CHAPTER - I

CH3 CH3

R

H CH3

2 CH3

la =R= H lb =R= OCH3 lc = R= OH

CH3

HO

0OAc

Fi CH3

3

4

SYNTHETIC STUDIES IN CARBAZOLES AND PYRIDOCARBAZOLES

1.1: Introduction

The 6H-pyrido[4, 3-b]carbazole alkaloids, ellipticine la, 9-

methoxyellipticine lb and olivacine 2, shows pronounced antitumour

activity in several animal and human tumour systems. A derivative of

9-hydroxyellipticine lc, 2-methyl-9-hydroxyelliptinium acetate 3

("elliptinium") is a clinically proven anticancer drug for the treatment

of metastatic breast cancer, myleoblastic leukemia and some solid

tumours2,1a. These compounds exhibit their anticancer activity via

DNA : (a) intercalation, (b) metabolism and subsequent covalent

bonding (c) generation of oxygen radicals and (d) inhibition of

topoisomerase la.

OR'

4 (a-h)

5

Carbazole is a natural product isolated from coal tar in 1872 by

Graebe and Glaser, while their alkaloids have aroused interest in the

last few years. A first Carbazole discovered was murrayanine (4c) in

19653 . Since, 1979 a number of Carbazole alkaloids have been

isolated from several groups of plants, microorganisms, and marine

sources4 . Compound 4(a-h) include 1-oxyaenated 3-Ci-substituted

Carbazoles of the C13 group like, Mukonine5a (4a) , Mukoeic acid 5b ,5c

(4b), Murrayanine 3 (4c), Koenoline 5d (4d), Murrayafoline 5e (4e),

Clausine E 5 f. 5g (4f), 0-demethyl murrayanine 5h (4g) and 1-hydroxy-3-

methyl carbazole 5i (4h).

4 Rl R2

at -0

(..) 7$

a) (._,

to 4

Me COOMe

Me COOH

Me CHO

Me CH2OH

Me Me

H COOMe

H CHO

H Me

Some of these show antibiotic6a, antifungal6b, and cytotoxic

properties 5d. Others show neoplasm inhibitory effects on mitosis 6c ,6 d

as well as good activity against the malarial parasite, plasmodium

falciparum, exhibited by some dimer carbazole 6ex. Carbazole

alkaloids are known to exhibit varied and significant biological

activities that include, antimicrobial 7 , antiviral$, and cytotoxic

properties9 . Hyellazolesl° (5a and 5b) were isolated from blue-algae

Hyella caespitosa by Moore, representing the first Carbazole alkaloids

of marine origin. Carbazomycine (6a and 6b) isolated from

streptoverticillum are the first antibiotics, which contain the Carbazole

6

nucleus7a, b '24". Many members of Carbazomycine family isolated from

the same species, are designated as Carbazomycine A-J.

Carbazomycin A (6a), shows very weak antifungal and antibacterial

activity, while Carbazomycin B (6b) is found to be active against

certain types of phytopathogenic fungi 7a.

OR

0 CH,

CH 3

OCH 3

CH 3

Ph

Ph

5a , R =11

6a, R= Mc 5b , R = CI

6 b, R =

Other Carbazole nucleus containing compounds that attracted

us were Carbazoquinocins (A-F), found in Streptomyces violaceus

2448-SVT2 by Seto in 1995, which have the o-quinone structure 12 .

Carbazoquinocin Al (7a), and Carbazoquinocin D2 (7b) is supposed

to possess a secondary chiral stereogenic center on the 1-alkyl

functionality 12 . Carbazoquinocines (A-F) exhibit strong inhibitory

activity against lipid peroxidation 12 . Carazostatin (8), a free radical

scavenger, was isolated from Streptomyces chromofuscusm by Kato in

1989 13 .

OH

iii

H

7a , R= ((m), Cii(c.113)(112Me 8

7 b , R = (CH, )4(.11(ci 13)CII2Me

7

1.2a: Synthesis of Pyridocarbazole alkaloids

Since the original isolation of these alkaloids and initial

discovery 14 of their anticancer activity, several synthetic approaches

to the pyrido[4,3-b]carbazole ring system have been described. In

1977, Sainsbury's published a review article which contained about

15 different routes towards - the synthesis of pyridocarbdzole system.

In 1980, R. Barone and M. Chanon's published a review which

focuses computer generated strategies for the construction of this

ring system. An article written by M. J. E. Hewlins, A. M. Oliveira

Campos and P. V. R. Shannon reviews synthesis reported from 1977

to 1982 17 . A more complete review since 1977 to Nov.1984 was

published by G. W. Gribble and M. G. Saulnier in 1985 18 . Another

review by V. K. Kansal and P. Potier appeared in 1986 1c. Later on in

1990, G. W. Gribble published a review 19 on "Synthetic approaches to

the ellipticine alkaloids via metalation and cycloaddition chemistry".

Again in 1991, G. W. Gribble 8 reviewed his work for 20 years in an

article entitled "Approaches to the synthesis of antitumour

Pyridocarbazole Alkaloids". A review involving thermal electrocyclic

reaction towards this ring system has also appeared 20 . Some of the

recent synthesis which are not included in the above mentioned

reviews are given below.

Thus M. Ishikura et al describes in his novel approach 21

(Scheme I), the palladium catalysed cross coupling reaction of

indolylborate with vinyl bromides to give hexatrienes, which are

subsequently converted to pyrido[4,3-b]carbazoles.

MeLi 1-1,0

8

1 1) BuTi /ITT

2) BEt,

Me

PdLn (5mol %) , THE

11

i Me

Scheme I

S. P. Modi et al describes an efficient route for this system 22

(Scheme H).

O

1N.,,,.,,,,,0—[ K MeLi

H ,./ --------__ Me --------/'\--. NaBH4

I ,,,,,_,,,, ,-. N

Mc

I i

Fl Me

Scheme H

Y. Miki et all treated N-Benzyl indole-2,3-dicarboxylic anhydride

with (3-bromo-4-pyridyl)triisopropoxy titanium to give 2-(3-

bromoisonicotinyl)indole-3-carboxylic acid which then was converted

to ellipticine in six steps23 (Scheme III).

Br\ ___,-.--„, ----"--s.,,, ,---- I) PPh 3=CH 2

11 II (63%) .. ‘i.--_-,...,.,---7:--„, .„---,'------ -2) -H:I/Pt02 —

ii 'I i (75%)

Ft

0

Br

H CH,

,SnBu

Pd(PPh0 4 97%

Me

Br

9

COON

Iy/ Br \\_

-

I 13n 0 THF/ -96 °C

86% B n

1)20% HCOOH (98%)

2) AlC13 (42%)

.0FA /

/', ------•-%-;;-''N r.

I II

1 H

10% HC I r.t ,(87%)

H CH, Me

Scheme III

S. Blechet et al have introduced a new concept "Domino

reactions" in the synthesis of indole alkaloids, which include olivacine

and ellipticine 24a,b (Scheme IV and V).

PhNHOH + R` CH2OH

the5nOCyCa'n5onlialkii7ene ' '7"--1 1 2h, 20° C

,1 H

C1,1

.Ao o

- IL 0 - ---- , cii2c12 cF3coon ,-------,„ „---------,,........„- -, Pd(13P11 3 )4

1 1

II _00, R 2 morpholine` 2) DDQ.dioxane, reflux Ih ---„,5..„---- ---__N .....2\i------<"—\---- \N..-- - H H

CN

Mc

Ild/C I decalin, reflux

II CN

CN

Scheme IV

ON N OHC

N PhNHOH 15mins, -25° C

0

toluene reflux

10

cyanoalkene 2.5hrs, 25° C

CN

H

Me o Me Me

DDQ, dioxane, reflux lh

CN H

CN

O

Scheme V

A new synthesis of the 6H-pyrido[4,3-b] carbazoles, ellipticine

and olivacine via cycloaddition of 2-phenylsialphony1-1,3-diene to

indoles is described by J. E. Backvall and N. A. Plobeck 25 (Scheme

VI).

R' R' H E 1_,, _1„,„,..„.„,, S02P11

+ I 1 i) LiC1-12CN...-

N,,.,.;.,,,,-.-- ,..,,N ,..-r....,,,,-- 2) Na (Hg)

1 f----- MgI Me H I-1 A

Me

R' IV ,..71

.,..------..":•,......_ ,..-----"`-,--..,_, ,„,--":-..., .---"--"---------.., tJ 1 cx 1 ) NaBH,, COCK I

1,,,,„------ Nj1)---, —,...----- ------ 2) ethylformate (120 °C) '---,:-/---- ''N"- '-=------ \.----- H

Me

R'

H le

Scheme VI

ch.loronil

R'

H I or Nle Ac 20/py

SO2 Ph R'

Me

11

S. P. Modi and S. Archer reported 26 a reaction involving 4-

methylpyrano[3,4-b]indol-3-one and (Dimethyl-triazinemidyl) pyridine

carboxylic acids. The latter being the precursor of 3,4-pyridynes

(Scheme VII).

RI

-+- I

N R

Me

Scheme VII

A synthesis has appeared, wherein 4-H-furo[3,4-b]indoles have

been prepared in 6-8 steps 27a, and used for regiospecific Diels Alder

reaction with ethyl acrylate to be converted to carbazole, that afforded

ellipticine (Scheme VIII).

°, • _ - 7/ OMe cj

Nr7

02 Ph

— 7 OMe

Me

Mc

Scheme VIII

G. W. Gribble and coworkers 27b have described a general and

efficient synthesis of the 6H-pyrido[4,3-b]carbazole ring system with

the key steps involving regiospecific acylation of a 2-lithio-

1 -(phenylsulphonyl)indole with 3,4-pyridine dicarboxylic acid

12

anhydride, cyclisation of the deprotected keto acid to keto lactam

with acetic anhydride, and the addition of methyl lithium to give after

reduction the target ring system ellipticine (Scheme IX).

R

-f- ts ---N Li LO2Ph

0 Ir,I R

/‘-I

N..--------- --:, -<;-'-''''-''''N (D. I I 1 NC-'--/N ,.%- -- N 'N ---.--

Id H - - -o -- 0011-

R

Ae20 1) CH, Li 2) NaBH,

Scheme IX

J. R. Domoy and A. Heymes 28 have reported total synthesis of

modified ellipticine via 2-chloronicotinic acid, 5-methoxy indole and

5- cyano indole in 11 to 13 steps (Scheme X).

Me NH(CH2),NEtz

Me° COOH MeO\

11 steps

CI

H

Me

Scheme X

C. K. Sha et a1 29 have reported the total synthesis of ellipticine

alkaloids using Diels Alder reaction of 2,4-dihydropyrrolo [3,4-

Nindole with 3,4-pyridyne giving a cycloadduct which was converted

to ellipticine and isoellipticine (Scheme XI).

HO

Me Me

NI' 1) HMTAITFA, reflux, 20 min

2) H2 SO4/ H2O reflux, 4hrs

Me

Me

13

CO0Bu`

Loosu'

DMAP

Me

I I - 0O2(Me),

kO z Ph

Scheme XI

J. P. M. Plug et a13° have synthesized 9-hydroxyellipticine via a

direct regioselective formylation, followed by Baeyer-Villiger oxidation

(Scheme XII).

