CifATTER 2

Tandem Utrittog-Diells-Aider reaction

Section II

Tandem Wittig-Diels-Alder reaction: Synthesis of pyrrolo and furano tetrahydrocarbazoles.

The indole moieties are very important in biological and medicinal chemistry. An

enormous fraction of the biological alkaloids known are based on the indole

nucleus. 1 Organic chemists have repeatedly turned to indole based compounds for

inspiration and indeed many indole containing compounds are marketed as

therapeutic agents 2 and there continues considerable emphasis on new methods for

the formation of benzopyrrole ring system. 3 Such methods add to the toolbox of

the synthetic chemist and aid in the chemical synthesis of indole alkaloids 4 .

Carbazoles (diphenylenimine) are relevant heteroaromatic compounds. Carbazole

was isolated first from coal tar in 1872 by Graebe and Glazer s and is currently

produced commercially from this source and crude oil on the scale of thousands of

tons per annum. In 1965, Chakraborty et al. described the isolation and antibiotic

properties of murrayanine from Murraya koenigii Spreng. 5 In India, the leaves of

this small tree (known as currypatta or curry-leaf tree) are used in curry. The

isolation of murrayanine was the first report of a naturally occurring carbazole

alkaloid. There is a strong interest shown in this area by chemists and biologists

due to its intriguing structural features and promising biological activities exhibited

by many carbazolc alkaloids. The explosive growth of carbazole chemistry is

emphasized by the large number of monographs, accounts, and reviews. 5

Substituted carbazoles are embodied in many naturally occurring compounds as

well as synthetic materials. During the past four decades, a wide variety of

biologically active carbazole alkaloids (Fig I) have been isolated from different

plant sources. Many of these natural products possess interesting biological

CH3

H H

H

Mukonal OMe

CHO

OMe

properties: antitumor, psychotropic, anti-inflammatory, antihistaminic, antibiotic,

antioxidative antimicrobial, anti-HIV and cardiovascular. 6 '7 In addition to this, the

[b] annelated carbazole derivatives are of interest because of their DNA interacting

properties. 8 Fused indole derivatives like carbazoles are found in several highly

potent natural products like ellipticine (tumor therapy, vinemine (Alzheimer

disease) and in large group of secale alkaloids. 9 Carbazole derivatives are also

widely used as organic materials, due to their photorefractive, photoconductive,

hole-transporting, and light emitting properties. )°

Most of the carbazole alkaloids have been isolated from the taxonomically related

higher plants of the genus Murraya, Glycosmis, and Clausena from the family

Rutaceae. The genus Murraya represents the richest source of carbazole alkaloids

from terrestrial plants. In addition, a few bacterial strains belonging to

Streptomyces sp are also known to produce these compounds. Additional natural

sources for carbazole alkaloids are, for example, 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 of carbazole alkaloids. 5

Tetrahydrocarbazole nucleus is found in numerous naturally occurring alkaloids

and synthetic analogues of medicinal importance" and the preparation of new and

various substituted derivatives is still a highly pursued objective. I2 The derivatives

of tetrahydocarbazoles play an important role in the synthesis of several indole

alkaloids. I3

Structure of some selected carbazole alkaloids are given below.

Glycozolidine Glycosinine

1 1 2

H

MeO

Murrastifoline-F

R6

EWG 12-16 kbar

ZnCl2/ 16kbar

Scheme I

1 1 3

OMe

Indizoline CH 3

olivacine

CH3

CH3

ellipticine

O

ellipticine quinone

OMe

Murrayafoline-A

Calothrixin B

Fig I

Synthesis of tetrahydrocarbazoles:

Among the large number of methods available for the synthesis of

tetrahydrocarbazoles," the methods involving Diels-Alder reactions deserve

special mention. Some selected methods for the synthesis of tetrahydrocarbazoles

wherein Diels-Alder cycloaddition reaction as the key step are described below.

Chataigner et al. 15 have synthesized tetrahydrocarbazoles by (4+2) cycloaddition

reaction under high pressure conditions or a combination of Lewis acid catalyst

(Scheme I).

H CN

CH3

NC

Abbiati et a/. 16 have synthesized the diastereomeric 3, 4-disubstituted and 1,2,3,4-

tetrahydrocarbazoles by Diels-Alder cycloaddition reactions between RE)-2-

vinyllindole-1-carboxylic acid ethyl esters and open chain C=C dienophiles

(Scheme II).

