-position acts as a dienophile.

Chapter Ha

Bleile and Otto have reported60 the synthesis o f pyrrolo [3,4-a] carbazole derivatives by cycloaddition between m aleim ide and 3-(l-methoxyvinyl)indole derivative (Scheme 6).

Laronze

et al.61

have reported that substituted 3-cyanomethyl-2-vinylindoles rearrange

via

thermal [1,5]-H shift into the corresponding indol-2,3-quindimethanes which then can be trapped b y dienophiles to afford tetrahydrcarbazoles (Scheme 7).

Scheme 7

Anisimova

et al.62

have presented a [4+2] cycloaddition o f methyl-3-nitroacrylate and 3-(2-nitroethenyl)indole in presence o f aluminium chloride in refluxing toluene.

28 | P a g e

Regioisomeric tetrahydrocarbazoles thus obtained under the reaction conditions underwent a dehydration and denitration to give corresponding carbazolylcarboxylates (Scheme 8).

Abbiati

et al,63

have synthesized the diastereomeric 3, 4-disubstituted and 1,2,3,4- tetrahydrocarbazoles b y D iels-A lder cycloaddition reactions betw een [(Zs)-2-vinyljindole- 1-carboxylic acid ethyl esters and open chain C=C dienophiles in presence o f magnesium perchlorate as lewis acid (Schem e 9).

An intram olecular H eck/D iels-A lder cycloaddition cascade has been developed to prepare nitrogen heterocycles by Fuwa and Sasaki64 (Scheme 10). In this case, indole-2,3- quinodimethane was generated from acyclic a-phosphono enecarbamate by means o f an

Chapter Ila

intramolecular Heck reaction, which was then trapped by using an appropriate dienophiles to yield corresponding tetrahydrocarbazoles

Lebold and K err65 have reported the Diels Alder reaction between quinone monoamine and cyclic diene leading to construction o f carbazoles in a regiospecific manner which resulted in the synthesis o f naturally occurring eustifolines A-D and glycomaurrol (Scheme 11). Later on, the authors extended this methodology for the synthesis o f clausamine A -D (Scheme 12).

Schem e 11

30 | P a g e

Schem e 12

Back

et al.66

have reported the synthesis o f 3-, 4-, and 6-substituted carbazoles

via

a Diels-Alder reaction betw een vinylogous 2-sulfonylindoles and dienophiles such as DMAD or methyl propiolate followed by elim ination o f the sulfone moiety with DBU.

Vinylogous 2-sulfonylindoles were prepared b y a heteroannulation o f o-iodoanilines with dienylsulfones and subsequent oxidation using DDQ.

Same group later reported67 a sim ilar reaction of o-iodoanilines with phenyl thio- 1,3-butadienes followed by DDQ oxidation to afford vinylogous 2-(phenylthio)indoles

Chapter Ha

which undergo a regioselective Diels-Alder reaction with methyl propiolate to afford 4- substituted carbazoles.

Carter and co-w orkers68 have described a synthesis o f halogenated carbazoles using a Diels-Alder reaction betw een chloro 2-nitrophenyl alkynes and substituted butadienes.

The alkynes were obtained from the corresponding benzaldehydes. Application o f this strategy for the synthesis o f anti-HIV agent siam enol is also shown.

Scheme 15

32 | P a g e

A new approach to carbazoles and benzannulated carbazoles by means o f intramolecular dehydro D iels-A lder reaction o f ynamides is reported by Saa and co­

workers.69 The ynam ides w ere prepared from o-iodoanilines

via

a Sonogashira coupling, iV-tosylation and iV-alkynation in good overall yields.

Petillo and co-w orkers70 have designed a synthesis o f 2,3,6,7-tetrasubstituted carbazoles employing a sequential D iels-A lder reaction o f diene generated insitu from N- benzyl-2,5-dimethyl-3,4-bisacetoxym ethylpyrroles and dienophiles such as maleic anhydride, maleimides, ethyl mateate, fumaronitrile and ethyl acrylate. The tetrahydrocarbazoles w ere then oxidised using DDQ.

Schem e 17 Results and discussion:

Although a plethora o f reports are available for the synthesis o f carbazole nucleus, the extraordinary biological activities associated with them always leave a scope for designing new m olecules or new strategies for their construction. Lactones and lactams are also functional m otifs w hich have attracted considerable attention due to their pharmacological properties. Hence we thought o f making fusion o f these units to make available a series o f som e furo and pyrroloearbazoles as shown below (Fig. 2).

Chapter Ila

Fig. 2

Our retrosynthetic analysis (schem e 18) o f these molecules 2 identified corresponding tetrahydro derivative 3 as the key intermediate. The tetracyclic system o f 3 could be constructed by an intram olecular Diels-Alder reaction from a precursor 4, which in turn could be easily generated

via

phosphorane (Wittig) chemistry.

Thus, the visualized strategy involved a Wittig reaction between indole-2- carboxaldehyde 5 and phosphorane 6 to give corresponding

trans

unsaturated ester which under the reaction conditions would undergo an intramolecular Diels-Alder cycloaddition followed by isom erisation o f the incipient new double bond to give stable tetrahydrocarbazole lactone. A lthough we expected the strategy to work smoothly to afford the tetrahydrocarbazoles, a possibility o f different modes o f intermolecular Diels-Alder cycloadditions yielding various undesirable products (as shown in scheme 19) could not be neglected.