Me

Me

R= H R= Me

Scheme XII

Another route for the synthetic analogues of pyridocabazoles

has been reported by A. K. Mohankrishan and P. C. Srinivasan from

N-protected-3-formyl indole by using Wittig reaction 3 ' (Scheme XIII).

Me • o

R3 cHo 0 pphi='CHCOOEt I ! B . ---',--,,,, \ .-----_, / II 2) NBS/ C:Ct, — I <15::- ------------1\V

- 1■1 \ -. 3) 1)(0E0 3 / /.:IL-_ \----''''' --- N ---------:-----------------. _..----

' 4) Nali/ UV, NO2ArCHO 0 2 Ph 5) 10% Pd/C in xylcne, / \

So,Ph mc ----"-------- '' R'

6) Ra-Ni/ TI-1F, Li_. I • R4

Scheme XIII

F CI CH3 F

H

Pd (PPh 3 )4

R = H, OEt

C H3

Br H

CH 3 F „___„SnB113

Mc

14

C. May and C. J. Moody32 has synthesized ellipticine via Diels

Alder reaction of pyrano[3,4-b] indol-3-one with pyridyne (Scheme

XIV).

Me

Me

Scheme XIV

A new convergent route to 1-substituted ellipticine has been

reported using 3-formyl indole and 2,3,4- trisubstituted pyridine 33

(Scheme XV).

Scheme XV

15

1.2b Few selected synthesis of carbazoles

Major synthetic approaches to the carbazole skeleton include

a) reductive cyclisation of 2-nitrobiphenyls 34

b) therma1 35 , photolytic 36, and palladium promoted cyclisation

of diphenylamines37 .

c) dehydrogenation of 1,2,3,4-tetrahydro carbazoles, which are

usually prepared by Fischer indole synthesis 38 , and

d) synthesis from indole precursors 39 .

Most of the synthesis have been restricted to simple carbazole

systems. Few methods adopted for the synthesis of carbazole skeleton

are mentioned below, as we were also interested towards synthesis of

biologically active carbazole systems. Synthesis of hyellazoles (5a,b),

have been established by Moody and Shah in 1988, in five steps from

indole-3-acetic acid 40 . While, Jackson and Moody have carried out

the synthesis of carazostatin by the same route" (Scheme XVI).

Me, r- Me,SiC=CCO,Et

8 PhBr,liat H

R=c 7H 1 „ 74% R= Ph, 62%

LAIN, dioxan, heat R= Ph, 92% R=C,H,, 99°A

./--, ___,--,..,,,,,OR'

jj 1 .--.,-."-- .--- n -- ---------- '''- CH,

H K

1)Hg(0Ac), , AcOH 2) BH,.113F,H20,0H

R= Ph, 41°/0 R=C,H,,, 44%

3) Mei, K2CO3

R= Ph, 92%

I I CH3

R

R R'

Ph CH3 hvellazole C7H1 5 H carazostatin

Scheme XVI

NH 2 CH,

0

OCH 3

H Ii O

16

Iron (Fe-carbonyl complex) mediated approach as a general

route to 3-hydroxycarbazole via quinone imine cyclisation 42 is shown

in Scheme XVII.

R'

R= R'

R3

(C0),Fe

(C0),Fe --+ I HN

1 R= R'

Fe(CO) 3

\,,

R'•

R3

R'

R3

Scheme XVII

Synthesis of carbazomycin G and H was effectively achieved by

Knolker43 et al using palladium acetate as catalyst for ring annulation

of 2-N-phenylaminoquinones (Scheme XVIII).

0 R1 OCH 3

Pd(0 Ac) 2 1) Mc Li

lid

0

Li 1,

CH,

I H CH 3

O

CI-13

Scheme XVIII

S02 Ph

V

,CO2CH3

CO2CH3

17

T. Kuroda et a144 have successfully synthesized heterocyclic

analogues of 1 -arylnaphthalene lignans (Scheme XIX).

,C HO et)

1)C1-1(0Me) 3 H 2) BuLi. TMEDA

RCHO SO2 Ph 3) le/ Ae20

Scheme XIX

Clive and co workers have synthesized carbazole in four steps

from o-bromo-N-tosyl aniline derivative 45 (Scheme XX).

OR OR

HCO Br H3C0 Br

Ph, SnH AIBN

N Ts Ts

OR I ,,,,_____--,,,,,,,,,

H H,C 0, - --------

■ 1-- -...Th /'' --'----).---- N ----- = -----------

Ts 11

OH

113CO3,,,,,_ ..-------.---.

..- ll 1 ) li

j '''-------""----- N ------------ - ---1

Pd/C

OH

H,C0

Na-Naphthalene

Scheme XX

a

OMe

Ph

18

J. Tamariz46 has in recent report synthesized carbazoles

(Scheme XXI).

0

1 ) Methyl vinyl Ketone, xylene 0 2) NaOH, rt

I I. 3 )Dimethylsulphate

Scheme XXI

0

CH3

H CH 3 0C113

Pd(OAc) 2

AcOH O

I j

OCH,

E. M. Becalli et a1 47 have synthesized 3-methoxy carbazole

alkaloids mainly hyellazole and 6-chlorohyellazole (Scheme XXII).

R2 Ph

1) Decalin, reflux -- OCOOEt

N.-j\ 3) NaH.Mel, TIC'

2) NaOH, aq Me0H

OCOOEt 4) NaOH, aq Me0H

Scheme XXII

COOEt

S. Hibino and coworkers 48 have reported synthesis of carbazole

alkaloids using Wittig reaction (Scheme XXIII).

,C HO

DMF Ph3P=CHOMe I

POCK

H H Me Me

ONte OMe

I +

COOMe 00Me CooMe H

Me Me Me

19

LAB

I-I Me

Scheme XXIII

Another synthesis of hyellazole (5a) reported has been depicted in

Scheme XXIV49 .

0 Ph 0 i-

/'

I I Me3SiI base

oMe' l

Ac Ph

Ac Ph

Me

0I'MS

OH

Heat 5a

• Ac Ph Ac Ph

Scheme XXIV

Bt

20

M. Iwao et aI50 have reported a regiospecific synthesis of

carbazoles via palladium-catalysed cross-coupling and aryne-

mediated cyclisation (Scheme XXV).

Boc

Br\

I I

CI

Pd(PPh3)7C1 2

NH / I Cl Boc

KNH2/ lig_NH, 11

Boc

H

Scheme XXV

A. R. Katritzky and coworkers 51 have reported efficient

synthesis of substituted carbazoles from 1-methy1-3-(benzotriazol-1-

yl-methyl) indole (Scheme XXVI)

Bt

1) n-BuLi

2) 0

R'

• - N

Iit = i L II -N-N

Scheme XXVI

21

1.3 Present work directed towards synthesis of

pyridocarbazole ring system

Careful examination of reported methods indicated that there

are large no of methods available for the synthesis of these important

alkaloids. However, we felt that there is enough scope for us to

develop a convenient methodology. One of the most efficient routes

for the synthesis of pyridocarbazole ring system was devised by

Cranwell and Saxton 52 and further modified by Birch et a1 53 . This

route employs a Pomerantz-Fritsch reaction on a 3-functionald

carbazole derivative. The major limitations of this method the

preparation of suitably functionalised carbazoles and particularly

carbazole required for the synthesis of olivacine. Having this in mind,

we thought of developing a method which would give us

regioselectively 3-functionalised carbazole which then would have

been converted to pyridocarbazole alkaloids. The steps visualised in

our approach are depicted in Scheme XXVII. Suitably substituted

indole was to be formylated or acylated to give the starting compound

10.

22

Compound 9-13 R R 1 R2

a

b

c

d

x x

x x

H

SO2Ph

H

SO2Ph

H

H

CH3

CH3

Then the 3-oxo group on indole 10 would have to be condensed

with the Wittig reagent 11 to give the a,I3- unsaturated ester 12a. This

ester was then to be ring annulated to give 3-functionalised

(carboethoxy group) carbazole and this could then be easily converted

to pyridocarbazole alkaloids as per literature method. Thus, to begin

with, 3- formyl indole (10a) and Wittig reagent 11 was prepared by

literature procedure. First an equivalent mixture of both these

compounds were stirred in dichloromethane at room temperature. On

observing no change on prolonged stirring, (monitored by tic), the

reaction mixture was refluxed but, no formation of product was

observed. Changing the solvent to chloroform, benzene, and toluene

also failed. Finally, when refluxed in xylene for six hours, complete

disappearance of the starting and formation of two new spots was

observed on tic. The lower spot matched with corresponding to

triphenylphosphine oxide. Xylene was removed by distillation under

vacuum and the residue remained was chromatographed on silica

gel. Initial fractions gave a colourless solid, which melted at 130°C.

Elemental analysis of this compound suggested C16H17NO2 as the

molecular formula. In its IR (nujol) spectrum it showed a band at

3340 cm-, which could be attributed to NH function of indole nucleus

and a band at 1680 cm -, in the carbonyl region, which could be due

to the conjugated ester group.

In PMR (CDC13) spectrum [Fig.1A] it showed a triplet (J=7.7 Hz)

at 1.365 and a quartet at 4.25 integrating for three and two protons

24

respectively. This could be attributed to OCH2CH3 group. It also

showed three multiplets at 3.48, 5.12, and 6.008 which integrated for

two, two, and one proton respectively. These peaks could be assigned

to -CH2-CH=CH2 group. A multiplet observed at 7.258 for two protons

could be assigned to C-5 and C-6 aromatic hydrogens. The two

multiplets seen at 7.48 and 7.528 for one proton each could be

attributed to aromatic hydrogens at C-7 and C-2 position. Another

multiplet was observed at 7.808 integrating for one proton, which

could be assigned to the olefinic proton (CH=C). A singlet (1H) which

appeared downfield at 8.548, exchanged with D20 which indicated

the presence of hydrogen on the nitrogen of indole nucleus. The mode

of formation and spectral properties exhibited by the solid suggested

that the compound could have structure A or B i.e it could be E or Z

ester.

Stereochemistry of the ester

0 OE t

H

A

According to literature, the Wittig reaction of carbonyl

compounds are known to provide a mixture of E and Z isomers of the

products. The nature and the ratio of E-Z isomers depend on the

reactivities of the carbonyl compound, the phosphorane and the

solvent used for the reaction. As only one product was obtained it

was necessary to decide the stereochemistry, whether it was E isomer

A or the Z isomer B.

Since the product was a trisubstituted olefin, the coupling

constant of the olefinic protons could not be used to decide the

stereochemistry of this ester. It was necessary to try and decide the

COOEt ----- ____,---...,...,„-COOEt ,

,--

----- 1 -1 1/ '‘ 1 -----" I 1

.2_2 '-!-, ' ------ 1 H

25

stereochemistry by comparison of the chemical shifts with the

calculated values 54 of the olefinic protons. The calculated values of

chemical shifts for the olefinic protons in esters A and B were found

to be 7.8 and 6.238. As the value was very much closer to the

chemical shift for the E isomer, the ester should have structure

A rather than B.

Next step in the projected synthesis was the ring annulation

step to build the carbazole nucleus. Initially cold conc.sulphuric acid

was added to the compound to try electrophilic alkylation. However,

either we got starting material when it was treated for a short time or

inseparable mixture after keeping for a longer time, indicating

decomposition of the starting. Next, we tried PPA, in this case also

decomposition of starting was observed with multiple spots seen on

tic. After that, compound 12a was treated with A1C13 in CH2C12.

Within minute tic indicated multiple spots with no trace of starting

compound. Failing to get the product via electrophilic substitution,

we thought of using Pd-C as a reagent for ring annulation. It was

thought that if Pd/C could isomerise the double bond to a conjugate

system, then there is possibility of 12+4] addition reaction taking

place which could lead to dihydrocarbazole, which can further

dehydrogenate to give the required carbazole.

COOEt

1 I I'd/C

H it

I

11

-CC)0Et

- - •

11 1

Hence, initially the reaction mixture was refluxed in toluene for

several hours but, no change was observed (tic). Changing the solvent

to xylene also did not indicate any change. So, it was thought that

26

high boiling solvent like diphenyl ether might be able to do the

required isomerisation. So, when 12a was refluxed in diphenyl ether

for one hour, tic indicated slightly less starting spot (less staining of

the spot was seen in iodine) and also slight fluorescence in uv light.

But, the rf value of the spot was same as that of the starting.

However, it was thought that we record a 1 H-NMR and to our delight

in addition to the peaks of the starting new peaks were also seen

corresponding to the expected product. The peak intensities indicated

about 20% of the product formation. So, next time the reaction

mixture was refluxed for four hours, and this time when the 1 H-NMR

was recorded it indicated about 50% of the product. But, in no case

we were able to separate the product from the starting. When the

reaction mixture was refluxed for six hours, it indicated that the

reaction was perhaps complete as the new spot on tic appeared to be

more fluorescent and also the staining of the reaction mixture was

less in iodine compared to the starting, even after keeping for

prolonged time in the iodine chamber. So, after filtration, the mixture

was chromatographed over silica gel. Initially, solvent diphenyl ether

was removed under vacuum. Pet.ether was used as eluent, then

changing the eluent to ethylacetate:pet.ether (1:9), the fluorescent

spot was separated , which melted at 151°C.

It's spectral properties given below indicated that it could be

the required carbazole 13a.

0

27

IR (KBr) : vmax 3440, 1680 cm -1

PMR (CDC13)(Fig.1B)

(8 )

1.45 t (J=7.7 Hz) 3H COOCH2 CH3

2.57 3H CH3

4.43 q (J=7.7 Hz) 2H COO CH2CH3

7.28 m 1H C6 -H

7.46 m 2H C7 -H C8 -H

7.95 m 1H C3 -H

8.09 m 1H C5 -H

8.12 1H NH

(exchangeable with D20)

8.67 m 1H C4 -H

On the basis of mode of formation, it's spectral data and

closeness of its melting point 151°C with the lit. 55m.p.152°C

suggested structure 13a for this compound. As this compound has

been converted to the olivacine 56 , this constituted a formal synthesis

of olivacine.

Having achieved success in regioselective synthesis of carbazole

precursor for olivacine in two steps, we thought of converting the

exercise into one step procedure. Thus, we mixed the three reactants

3-formyl indole (10a), phosphorane 11 and 10% Pd/C in diphenyl

ether and refluxed for six hours. After filtration and column

chromatography, compound 13a was obtained in 80% yield.

1

2

i

RE

GIO

NA

L S

OP

HI

at

29

Thus, we were able to synthesize carbazole precursor to olivacine in a

one pot experiment. Having successfully prepared the above, we

thought of extending this methodology towards synthesis of ellipticine

(la). Here, in place of 3-formyl indole we required 3-acetyl indole

(10c). But, the later when treated with the Wittig reagent 11 failed to

react under variety of conditions that included neat heating, heating

in diphenyl ether for prolonged time resulting invariably in oxidation

of the Wittig reagent to triphenylphosphine oxide. As evident, the

structure of 3-acetyl indole, which is a vinylogous amide, was

expected to be inert towards reaction with the stable Wittig reagent

11. Addition of benzoic acid as a catalyst was also tried but, without

success as it was known to catalyse Wittig reaction of stable

phosphoranes with acetophenone derivatives.

We then thought of increasing the electrophilicity of the

carbonyl group by introducing an electron withdrawing group on

nitrogen of indole nucleus, there by reducing the vinylogous nature of

the ketone 10c and perhaps this reactant would react with the Wittig

reagent 11. Thus, following route was adopted wherein indole was

first N-protected by introducing benzene sulphonyl group according

to literature procedure 57 . Compound 10b was then acetylated to give

10d 58 .

it

9a 9b 10d

Once N- benzenesulphonyl-3-acetyl indole 10d was obtained,

we subjected it to Wittig reaction under variety of conditions e.g neat

heating, refluxing diphenyl ether, in presence of benzoic acid, in

refluxing acetic acid and even in presence of 10% Pd/C but, without

success. Recently a report has appeared wherein microwave

OOEt

oEt H2

OEt H

C H3

C H1 OEt

30

reaction 59 was used to speed up Wittig reactions involving stable

Wittig reagents and ketones furnishing good yields. But, when we

tried the same for our reaction by adsorbing the reactants on silica

gel or montomorilonite under microwave conditions, it failed to react.

Simultaneously, we made an attempt to synthesize olivacine

from already prepared carbazole precursor 13a. For which we tried to

slightly modify Pomerang-Fritsch synthesis for the construction of

pyridine ring on the carbazole skeleton to make olivacine (Scheme

XXVIII).

Cl

2

POC

NR,

CH3

14

CH,

Scheme XXVIII

It was visualized that if an amide can be prepared by

condensation between ester 13a and 2,2-diethoxy ethanamine, this

could then be cyclised with phosphorous oxychloride to give 14,

which then can either be converted to olivacine or could give us an

access to biologically more active derivatives of pyridocarbazole

system by doing nucleophilic substitution of chlorine with different

amines. However, all our attempts to condense the ester 13a with

amine failed.

COOEt

HOOC-

1

4(a-h)

OH

Scheme XXIX

31

We also attempted synthesis of carbazole Mukonine(4a) 5a

and related alkaloids 5 b -5h from carboethoxy ester 12. Our strategy for

the synthesis of this was as follows (Scheme XXIX).

We were interested in selective oxidation of the isolated double

bond. Ruthenium tetraoxide is a well known oxidising agent 6° for

double bonds, we attempted it. But, while we were working, a report 61

on Mukonine appeared on similar lines. So, we did not go ahead with

our plan.

32

Having failed to get condensation between Wittig reagent 11

and 3-acetyl indole (10c) as well as N-benzenesulphonyl-3-acetyl

indole (10d), we thought that it may be worthwhile if instead, we use

2-acetyl indole, which had greater chances of reacting with the Wittig

reagent as it is no more a vinylogous amide. Our strategy for the use

of 2-acetyl indole for the synthesis of pyridocarbazoles was as shown

in Scheme XXX.

[0]

33

1.4a Synthesis and natural occurrence of 2-acyl

indoles

As we required 2-acetyl indole we looked in the literature for

their synthesis. A few 2-acylindoles like Crooksidine 62 (15) and

alkaloid salvadoricine63 (16) have been isolated from plants.

• ,/0

H r

CH 3

Et

▪CH3

11

CH 3

15

16

2-Acyl indole have been used for the synthesis 64 of alkaloid

methueine and 2-Benzoyl indoles have been used for the synthesis 65

of carbazole alkaloids like hyellazole (5a) and chlorohyellazole (5b).

Although various procedures are available for the synthesis of 3-acyl

and 3-benzoyl indoles, very few methods are known for 2-acyl and

2-benzoyl indoles. Few of the known synthesis are depicted below.

Synthesis of 2-acyl indoles via lithiation reaction has been

reported 66 (Scheme XXXI).

Scheme XXXI

Ph

0

(32%)

Ph

Ph

4" 2 CO PdC1 2 (PPh 3 ) 2

SnC12 , 100 °C

34

A method for synthesis of 2-benzoyl indole in moderate yield

has been reported from indole-2-carboxylic acid 67 (Scheme XXXII).

1 ) S OC 12

2) Ph 2Cd / C6 146

Scheme XXXII

2-acyl indoles have been synthesized in very low yields via

intramolecular Wittig reaction 68 (Scheme XXXIII).

C0011

Scheme XXXIII

Synthesis involving o-nitro chalcones reacting with carbon

monoxide in presence of palladium complex 69 and also with triethyl

phosphite" is depicted in Scheme XXXIV & Scheme XXXV)

0

0

(52%)

Scheme XXXIV

I

NO2 (17%)

(CHPH)

CH3

CH ./

P(OEt)3

35

Scheme XXXV

G. W. Gribble as a part of new reactions of 3-vinylindoles have

synthesized 1,2-Dimethy1-3-(2-indolylcarbonyl)piperidine 71 (Scheme

XXXVI).

ea, CH3

,,,,,„..- CH 0 4,---„--- ----,:›

I

-,N

,,,,,..,,,-,j-\ `,..,_,-,-;3' NO

CH3

1) NaOH

2) p.TSA ... P(OEt)3

no reaction

1) CH3 I 2) NaBH4 3) H2 4) H2 0

Scheme XXXVI

0

36

1.4b Present work in synthesis of 2-acyl and 2-benzoyl

indoles

As already mentioned earlier, we visualised a methodology for

the synthesis of ellipticine alkaloids (Scheme XXX). In view of which

we required sizeable amount of 2-acyl indole. Looking at the above

mentioned methods, we felt that none of them could serve our

purpose for synthesis of 2-acyl indoles, as such the method by

Sundbere attracted us and we decided to improve on that method,

overlooking the failure of Gribble to achieve direct synthesis of 2-acyl

indole71 . Also, in recent years Domino reactions 24 have attracted

considerable attention of organic chemist, as they provide easy entry

to complex molecules by including two or more transformations in

one pot. Earlier, we had achieved success in synthesizing carbazole

precursor to olivacine, wherein three reactions viz. Wittig reaction,

isomerisation of the double bond, [4+2] cycloaddition and

aromatisation occurred in tandem manner.

Thus, we visualised that four reactions viz. Wittig reaction,

generation of nitrene, addition of nitrene to carbon-carbon double

bond, opening of the aziridine ring and formation of indole could

occur in tandem manner. (Scheme XXXVII).

As the seen in the above (Scheme XXXVII), it is observed that the first

step involves Wittig reaction to take place for the formation of o-nitro

NaOH

Et0H

OAc) 2 RCOCH 3

NO2 NO 2

N 2 0 2 or

HNO 3 /AcOH

R CO CH 3 jC R CHO

NO 2

NaOH Et0H

37

chalcones. So, it was needed to look into the literature methods

reported for the synthesis of it. We came across three methods

reported for the synthesis of o-nitrochalcones. (Scheme XXXVIII).