34 | P a g e

Schem e 19

Initially for this, indole-2-carboxaldehyde was prepared as shown in scheme 20. 2- Nitrobenzaldehyde 7 on treatm ent with ethyl (triphenylphosphoranylidine)acetate 8 in presence o f triphenylphosphine in refluxing diphenyl ether underwent a Wittig reaction followed by nitrene insertion to furnish indole-2-carboxylate 9 as a colourless crystalline solid having m. p. = 122-124°C (Lit. m. p.= 125-126°C)71. Its IR spectrum showed strong bands at 1691cm'1 and 3218 cm '1 indicating the presence o f carbonyl and NH functionality. In its ’H N M R spectrum a triplet at

S

1.45 (3H,

J

= 7.2 Hz) and a quartet at

5

4.45 (2H,

J = 1 2

Hz) w ere assigned to the ethyl group o f the ester. The indole protons appeared at <5 7.18 (t, 1H

, J =

7.8Hz, HC-6), 7.27 (s, 1H, HC-3), 7.35 (t, 1H,

J =

7.8Hz, HC-5), 7.46 (d, 1H,

J =

8.1Hz, HC-7) and 7.72 (d, 1H, 7 = 8.1Hz, HC-4). The NH proton appeared as a broad singlet at

S

9.10.

Compound 9 on further reduction w ith LAH afforded the alcohol 10 as a white solid having a m. p. = 70-72°C (Lit. m .p.= 71-72°C)72. It was then subjected to oxidation with several oxidizing agents as shown in schem e 20. However, maximum yield o f the aldehyde 5 was obtained w ith freshly prepared MnC>2.

Chapter Ila

7

O

Ph,P OEt PPh3

Ph20, reflux 85%

COOEt N 0 2

5 H CHO

PCC, NaOAc, CH2CI2, 10%

DMP, CH2CI2, 20% or M n02, CH2CI2, 70%or

c o —

9 H LAH, THF 0°C-rt

90%

Schem e 20

The required allyl (triphenylphosphoranylidine)acetate73 13 was prepared according to Scheme 21. Allyl alcohol was acylated by brom oacetyl bromide in presence o f pyridine.

OH

b r o m o a c e ty l b r o m id e p y r id in e , 0 ° C

O

PPh3

11

B r O

PhoP.

12

O

NaOH > Ph3P ^ A Q^ ^

13

S chem e 21

The strong IR (KBr) peak at 1750 cm '1 indicated the presence o f the ester group in compound 11.

Its ‘H NM R (400 M H z, CDC13) spectrum displayed signals at

S

3.83 (2H, CH2Br),

S

4.61 (2H, s, CH20 ),

S

5.55-5.64 (2H, m, CH2=C H ) and 5.82-5.90 (1H, m, CH2=CH), further confirming the structure. Thus on the basis o f mode o f formation & spectral properties structure 11 was assigned to it.

The allyl bromoacetate74 (11) was treated with triphenylphosphine to give corresponding phosphonium salt 12

.

m . p. = 222-223 C, IR (vmax): 1722 c m '^ O O ) .

36 | P a g e

*H NMR (CDC13, 300 M Hz):

S

4.40 d (J = 5.7 Hz) 2H c h2o

<5 5.10 m 2H CH=CH2

S

5.55 d (J = 9.9 Hz) 2H CH2-P+Ph3 Br

<5 5.78 m 1H c h=c h2

<5 7.58-7.94 m 15H Ar-H

13C NMR (CDC13, 75M H z): <5 33.0 (CH 2-P+Ph3), 67.1 (CH20 ) , 117.7 (3 X Cq), 119.7 (CH=CH2), 130.2 [C H =C H 2 & 6 X CArH

{ortho)],

133.9 [6 X CArH

{meta)],

135.2 [3 X Cath

(para)],

164.0 (C = 0 ).

Based on the mode o f form ation & spectral properties mentioned above, structure 12 was assigned to this com pound.

The phosphonium salt 12 was then treated w ith aq. sodium hydroxide to obtain the required allyl (triphenylphosphoranylidine)acetate 13.

Based on the mode o f form ation & spectral properties mentioned below, structure 13 was assigned to the com pound, m.p. = 72-73°C, IR (vmax): 1734 cm_l(C =0).

'H NMR (CDC13, 300 M H z): 13

<5 2.9 Broad hum p 1H CH=PPh3

<5 4.41 brs 2H c h2o

<5 4.98 m 2H c h=c h2

<5 5.80 m 1H c h=c h2

<5 7.21-7.66 m 15H Ar-H

13C NMR (CDC13, 75M Hz): <5 30.1 (C H =PPh3), 63.0 (CH20 ) 115.8 (CH=CH2), 128.6 [CH=CH2 & 6 X CArH

(ortho)],

130.9 (3 X Cq), 132.9 [6 X Ca,h

(meta)],

132.9 [3 X CArH

(para)],

170.7 (C =0).

HRM S:

m/z

361.1353 (observed), calculated for C23H2i 0 2P (M +H)+: 361.1357.