Scheme XXXVIII

The first method72 do not give good yield, in the second

method73 an additional step of protection of aldehyde is required and

the last is selective with respect to need for a suitable substrate'''.

Having observed that Wittig reaction is not reported for the synthesis

of o-nitrochalcones we proceeded with our approach initially in a

stepwise manner. We mixed o-nitrobenzaldehyde (17a), phosphorane

18a in equal proportions and refluxed in methanol (Scheme XXXIX).

38

After two hours the reaction reached to completion (indicated

by tic), the solvent was evaporated on water bath and the residue

obtained was column chromatographed over silica gel using ethyl

acetate:pet.ether (1:9) as eluent. Initial fractions gave solid which

melted at 54°C. In ifs IR spectrum it showed a band in the carbonyl

region which could be attributed to the keto group 4-(2'-nitropheny1)-

3-propen-2-one. In it's PMR spectrum (CDC13), it showed a singlet at

2.526 integrating for three protons which could be assigned to COCH3

group. A doublet for one proton with J= 16.7 Hz appeared at 6.646

which could be due to a proton of the a, (3- unsaturated ketone

(CH=CH-00). In the aromatic region between 7.00-8.316, a multiplet

was seen for three protons which could be due to three aromatic

hydrogens on 4, 5, and 6 carbon atoms. A doublet with J=16.7 Hz for

one hydrogen appeared at 8.066. This could be due to the id-proton of

the a, id- unsaturated ketone (CH=CH-00). The downfield nature of

this proton indicated that it could be cis to the carbonyl group. Also

the coupling constant J= 16.7 Hz , suggested that the geometry of the

olefin as 'E isomer. A doublet at 8.186 was also seen with J= 9 Hz.

This could be attributed to aromatic hydrogen (C3-H) next to nitro

group. Thus, based on the spectral data, mode of formation and the

melting point 54°C which was in close agreement with the lit. 75 m.p.

56°C suggested that the compound could have the structure 19a.

The yield of the product was found to be 90%.

The product 19a was then subjected to reductive cyclisation by

mixing with 2 eqsa of triphenyl phosphine and heating in diphenyl

ether at 180°C for two hours (monitored by tic). Normal workup gave

a solid which melted at 152°C.

In ,it's IR spectrum, it showed a band at 3300 cm -1 which could

be due to the NH group of indole and also a band in the carbonyl

region at 1650 cm -1 which may be due to COCH3 group. In it's PMR

(spectrum) [Fig.1C], it showed a singlet integrating for three

hydrogens at 2.646 which could be attributed to methyl grouping

0 I 0

CH3

• ■ ••• , 1 71.-11

i • I:: ; i ! ■ I --1 -- 1 1 i . 1 i • ..d 1Y: I. - r _i.", 11 1 1 I I ' I___ 1

• . , • _____. t_ ,. , .

_.__......!.___' ... • ! I- La ....._____I I 1 1 i f--- 1-- ; i i !- 1' l': I 1

- 1-7- 1-. 1-7- r---- i --- 1- !:- 1-7i" --.--- , -- ! •.

• ; •

_I ! L- ir

I I i ! I

--ECII--- i

-! • t -.! li I I 1

1, 1 L • . • •••• ■ • - r-- i -

' I 1 • - :i:- . i . 1-1

„,. . , .

I 1 1. • - -77-j--I- ' 1 7-1

. '' - --, -:-Str".;. • '-z1 --- Cana I gi .'s 1 ' • ::?, MIE2 !, i'.. P-•

Scheme XXXX

R NO 2

17(a-c)

Ph2 0 0

N/ R2 H

18(a-b) 20(a-f)

PPh 3

R 3

0

19 (a-f)

40

attached to a carbonyl group. In the aromatic region, it showed a

multiplet for five protons which could be assigned to the four

aromatic proton and one C3 proton of the indole nucleus. A broad

singlet at 9.555 was seen which exchanged with D20 indicating the

presence of NH group. Thus, on the basis of it's mode of formation,

spectral data, and the similarity of it's melting point with the lit. 76

m.p.152°C, suggested that the compound obtained has structure of

2-acetyl indole (20a). The yield of the compound was found to be

57%.

Once the confirmation of structures 19a and 20a was done, as

we had proposed earlier (Scheme XXVII), we were now in position to

carry out the process in tandem manner. For this experiment we

refluxed the mixture of 2-nitrobenzaldehyde (17a), phosphorane- 16a

and two equivalent of triphenyl phosphine in diphenyl ether. After

two hours tic indicated formation of the product i.e 2-acetyl indole

(20a). Usual workup, followed by column chromatography, furnished

the expected product 20a. The spectral properties as well as it's

melting point matched with the authentic 2-acetyl indole prepared

earlier in two step sequence. The yield of 2-acetyl indole was found to

be 48%.

The promising results obtained for one pot synthesis of 2-acetyl

indole prompted us to use this methodology for synthesis of

substituted 2-acetyl indoles (Scheme XXXX).

41

Compound

17 (a-c)

R1 R2

a

b

c

H H

OCH2O

OCH3 OCH3

Compound

18 (a-b)

R3

a

b

CH3

Ph

Compound

(19 & 20 (a-f)

R1 R2 R3

ai -CD

c.) T

i a) c.

H H

OCH2O

OCH3 OCH3

H H

OCH2O

OCH3 OCH3

CH3

CH3

CH3

Ph

Ph

Ph

Since, we had pipernal and veratraldehyde with us, we used

these compounds to prepare their corresponding nitrobenzaldehydes.

First we converted pipernal to 2-nitropipernal (17b) as per literature

procedure". This 2-nitropipernal was then mixed with phosphorane

18a and two equivalent of triphenyl phosphine and refluxed in

diphenyl ether. The reaction reached to completion after two hours

(monitored by tic). Usual workup provided a solid, which melted at

170°C. It's spectral data (given below), suggested the structure to be

20b.

bs

(exchangeab

1H

le with D20)

2.54

6.02

6.91

7.10

7.35

9.43

3H

2H

1H

1H

1H

CH3

OCH2O

C7-H

C4-H

C3-H

NH

42

IR (KBR) : vmax 3300, 1640 cm -1

PMR (CDC13) :

(5 )

Elemental analysis (given below)

•

C(%) H(%)

Found 64.88 4.33

Ci ,H9NO3 Requires 65.02 4.46

It's mode of formation, spectral data and elemental analysis

suggested that the compound could have structure 20b. The yield of

the product was found to be 43%. Similarly, veratralaldehyde was

subjected to the same exercise i.e preparing 2-nitroveratraldehyde

(17c) as per literature procedure 78 and subjecting it to the same

reaction conditions as above. Here too, refluxing the reaction mixture

containing 2-nitroveratraldehyde, phosphorane 18a and two

2.56 3H C H3

3.95 6H 2xO CH3

6.89 1H C7 - H

7.16 1H C5-H

7.37 1H C3 -H

9.35 bs 1H NH

(exchangeable wit h D20)

43

equivalent of triphenyl phosphine required two hours for the reaction

to reach to completion (monitored by tic). Solid obtained after usual

workup melted at 148°C. It's spectral data (given below).

IR (KBr) : vin. 3290, 1640 cm -1

PMR (CDCI3) : [Fig.11)]

(8 )

Elemental Analysis (given below)

C(%) H(%)

C 12H i3NO3

Found

Requires

65.50

65.75

5.85

5.97

iJ

DEPARTMENT OF CHFMIL;FRY 1:\T../FIly OF POOM.A

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45

The above data suggested the structure 20c for the compound.

The yield of this product was found to be 36%.

The successful synthesis of three 2-acetyl indoles tempted us to

try our hand at synthesizing 2-benzoyl indole as also the reported

methods gave moderate yields. For adopting our one pot approach,

we required phosphorane 18b, which was synthesized according

to reported procedure i.e acetophenone converted to

bromoacetophenone 79 , followed by treatment with triphenyl

phosphine and work up using 2N sodium hydroxide. Once

phosphorane 18b was obtained80, it was treated with

2-nitrobenzaldehyde (17a) and two equivalent of triphenyl phosphine

under refluxing conditions in diphenyl ether. The reaction showed

disappearance of the starting and appearance of a new spot along

with triphenyl phosphine oxide (indicated by 'tic) after two hours.

Usual workup gave a solid, which melted at 145 - 147°C. The spectral

data of the compound showed following observations. In it's IR (KBr)

spectrum it showed a band in the region at 3300 cm -1 , which could

be attributed to the NH group in the compound. It also showed a

band in the carbonyl region i.e at 1650 cm -1 , that could be due to the

carbonyl of the benzoyl group. In it's PMR spectrum (CDC13), a

multiplet was seen 7.0-8.28 in the aromatic proton region, which

integrated for ten protons, that could be assigned to all the ten

aromatic hydrogens in the expected product. Also a peak as broad

singlet was seen at 9.38, integrating for one proton in the far

downfield region, exchangeable with D20, which could be due to the

presence of NH hydrogen in the compound. It's mode of formation,

spectral analysis, and above all the melting point 145-147°C matched

with the lit. 7° m.p.151-152°C confirmed that the structure could be

20d i.e 2-benzoyl indole. The yield was found to be 40%.

Since 2-benzoyl indole could also be synthesized by this

method, we repeated the similar strategy for synthesis of substituted

2-benzoyl indoles from 2-nitropipernal and 2-nitroveratraldehyde.

2-nitropipernal (17b), phosphorane 18b, and two equivalent of

6.02 2H OCH2O

6.89-8.12 m 8H Ar-H & C3-H

9.64 bs 1H NH

(exchangeable with D20)

•

46

triphenyl phosphine were mixed in diphenyl ether and refluxed for

two hours. TLC indicated the formation of the new spot along with

triphenyl phosphine oxide. The residue obtained after distilling off the

solvent was chromatographed over silica gel using

ethylacetate:pet.ether (3:7) and then recrystallised with

chloroform+pet.ether. The solid obtained after purification melted at

200°C.

In its spectral data i.e IR and PMR spectrum it showed the

following (given below).

IR (KBr) : vmax 3300, 1610 cm -1

PMR (CDC13): [Fig.E]

(8)

Elemental analysis (given below)

C(%) H(%)

Found 72.33 4.09

CI6H11NO3 Requires 72.44 4.18

The above observations suggested structure 20e for the

compound. The yield was found to be 30%.

4=,

•

m

bs

3H

3H

1H

7H

1H

(exchangeable with D20)

3.9

3.95

6.9

7.05-7.9

9.35

OCH3

OCH3

C7 - H

Ar-H

NH

48

Similarly, 2-nitroveratraldehyde (17c) was subjected to treatment

with phosphorane 18b and two equivalent of triphenyl phosphine and

refluxed in diphenyl ether for two hours. Usual workup gave a solid,

which melted at 180°C. It's spectral data (given below).

IR (KBr) : vmax 3280, 1600 cm -1

PMR (CDC13) :

( 6 )

Above spectral data and also the melting point 180°C matched

with the lit. 81 m.p.176-178°C, confirmed that the structure could be

20e.

As, observed we could in total synthesize two more 2-acyl and

three 2-benzoyl indoles apart from the parent 2-acetyl indole. As we

had started the approach in stepwise manner during synthesis of

2-acetyl indoles, we thought to isolate and characterise the

intermediate nitroketones obtained in the remaining reactions and

further subject them to synthesis to their corresponding 2-acyl and

2-benzoyl indoles.

So, starting with compound 17b, we refluxed it with

phosphorane 18a in methanol for two hours. After keeping overnight,

the solid separated was filtered and recrystallised using methanol.

This solid melted at 160°C. Its structure studied by it's spectral data.

49

IR (KBr) : v.1690 cm - i-

PMR (CDC13) : [Fig.1F]

(5 )

2.45

6.25

s

s

3H

2H

CH3

OCH2O

6.58 d(J= 16.7 Hz) 1H CH=CH-CO

7.08 s 1H Ar6-H

7.70 s 1H Ar3-H

8.08 d(J= 16.7 Hz) 1H CH=CH-CO

So, based on it's mode of formation and spectral data, structure

18b could be assigned to the compound. The yield was found to be

86%. Similarly, compound 17c was subjected to the same reaction

conditions, here too solid was obtained directly, which was filtered

and recrystallised using methanol. The pure solid exhibited following

spectral analysis

IR (KBr) : vinax 1670 cm-1

PMR (CDC13) :

( 5 )

2.29

4.03

s

s

3H

6H

C1-13

2xOCH3

6.58 d(J= 16.7 Hz) 1H CH=CH-CO

7.06 s 1H Ar6-H

7.79 s 1H Ar3-H

8.20 d(J= 16.7 Hz) 1H CH=CH-CO

On the basis of the above observations w.r.t it's spectral

analysis, and also similarity of the melting point 168°C to the

lit. 82 m.p.172°C structure 19b was predicted for the compound.

•

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51

Then, compound 17a and phosphorane 18b was refluxed in

methanol for two hours and kept overnight. The solid, which

separated out was filtered, recrystallised and characterised by

spectral data.

In its IR spectrum it showed a band at 1670 cm - ' in the

carbonyl region, which could be attributed to the conjugated carbonyl

group of ketone. In it's PMR (CDC13) spectrum, a multiplet was seen

in the aromatic region, integrating for eleven protons, which could be

attributed to the nine aromatic hydrogens and the two hydrogens at a

and 13 positions of conjugated carbonyl group. In accordance with the

above and the melting point 126°C, which matched with the lit. 73

m.p.127-128°C, structure suggested was 19d.

Next, the reaction was carried out on 2-nitropipernal (17b) and

2-nitro veratraldehyde (17c) with the phosphorane 18b. First,

compound 17b was refluxed with 18b in methanol for two hours. The

solid which separated out after keeping the reaction mixture

overnight, was filtered and recrystallised using methanol. The melting

point was determined to be 154°C. It's spectral data is given below.

IR (KBr) : v max 1670 cm -1

PMR (CDC13) : [Fig.10]

(6)

6.29 s 2H OCH2O

7.17 s 1H Ar-H

7.31 d(J= 16.7 Hz) 1H CH=CH-CO

7.66 m 4H Ar-H

8.12 m 2H Ar-H

8.26 d(J= 16.7 Hz) 1H CH=CH-CO

D::=--V-:"..P:IEN,11 • OE r.c POONA

Flo I G

53

Elemental analysis (given below)

C(%) H(%)

Found

C16H111\105 Requires

64.84

64.64

3.99

3.73

So, based on the above spectral and elemental analysis

structure 19e could be assigned to the compound

Then, compound 17c and phosphorane 18b was, refluxed in

methanol for two hours and kept overnight. The solid, which

separated out was filtered, recrystallised and characterised by

spectral data.

In its IR spectrum it showed a band at 1660 cm -1 in the

carbonyl region, which could be attributed to the conjugated carbonyl

group of ketone.

IR (KBr) : vmax 1670 cm -,

PMR (CDC13) : [Fig. 1H]

[E :Z; 7:3]

(5)

3.92 s 3H OCH3 [2]

4.02 s 3H OCH3 [2]

4.14 s 3H OCH3 [E]

4.2 s 3H OCH3 [E]

6.95 d(J= 11.7 Hz) 1H CH=CH-CO[2]

7.28 d(J= 16.7 Hz) 1H CH=CH-CO[E]

7.31-8.22 m 1H Ar-H 86CH=CH-CO[Z]

8.37 d(J= 16.7 Hz) 1H CH=CH-CO[E]

The above spectral data and similarity of it's melting point

181°C with the lit." m.p.182-183°C suggested structure 19f for the

compound.

S

DEPARTMENT OF CHEMISTRY , UNIVERSITY OF POONA

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, 1 111', • '! . I 1 ![___ 1 1!: I I I I ,I-11 II ; II

4!I 1 I 11 , , 1---

III. IL__. '.. II 1 1 i

11:,___L• 1 II I : 1 I 1 , , 1 ' ' ' 7 1 1 Ull

1 I • i , i I I ' i I i . ! 1 1 1 1 1 ! • 1 1 ... I I 1 ! . • . , : i ■

V I 11 W

1 1 ; 1 I I! ; 1 1- 1 1 I t ■ I i I 1 I . 1 I I ;

, 1 i'( 1 1 1 ; i 1 1 1 1 If

. 1 , i 1 1 I! 1 1 1 1 . 1 1 1 i .. ' L 1 ;

1 ..4 1 1 : 1! I i : I . 1 1 I 1 I I I 1 z 1 I : : I 1 1 I 1 ! i : I 1 1 II . ;

1 71 ; 1 i : . 1 i

__; I I : 1 ; 1, . M i 1 1 t 1 I ' ■ 1 ! I , I . I I '

. 1

I 1 11 ; Li ._ 1 .L

1 I i 1 ;

1 II ' 1 ; 1 I I

11 I I I

AI

1 I . • i

I Il -- i

1 I 1 i Mill :._. I i 1 1 ' • I 11111111111i ! : 1 1 . ! Au" • , " IIIII

1 I 1 I . , .- I •_ . I•11, i

1 MIIIIMII 1 1 1 I .41181=111E11- : ;

1 1 '11: ' 1 1

, . ly a

I 1 . , . • 1. i . , .._ ._.„. . .-- ---' • . ....

Fig. 1 H

55

After characterizing the structures of nitroketones 19(a-f), we

used them to convert to their corresponding 2-acetyl and 2-benzoyl

indoles. Here the substrates 19(a-f) were treated with two equivalent

of triphenyl phosphine and heated at 180° in diphenyl ether. In each

of these reactions, the time required for the conversion was 8 hours.

The workup of reactions were carried out by initially distilling off

diphenyl ether and then the residue obtained was chromatographed

using appropriatate solvent system. Recrystallisation of the solid

obtained gave pure compounds whose structures were characterised

by comparison with the products obtained by one pot method i.e, IR

superimposability, co-TLC, also the similarity of the melting point.

The results with respect to yields obtained are given below.

Compound Yield (%)

20 (b-f)

b 52

c 42

d 48

e 52

f 44

Once we obtained 2-acetyl indole in sizeable amount, we

turned on to our plan described earlier (Scheme XXX),. We mixed 2-

acetyl indole with phosphorane 11 under variety of condition by

changing solvent from toluene, xylene to diphenyl ether, adding

benzoic acid as catalyst, it failed to deliver any results. We also tried

neat heating of the reactants but here too reaction failed to take

place. Even microwave condition failed to give the expected result.

56

1.5 Present work directed towards synthesis of

carbazole ring system

Since we failed to synthesize carbazole precursor to ellipticine,

we tried to attempt synthesis of carbazoquinocin (7a) from 2-acetyl

indole. Our plan for synthesizing carbazoquinocin was as follows

(Scheme. XXXXI).

CH 2-- CCX1t

r-CCCEt l

H

H

H CH 3

CH Carl

_)11 OCC:Et

H CII

C1-I

O ,0

aI

LAH

al 3

N H

ai 3

achora____000a

Here the first step was to react 2-acetyl indole with diethyl

succinate under Stobbe condensation. When we tried this reaction it

failed to give Stobbe product.

We tried to use Wittig-Horner reaction as it is known to give

better yield (Scheme MOM).

coo-{-0 I I

57

1,1(0EQ,P COOEt

II

Th∎1 C" K 2CO3 , DMF

H I I 0

COOEt CH,

SchemeXXXXlI

However, again we failed to get the product. So, it was thought

that may be exchangeable hydrogen on indole nitrogen may be

causing failure. So, it was decided to protect as it's benzylsulphonyl

amide. This attempt also did not yield any result. Further, work is

needed to be done particularly using Emmons reaction.

58

1.6 CONCLUSION

1) We were able to demonstrate that stable Wittig reagent could

be used for the synthesis of carbazole precursor to olivacine.

Thereby, it constitutes a formal synthesis of olivacine. However,

we could not extend it for the synthesis of ellipticine.

2) A convenient method for the synthesis of 2-acyl and

2-benzoyl indoles has been developed.

1.7 EXPERIMENTAL

Expt.1.1 Preparation of triphenyl-a-ethoxycarbonyl-

methylene phosphorane

C-D PPh3 + BrCH2COOEt

Ph3P—CH2COOEt

Br NaOH

A?____CHC 0 OEt

Expt.1.2 Preparation of carboethoxv-(a-ally1)-

methylidene triphenvl phosphorane (11)

Br

Ph3P_CHCOOEt Ph 3 P—CH

° Br COOEt

Ph 3P^C

N-COOEt

11

59

•

Expt.1.3 Preparation of 3-Formyl indole (10a)

DMF, POC13 4 j -/j4D I U

HN H

9a 10a

Expt.1.4 Preparation of ethyl-(2-allv1-3-(3'-1H-indoly1)

propeonate (12)

10a

12

Expt.1.5 Preparation of 2-ethoxycarbony1-

4-methirlcarbazole (13)

COOFt

10% Pd/C

Ph20

12

13

H

0 1

H

Ph 3P -\\ COOEt

/COOEt

N 11

60

Pd/C, Ph20, reflux

COOEt

COOEt )

H

13 10a

PhS02C1 0 I '

H

CH3

O2Ph

Ac20 anhy AlC13

0 SO2Ph

Expt.1.6 One pot preparation of 2-ethoxycarbony1-

4-methylearbazole (13)

H

Ph 31

0 1 1

Expt.1.7 Preparation of N-tosylindole (10b)

9a 10b

Expt.1.8 Preparation of N-tosyl-3-acetylindole (10d)

9b 10d

H

61

62

PPh3

dry benzene C I CH2C0 CH, Ph3P—CH2COCH3

(

C

CH3 0 + Ph3P_CHCOCH3 Me0H

\\ NO2

19a 17a 18a

Expt.1.9 Preparation of triphen.yl-a-acetyl

methylene phosphorane (18a)

NaOH

Ph 3 P CH CO CH 3

18a

Expt.1.10 Preparation of 4-(2'-nitropheny1)-

3-buten-2-one (19a)

Expt.1.11 Preparation of 2-acetyl indole (20a)

VT -3

0 2eq PPh3 ,

1'1120, reflux 0 NO2

H CH3

19a 20a

63

HO

NO2

, 0

H3

Ph3P=CHCOCFI3

2 eqPPh 3, Ph20

17a 20a

CHO

HNO3

CHO

0 NO NO2

Expt.1.12 One pot preparation of 2-acetyl indole (20a)

Expt.1.13 Preparation of 4,5-methylenedioxy-

2-nitrobenzaldehyde (17b)

17b

Expt.1.14 Preparation of 4,5-dimethoxy-

2-nitrobenzaldehyde (17c)

1 13C0 C HO CHO

HOY 2

17c

HNO3

64

Expt.1.15 One pot preparation of 2-acetyl-5,

6-methylenedioxy indole (20b)

0 / Ph3P=CHCOCH3 / -- , N 0

2eePhi Ph20 <, j I L„...... ., NO------- NO2 N. ...,,,------,, \----- ----/ P '.„.„,,..,,,,7"----,,,...

'0 N . H

CH3

17b

20b

Expt.1.16 One pot preparation of 2-acetyl-5,

6-dimethoxy indole (20c)

H3C0 CHO H3C0_,,,..,....,____,----,..

Ph3P=CHCOCH3 U 11 0 ---

2eqPPh3, Ph 20 H 3C0 NO2 H 3C0 ---.. - F.1 .--'' -

H CH 3

17c 20c

CI-I0

65

CH2Br

0 I I PPh 3

+ 0 2eqPP113, P1120

NO2

Expt.1.17 Preparation of bromoacetyl benzene/

bromoacetophenone

Expt.1.18 Preparation of triphenyl-a-benzoyl methylene

phosphorane (18b)

-cH2Br

) PPh3

NaOH

18b

Br2 glacial acetic acid

H

Expt.1.19 One pot preparation of 2-benzoyl indole (20d)

17a 18b 20d

66

O HO

I 2eqPPh 3. Ph

17b 18b

17c 18b 20f

20e

Expt.1.20 One pot preparation of 2-benzoyl-5,

6-methylenedioxy indole (20e)

Expt.1.21 One pot preparation of 2-benzoyl-5,

6-dimethoxy indole (20f)

0 ,,,C HO I I _,,, PPh 3 H3CO3., -------,, ,--------'---------- '-------.<---

_, (----) 2eciPPh3, Ph20 I

H3C0.--- '''''-"-------'-\ \ No 2 ''''\./..-- I-13C

Ph

Expt.1.22 Preparation of 4,5-methylenedioxy-

2-nitro-3-buten-2-one (19b)

0

'NO2

19b

CHO

0 Ph3P=CHCOCH MC011

N 'NO2

17b 18a

0

67

Me0H

CHO

Ph3P=CHCOCH3 `NO2

CH3

0 H3C0 \ NO2

17c 18a 19c

-Ph

'NNO2

+ Ph3PHCOPh

18b 19d

Expt. 1.25 Preparation of 3-(2'nitro-4',5'-methylene-

dioxy)-1-phenyl-2-propenone (19e)

17a

17b 18b 19e

Expt 1.23 Preparation of 4,5-dimethoxy-

2-nitro-3-buten-2-one (19c)

Expt. 1.24 Preparation of 3-(2'-nitrophenv1)-

1-phenyl-2-propenone (19d)

0 + Ph3PLICOPh

\O- NO 2

N

Me0H reflux

0 Hco

I (—)

HO \\ NO2

I 0 Ph3P_CHCOPh

1-10-- \No2

19f 17c 18b

19b 20b

NO2 N Ho)

0

2cciPPh3, Ph20 180 ° C

19c 20c

Expt. 1.26 Preparation of 3-12'-nitro-4',5'-dimethoxy)-

1-pheny1-2-one (19f)

Expt. 1.27 Preparation of 2-acetyl-5,6-methylenedioxy

indole (20b)

Expt. 1.28 Preparation of 2-acetyl-5,6-dimethoxy

indole (20c)

68

Expt. 1.29 Preparation of 2-benzoyl indole (20d)

0 I I

0 2eqPPh 3 , Ph20 180°C

19d

20d

Expt. 1.30 Preparation of 2-benzo54-5,6-methylenedioxy

indole (20e)

0

••— Ph 2eq1313113, Ph20

I 180°C 0

0

Ph

19e 20e

Ph

Expt.1.31 Preparation of 2-benzov1-5,6-dimethoxy

indole (20f)

H3C Ph

2eciPP113, Ph20 iI 1 -o 180°C

H3C0 - 11 NO2

19f 20f

Ph

69

70

Expt.1.1 Preparation of triphenyl-a-ethoxycarbonyl

methylene phosphorane

Addition of a solution of triphenyl phosphine (15.7g, 60mmol)

in dry benzene (30m1) to a solution of ethylbromoacetate (11.7g,

60mmol) in dry benzene (10m1) at room temperature, resulted in an

elevation in temperature to about 70°C and the precipitation of a salt.

After allowing the mixture to cool to room temperature, it was

vigorously shaken and left overnight. The separated solid was filtered,

washed with dry benzene and dried.

The stirred solution of the above salt in water (150m1) and

benzene (100m1) was neutralised by aqueous sodium hydroxide to a

phenolphthalein end point. The benzene layer was separated, dried

(anhy. Na2SO4) and concentrated to about 1/3rd volume. Addition of

n-hexane (40-60°) resulted in the separation of the crystalline

product which was filtered and dried to afford triphenyl-a-

ethoxycarbonylmethylene phosphorane (14.6g, 70%) m.p.125-126°C

(lit. 83m.p. 125-127°C).

Expt.1.2 Preparation of carboethoxy-(a-ally1)-

methylidene triphenyl phosphorane (11)

A mixture of allyl bromide (25m1) and carboethoxymethylene

triphenyl phosphorane (10g, 2.87mmol) was refluxed for 5 hours and

kept overnight. It was filtered and the solid obtained was washed with

dry ether. On recrystallisation from chloroform+pet.ether it furnished

salt (8.1g, 60%) m.p.150-151°C. The above salt was dissolved in

water (125m1) and benzene (100m1) was added to it. Phenolphthalein

(1 or 2 drops) was added to it. Sodium hydroxide solution (10N) was

added to it with stirring till the pink colour persisted. The benzene

layer was separated and the aqueous layer was extracted with

benzene (50m1). The combined benzene layer was dried

73

dichloromethane:n-hexane (1:9) furnished pure white crystals as

product 10b (1.4g,81.85%) m.p.75°C (lit. 57m.p.75-79°C).

Expt.1.8 Preparation of N-tosyl-3 -acetylindole (10d)

A stirred suspension of Aluminium chloride (0.83g, 6.2mmol) in

dry CH2C12(17m1) under pressure was slowly treated with acetic

anhydride (0.679m1, 6.6mmol). The solution was stirred at room

temperature for 0.25hr. and then treated with a solution of 1-phenyl

sulphonylindole (10b) (0.75g, 3.1mmol) in dry dichloromethane

(10m1). The mixture was stirred for 0.5hr. poured over crushed ice

(50g) and and extracted with dichloromethane (3x125m1). The

combined organic extracts were then washed with brine (250m1),

saturated aqueous sodium bicarbonate (250m1) & brine (250m1) dried

over potassium carbonate & concentrated in vacuum. The crude

product was recrystallised using methanol (0.434g,45°/0) m.p.153°C

(lit. 59m.p. 155°C)

Expt.1.9 Preparation of triphenyl-a-acetyl methylene

phosphorane (18a)

Addition of a solution of triphenylphosphine (14. lg, 50mmol) in

dry benzene (5m1) to a solution .of chloroacetone (5g, 50mmole) in dry

benzene (5m1) at room temperature. The reaction mixture was

vigorously shaken and left overnight. The separated solid was filtered,

washed with dry benzene and dried.

The stirred solution of the above salt in water (10m1) and

benzene (15m1) was neutralised by aq.sodium hydroxide to a

phenolphthalein end point. The benzene layer was separated, dried

over anhy.Na2SO4 & concentrated (to about 1/3 rd volume). Crystalline

product was obtained by addition of n-hexane, which was filtered &

74

dried to afford triphenyl-a-acetyl methylene phosphorane (3.32, 80%).

m.p.205 °C (lit. 80m.p.205-206 °C).

Expt.1-10 Preparation of 4-(2'-nitropheny1)-3-buten-2-

one (19a)

A mixture of 2-nitrobenzaldehyde (2.0g, 13.2mmol) and

phosphorane 18a (4.11g, 13mmol) in methanol (15m1) was refluxed

for two hours. Methanol was removed on water bath and the residue

was chromatographed over silicagel using ethylacetate:pet.ether (1:9)

as an eluent. Solid obtained was recrystallised using methanol, 19a

(2.02, 80%) m.p.54°C (lit.75m.p.56-57°C).

Expt.1 - 11 Preparation of 2 -acetyl indole (20a)

Compound 19a (1g, 5.2mmol) with triphenyl phosphine (3.01g,

11.5mmol) was heated in diphenylether (5m1) at 180°C for 2 hrs.

Chromatography over silica gel using ethyl acetate: pet.ether (3:7) as

eluent furnished solid, which was recrystallised using

dichloromethane:pet.ether (5:5) (0.474g, 57%) m.p.152°C (lit. 76m.p.

152°C).

Expt.1 - 12 One pot preparation of 2 -acetyl indole (20a)

Compound 17a (0.5g, 3.3mmol), phosphorane 18a (1.05g,

3.3mmol) and triphenyl phosphine (1.73g, 6.6mmol) was refluxed in

diphenylether (5m1) for 2 hrs. Diphenyl ether was distilled under

vacuum.' Chromatography over silica gel using ethyl acetate:pet.ether

(3:7) as eluent furnished solid, which was recrystallised using

dichloromethane:pet.ether (5:5) (0.247g, 48%) m.p.152°C (lit. 76m.p.

152°C)

75

Expt.1.13 Preparation of 4,5-methylenedioxy-2-nitro

benzaldehyde (17b)

4,5-methylenedioxybenzaldehyde (2.0g, 13mmol) was heated

with conc.nitric acid (15m1) at 60°C for about 15-20mins. time

duration. Then the reaction mixture was poured into crushed ice

pieces with constant stirring. Yellow coloured precipitate separated

out, which was filtered and recrystallised using ethyl alcohol (1.71g,

66%) m.p.90°C (lit. 77 m.p.880C).

Expt.1.14 Preparation of 4,5-dimethoxy - 2-

nitrobenzaldehyde (17c)

Followed the same procedure as expt.1.13, yield (1.75g, 69%),

rn.p.129°C (lit. 78m.p.128-133°C).

Expt.1.15 One pot preparation of 2-acety1-5,6-

methylenedioxy indole (20b)

Followed the same procedure as expt.1.12, yield (0.09g,

43.22%), m.p.170°C.

Expt.1.16 One pot preparation of 2-acety1-5,6-

dimethoxy indole (20c)

Followed the same procedure for preparation as expt.1.12, yield

(0.07g, 36%), m.p.148°C.

76

Expt.1.17 Preparation of bromoacetyl benzene/

bromoacetophenone

Bromine (1.95m1) was added dropwise to a stirred solution

containing acetophenone (7.5g, 60mmol) and a drop of 48%

hydrobromic acid in 50m1 of glacial acetic acid in an ice bath. The

rate of addition was adjusted so that the temperature never exceeds

20°C. After the addition , stirring was continued for 30 mins. at room

temperature.

Calculated lml of the solution was withdrawn and crystallised

by scratching with a glass rod, while the remaining solution was

cooled to 3-4°C. The seed crystals were added, whereupon phenacyl

bromide precipitated out of solution. The colourless crystals were

collected by filtration, washed several times with a total of 30m1 of

ethanol/water (1:1) and dried in vacuum. The yield was (5.9g,

47.44%) m.p.47°C (lit. 79m.p.47-48 °C).

Expt.1.18 Preparation of triphenyl-a-benzoyl

methylenephosphorane (18b)

Addition of a solution of triphenylphosphine (6.55g, 25mmol) in

dry benzene (5m1) to a solution of bromoacetophenone (5.0g, 25mmol)

in dry benzene (5m1) at room temperature. The reaction mixture was

vigorously shaken and left overnight. The separated solid was filtered,

washed with dry benzene and dried.

The stirred solution of the above salt in water (10m1) and

benzene (15m1) was neutralised by aq.sodium hydroxide to a

phenolphthalein end point. The benzene layer was separated, dried

over anhy.Na2SO4 & concentrated (to about 1/3rd volume). Crystalline

product was obtained by addition of n-hexane, which was filtered &

dried to afford triphenyl-a-benzoyl methylene phosphorane (4.5,

47.8%) m.p.181°C (lit. 80 m.p.181-182°C)

77

Expt.1.19 One pot preparation of 2-benzoyl indole

(20d)

Compound 17a (0.5g, 3.3mmol), phosphorane 18b (1.25g,

3.3mmol) and triphenyl phosphine (1.73g, 6.6mmol) was refluxed in

diphenylether (5m1) for 2 hrs. Diphenyl ether was distilled under

vacuum. Chromatography over silica gel using ethyl acetate:pet.ether

(3:7) as eluent furnished solid, which was recrystallised using

dichloromethane:pet.ether (5:5) (0.21g, 48.5%) m.p.147°C

151-152°C)

Expt.1.20 One pot preparation of 2-benzoy1-5,6-

methylenedioxy indole (20e)

Followed the same procedure as expt.1.19, yield (0.06g, 30%),

m.p.200°C.

Expt.1.21 One pot preparation of 2-benzoy1-5,6-

dimethoxy indole (20f).

Followed the same procedure as expt.1.19, yield (0.08g, 30%),

m.p. 180°C (lit. 81 m.p.176-178°C).

Expt.1.22 Preparation of 4,5-methylenedioxy-2-

nitro-3-buten-2-one (19b)

4,5-methylenedioxy-2-nitrobenzaldehyde (1.0g, 5.1mmol) was

refluxed with phosphorane 18a (1.63, 5.1mmol) in methanol (5m1) for

two hours. Solid separated on keeping overnight was filtered, washed

with little methanol & dried. Recrystallisation using methanol

furnished pure product 19b (1.04g, 86%) m.p.160°C.

78

Expt 1.23 Preparation of 4,5-dimethoxy-2-nitro-3-

buten-2-one (19c)

Followed the same procedure as expt.1.22, yield (1.0g, 84%),

m.p.168°C (lit. 82 m.p.172°C).

Expt. 1.24 Preparation of 3-(2'-nitropheny1)-1-pheny1-2-

propenone (19d)

Followed the same procedure as expt.1.22, using phosphorane

18b yield (2.25g, 67%), m.p.126 °C (lit." m.p.127-128 °C).

Expt. 1.25 Preparation of 3-(2'nitro-4',5'-

methylenedioxy)-1-pheny1-2-propenone

(19e)

Compound 17b (0.5g, 2.5mmol) was refluxed with phosphorane

18b (0.97g, 2.5mmol) in methanol (10m1) for 2 hours and kept

overnight. The solid separated was filtered and dried.

Recrystallisation using methanol gave pure product 19e (0.575g,

75.5%) m.p.154°C.

Expt. 1.26 Preparation of 3-(2'-nitro-4',5'-dimethoxy)-1-

pheny1-2-one (19f)

Followed the same procedure as Expt.1.25, yield (0.461g,

62%), m.p.180°C (lit. 81 m.p.182-183°C).

•

79

Expt. 1.27 Preparation of 2-acety1-5,6-

methylenedioxy indole (20b)

Compound 19b (0.5g, 2.1mmol) was heated with triphenyl

phosphine (1.22g, 4.6 mmol) in diphenyl ether (5m1) at 180°C for 8

hours. The reaction mixture on cooling was chromatographed using

ethylacetate:pet.ether (3:7) as eluent furnished product 20b (0.224g,

52%) m.p.170°C.

Expt. 1.28 Preparation of 2-acetyl-5,6-dimethoxy

indole (20c)

Followed the same procedure as Expt. 1.27, yield (0.183g, 42%),

m.p.148 °C.

Expt. 1.29 Preparation of 2-benzoyl indole (20d)

Followed the same procedure as Expt. 1.27, yield (0.170g,

48.5%), m.p.1470C (lit." m.p.151-152 °C).

Expt. 1.30 Preparation of 2-benzoy1-5,6-

methylenedioxy indole (20e)

Followed the same procedure as expt.1.27, yield (0.095g,

52.40%), m.p.200°C.

Expt. 1.31 Preparation of 2-benzoy1-5,6-dimethoxy

indole (20f)

Followed the same procedure as expt.1.27, yield (0.08g, 44.5%),

m.p.181°C.

80

1.8 REFERENCES

1) a) C. Auclair, Arch.Biochem.Biophys., 1, 259, (1989).

b) M. Suffness and G. A. Cordell, In The Alkaloids, Vol. 25, A.

Brossi, ed. Academic Press, New York, 1, (1985).

c) V. K. Kansal and P. Potier, Tetrahedron, 42, 2389, (1986).

d) U. Pindur, Pharmazie, 47, (1987).

2) a) J. G. Rouesse, T. LeChevalier, P. Caille, J. M. Mondesir, H.S.

Gamier, F. M. Levim, M. Spielmann, R. DeJager, and J. L.

Arnie!, Cancer Treat.Rep., 69, 707, (1985).

b) P. Caille, J. M. Mondesir, J. P. Dotz, P. Kerbrat, A.

Goodman, J. P. Ducret, C. Theodore, M. Spielman, J.

Rouesse, J. L. Amiel, Cancer Treat.Rep., 69, 901, (1985).

c) C. N. Sternberg, A. Yagoda, E. Casper, M. Scoppetuolo, H. I.

Scher, Anticancer Res., 5, 415, (1985).

d) A. I. Einzig, R. J. Gralla, B. R. Leyland-Jones, D. P. Kelsen,

I. Cibas, E. Lewis, and E. Greenberg, Cancer Inves., 3, 235,

(1985).

3) D. P. Chakraborty, B. K. Barman and P. K. Bose, Tetrahedron,

21, 681, (1965).

4) a) R. S. Kapil, 'The Alkaloids: The Carbazole Alkaloids,' Vol. 13,

ed. By R. H. F. Manske, Academic Press, Inc., New York,

273, (1971).

b) D. P. Chakraborty, Fortch.Chem.Org.Naturst., 34, 299,

(1977).

c) D. P. Chakraborty, Trans.Bose Res.Inst., 47, 49, (1984).

d) H. P. Husson,' The Alkaloids: Simple Indole Alkaloids

Including /3-Carbolines and Carbazoles,' Vol. 26, ed. By A.

Brossi,Academic Press, Inc., Orland, 1, (1985).

d) P. Bhattacharya and D. P. Chakraborty, Fortsch. Chem.

Org.Naturst., 52, 159, (1987).

5) a) D. P. Chakraborty, P. Bhattacharya, S. Roy, S. P.

Bhattacharya and A. K. Biswas, Phytochemistry, 17, 834,

(1978).

81

b) B. K. Chowdhury and D. P. Chakraborty, Chernind.

(London), 549, (1969).

c) B. K. Chowdhury and D. P. Chakraborty, Phytochemistry,

10, (1967).

d) M. Fiebig, J. M. Pezzuto, D. D. Soejarto and A. D. Kinghorn,

Phytochemistry, 24, 3041, (1985).

e) H. Furukawa, T. -S. Wu, T. Ohta and C. - S. Kuoh,

Chem.Pharm.Bull. 33, 4132, (1985).

f) T. -S. Wu, S. -C. Huang, P. -L. Wu and C. -M. Teng,

PhytoChemistry, 43, 133, (1996).

g) C. Ito, S. Katsuno, H. Ohta, M. Omura, I. Kajiura and H.

Furukawa, Chem.Pharm.Bull., 45, 48, (1997).

h) B. T. Ngadjui, J. F. Ayafor, B. L. Sondengam and J. D.

Connolly, Phytochemistry, 28, 1517, (1989).

i) P. Bhattacharya, A. K. Maiti, K. Basu and B. K. Chowdhury,

Phytochemistry, 35, 1085, (1994).

6) a) D. P. Chakraborty, K. Das, B. P. Das and B. K. Chowdhury,

Trans.Bose Res.Inst. Calcutta, 38, 1, (1975); Chem.Abstr.

86: 51029z, (1977).

b) K. C. Das, D. P. Chakraborty and P. K. Bose, Experentia, 21,

340, (1965).

c) M. Sarma, Sci.Cult., 42, 285, (1976); Chem.Abstr., 85:

72096p, (1976).

d) M. Sarma, Indian J.Exp.Biol., 18, 787, (1980); Chem.Abstr.,

93: 198373k, (1980).

e) G. Bringmann, A. Ledermann, J. Holenz, M.-T. kao, U.

Busse, H. G. Wu and G. Franchois, G. Planta.Med., 64, 54,

(1998).

f) G. Bringmann, A. Ledermann and G. Francois, Heterocycles,

40, 293, (1995).

7) a) K. Sakano, K. Ishimaru and S. Nakamura, J.Antibiotics, 33,

683, (1980).

b) K. Sakano and S. Nakamura, J.Antibiotics, 33, 961, (1980).

82

c) S. Nakamura, Trans.Bose Res.Inst., 47, 69, (1984).

8) M. R. TePaske, J. B. Gloer, D. T. Wicklow and P. F. Dowd,

J.Org. Chem., 54, 4743, (1989).

9) a) L. M. Rice and K. R. Scot, J.Med.Chem., 13, 308, (1970).

b) M. Fiebig, J. M. Pezzuto, D. D. Soejarto and A. D. Kinghorn,

Phytochemistry, 24, 3041, (1985).

c) M. R. TePaske, J. B. Gloer, D. T. Wicklow and P. F. Dowd,

Tetrahedron Lett., 30, 5965, (1989).

10) J. H. Cardellina, M. P. Kirkup, R. E. Moore, J. S. Mynderse, K.

Seff and C. J. Simmons, Tetrahedron Lett., 4915, (1979).

11) M. Kaneda, K. Sakano, S. Nakamura, Y. Kushi and Y. Iitaka,

Heterocycles, 15, 993, (1981).

12) M. Tanaka, K. Shin-Ya, K. Furihata and H. Seto, J.Antibiotics,

48, 326, (1995).

13) S. Kato, H. Kawai, T. Kawasaki, Y. Toda, T. Urata and Y.

Hayakawa, J.Antibiotics, 42, 1879, (1989).

14) a) L. K. Dalton, S. Demerac, B. C. Elmes, J. W. Loder, J. M.

Swan and T. Teitei, Aust.J.Chem., 20, 2715, (1967).

b) G. H. Svoboda, G. A. Poore and M.L. Montfort, J.Pharrn.Sci.,

57, 1720, (1968).

15) M. Sainsbury, Synthesis, 43, (1977).

16) R. Barone and M. Chanon, Heterocycles, 16, 1357, (1981).

17) M. J. E. Hewlins, A. M. Oliveire-Campos and P. V. R. Shannon,

Synthesis, 289, (1985).

18) G. W. Gribble and M. G. Saulnier, Heterocycles, 23, 1277,

(1985).

19) G. W. Gribble, 'Advances in Heterocyclic Natural Product

Synthesis, Vol. 1, 43, (1990).

20) T. Choshi, E. Sugano, and S. Hibano, Fukuyama Daigaku

Yakugak-ubu Kenkyu Neupo, 15, 1, (1997).

21) M. Ishikura, T. Yaginuma, I. Agata, Y. Miwa, R. Yanaka and T.

Taga, Synlett, 214, (1997).

83

22) S. P. Modi, M. A. Michael and S. Archer, Tetrahedron, 47, 6539,

(1991).

23) Y. Miki, Y. Tada, N. Yanase, H. Hachiken, and K. Matsushita,

Tetrahedron Lett, 37, 7753, (1996).

24) a) S. Blechert, R. Knier, H. Schroers and T. Wirth, Synthesis,

592, (1995).

b) L. F. Tietze and U. Beifuss, Angew.Chem., Inter.ed., 32, 131,

(1993).

25) J. E. Backvall and N. A. Plobeck, J.Org.Chem., 55, 4528,

(1990).

26) S. P. Modi and S. Archer, J.Org.Chem., 54, 3084, (1989).

27) a) G. W. Gribble, D. K. Keavy, D. A. Davis, M. G. Saulnier, B.

Peleman, T. C. Timothy, H. P. Sibi, E. R. Olson and J. J.

Belbruno, J.Org.Chem., 57, 5878, (1992).

b) G. W. Gribble, M. G. Saulnier, J. A. 0- Nutaitis and D. M.

Ketcha, J.Org.Chem., 57, 5891, (1992).

28) J. R. Domoy and A. Heymes, Tetrahedron, 9, 2915, (1993).

29) C. K. Sha, C. P. Tsou, C. Y. Tsai, J. M. Liu, R. S. Lee and J. F.

Yang, Yougi Hauxue, 13, 162, (1993). Chem.Abstr., 119:

72901t, (1993).

30) J. P. M. Plug, G. J. Koomen and U. K. Pandit, Synthesis, 1221,

(1992).

31) A. K. MohanKrishnan and P. C. Srinivasan, J.Org.Chem., 60,

1939, (1995).

32) C. May and C. J. Moody, J.Chem.Soc.,Perkin Trans.1, 247,

(1988).

33) G. Queguiner, J.Org.Chem., 57, 565, (1995).

34) a) J. I. G. Cadogan, Synthesis, 1, 11, (1969).

b) S. P. Kureel, R. S. Kapil and S. P. Popli, J.Chem.

Soc.,Chem.Commun., 110, (1969).

c) S. P. Kurrel, R. S. Kapil and S. P. Popli, Chem.and Ind.,

1262, (1970).

d) R. B. Sharma and R. S. Kapil, Chem. and Ind., 268, (1982).

84

35) a) A. Islam, P. Bhattacharya and D. P. Chakraborty, J.Chem.

Soc., Chem.Commun., 537, (1972).

b) P. Bhattacharya, A. R. Mitra and D. P. Chakraborty, J.Indian

Chem.Soc., 53, 321, (1976).

36) W. Carruthers, J. Che m. Soc. , Che m. Commun. , 272, (1966).

37) a) B. Akermark, L. Eberson, E. Jonsson and E. Pettersson,

J.Org.Chem., 40, 1365, (1975).

b) H. Furukawa C. Ito, M. Yogo and T. -S. Wu, Chem.

Pharm.Bull., 34, 2672, (1986).

38) a) J. D. Crum and P. W. Sprague, J.Chem. Soc.,Chem.

Commun., 417, (1966).

b) D. P. Chakraborty and B. K. Chowdhury, J.Org.Chern., 33,

1265, (1968).

c) D. P. Chakraborty, K. C. Das and B. K. Chowdhury,

Phytochemistry, 8, 773, (1969).

39) J. Bergman and B. Pelcman, Pure and Appl.Chem., 62, 1967,

(1990).

40) C. J. Moody and P.J. Shah, J.Chem.Soc.,Perkin Trans.1, 376,

(1989); ibid, 2463, (1989).

41) a) P. M. Jackson and C. J. Moody, Synlett, 521, (1990).

b) P. M. Jackson, C. J. Moody and R. J. Mortimer,

J.Chem.Soc.,Perkin Trans.1, 2941, (1991).

42) H. J. Knolker, M. Bauermeister, J. B. Bannek and M. Wolport,

Synthesis, 397, (1995).

43) H. J. Knolker, and W. Frohner, J.Chem.Soc.,Perkin Trans.1,

173, (1998).

44) T. Kuroda, M. Takashashi, T. Ogiku, H. Ohmizu, T. Nishitani,

K. Kondo and T. Twarak, J.Org.Chem., 59, 7353, (1994).

45) D. L. J. Clive, N. Etkin, T. Joseph and J. W. Lown, J.Org.Chem.,

58, 2442, (1993).

46) J. Tamariz, Synlett, 87, (1998).

47) E. M. Beccalli, A. Marchesini and T. Pilati, J.Chem.Soc.,Perkin

Trans.1, 579, (1994).

85

48) S. Hibino, A. Tonari, T. Choshi and E. Suginon, Heterocycles,

35, 441, (1993).

49) T. Kawasaki, Y. Nonaka and M. Sakamoto,

J.Chem.Soc.,Chem.Commun., 43, (1989).

50) M. Iwao, H. Takehara, S. Furukawa and M. Watanabe,

Heterocycles, 36, 1483, (1993).

51) A. R. Katritzky, G. Zhang, L. Xie and I. Ghiviriga, J.Org.Chem.,

61, 7558, (1996).

52) P. A. Cranwell and J. E. Saxton, J.Chem.Soc., 3482, (1962).

53) J. A. Birch, A. H. Jackson and P. V. R. Shannon,

J.Chem.Soc.,Perkin Trans.1, 2185, (1974).

54) E. Pretsch, T. Clerc, J. Seibl and W. Simon, Taabellen Zur

Strukturaufklarung Organischer Verbindungemit

Spektwskopichen Methodin, Springer, Berlin, (1975).

55) C. J. Moody and P. J. Shah, J.Chem.Soc.,Perkin Trans.1, 1407,

(1988) . .

56) I. Hogan, P. Jenkins and M. Sainsbury, Tetrahedron. Lett.,

6505, (1988).

57) R. J. Sundberg and H. F. Russel, J.Org.Chem., 38, 3324,

(1973).

58) D. M. Ketcha and G. W. Gribble, J.Org.Chem., 50, 5451, (1985).

59) A. Spinella, T. Fortunate and A. Sorienta, Synlett, 93, (1997).

60) Per H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless,

J.Org.Chem., 46, 393, (1981).

61) G. Bringmann, S. Tasler, H. Endress, K. Peters and E.-M.

Peters, Synthesis, 1501, (1998).

62) P. Aelinoe, G. Massiot and B. Menhour, Nat.Prod.Lett., 15, 197,

(1994).

63) 5. Malik, S.S Ahmad, S. I. Harder and A. Muzaffar,

Tetrahedron Lett., 163, (1987).

64) M. L. Bennasar, B. Vidol and J. Bosch, J.Org.Chem., 62, 3597,

(1997).

86

65) S. Kano, E. Sugino, S. Shibuya and S. Hino, J.Org.Chem., 46,

3856, (1981).

66) P.-Deprez, C. Rivalle, C. Huel, J. Belehrdek, C. Paoletti and E.

Bisagni, J. Chem. Soc. ,Perkin Trans. 1, 3165, (1991).

67) R. V. Jardine and R. K. Brown, Can.J.Chem., 41, 067, (1963).

68) L. Capuano, A. Ahlhelm and H. Hartman, Chem.Ber., 119,

2069, (1986).

69) M. Akazano, T. Konds and Y. Watanabe, Chem.Lett., 5, 769,

(1992).

70) R. J. Sundberg, J.Org.Chem., 30, 3604, (1965).

71) G. W. Gribble, J.Org.Chem., 38, 4074, (1973).

72) E. A. Walker, J.Chem.Soc., 2041, (1957).

73) W. Davey and J. R. Gwitt, J.Chem.Soc., 1008, (1957).

74) K. Rao, J.Heterocycl.Chem., 725, (1975).

75) K. B. L. Mathur, H. S. Mehra, D. R. Sharma and V. P. Chachra,

Indian J.Chem., 22B, 388, (1983).

76) K. S. Bhandhari and V. Snieckcus, Can.J.Chem., 49, 2354,

(1971).

77) A. H. Salway, J.Chem.Soc., 1155, (1909).

78) C. A. Fletscher, Org.Reactions, 33, 65, (1953).

79) Reactions and Syntheses in the Organic Chemistry laboratory,

'Synthesis and Transformations of functional Groups',

University Science books, (1989).

80) F. Ramirez and S. Dershowitz, J.Org.Chem., 22, 41, (1957).

81) A. P. Aher, M.Phil.thesis, Poona University, Poona, (1996).

82) J. Harley-Mason, J.Chem.Soc., 244, (1948).

83) D, B. Denny and T. J. Ross, J.Org.Chem., 27, 998, (1962).

84) R.. S. Mali, S. G. Tilve, A. R. Manekar, and S. Y. Yeola,

• Heterocycles, 26, 121, (1987).

85) a) G. H. Smith, J.Chem.Soc., 3842, (1954).

b) P. N. James and H. R. Snyder, Org.Synth.Coll.Vol.IV, 539,

(1963).