R4

46-68%

Scheme II

In Scheme III, Diels-Alder reaction of acceptor-substituted 2-vinylindoles with carbodienophiles in the synthesis of tetrahydrocarbazoles described by Blechert and Wirth 17 is shown.

Scheme III

Backvall and Plobeck have reported the synthesis of the antitumor alkaloids

ellipticine and olivacine, starting from indole. The cycloaddition of 3-

(phenylsulphony1)-2,4-hexadiene or 2-(phenylsulpony1)-1,2-pentadiene with the

magnesium salt of indole followed by C-C-N chain addition via Michael addition.

Subsequent Bischler-Napieralski cyclisation and aromatization afforded ellipticine

and olivacine (Scheme IV).

1 1 4

CH3

CH3 CH3

R i =CH 3 R2=H

R1=H R 2=OH 3

SO 2Ph

TIPSO

OH

Eustifolines A-D and Glycomaurrol

NHTs

OH

Plieninger

indolisation Ts

Diets-Alder

SO2Ph

Scheme IV

Lebold and Kerr have reported 19 the Diels alder reaction between quinine

monoamine and cyclic diene which allows construction of carbazoles in a

regiospecific manner which resulted in the synthesis of naturally occurring

eustifolines A-D and glycomaurrol (Scheme V). Later on, the authors extended this

methodology for the synthesis of clausamine A-D (Scheme VI).

Scheme V

1 1 5

NHTs

MeO MeO

Diets-Alder Plieninger

indolisation

OMe

OH

Clausamine

Scheme VI

An intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic a-

phosphono enecarbamate has been developed to prepare nitrogen heterocycles by

Fuwa and Sasaki2° (Scheme VII).

CH2 0 Pd(0)

II ---4"-

P base 1\K-4'''0"-- I OPh IS CH2 OPh

Scheme VII

Anisimova et a/. 21 reported the synthesis of carbazoles via tetrahydrocarbazoles by

using Diels Alder reaction between methyl-3-nitroacrylate and 3-(2-

nitroethenyl)indole. The reaction was carried out in toluene in the presence of

aluminium chloride (Scheme VIII).

1 1 6

0 2 N

(COOEt

H

H COOEt

COOEt NO 2

COOEt

MeO

Toluene

Tos

Scheme VIII

Bleile and Otto have reported 22 the synthesis of pyrallo [3,4-a] carbazole

derivatives by cycloaddition between maleimide and 3-(1-methoxyvinyl)indole

derivative (Scheme IX).

Scheme IX

1 1 7

E= CgMe

Br-

Pindur's group 23 has shown the synthesis of 2-vinylindole and its Diels-Alder

reactions with CC-dienophiles to form carbazole derivatives (Scheme X).

Scheme X

Noland et a/. 24 have synthesized tetrahydrcarbazoles by using indole, ketone or

aldehyde, and maleimide with acid catalyst in one pot (Scheme XI).

R(N/R4

4 0 -7L 0

R 5

Scheme XI

118

CN

Laronze et al.25 have reported that substituted 3-cynomethy1-2-vinylindoles

rearrange via thermal [1,5]-I shift into the corresponding indol-2,3-quindimethanes

which then can be trapped by dienophiles to afford tetrahydrcarbazoles (Scheme

XII).

Scheme XII

1 1 9

Present work:

In the previous section we had demonstrated successful application of tandem

Wittig-Diels-Alder reaction for the construction of AB ring of

furanosesquiterpenes. We envisaged that the same methodology could be used for

the construction of furano and pyrrolo tetrahydrocarbazoles 1. Our strategy

towards this is depicted in scheme XIII.

X = 0, NBn

= 112 H, H or CH3, CH3

Our strategy involved reaction of indole-3-carboxyaldehyde with the substituted

ally! (triphenylphosphoranylidine)acetate/N-allyl-N-benzy1-2-(triphenylphosphoran

ylidene)acetamide (used in the previous section) to provide the unsaturated

ester/amide which then in situ would undergo intramolecular Diels-Alder reaction

to provide the targeted furano and pyrrolo intramolecular tetrahydrocarbazoles in a

one pot. The tetrahydrocarbazoles then could be conveniently converted to

carbazole compounds as depicted in scheme XIII. However the other possibility of

intermolecular Diels Alder reaction (Scheme XIV) of the intermediate diene could

not be discarded at this stage.

120

XFR 2

Ri CHO Ph 3P

Diphenyl ether

X= 0, NBn

Scheme XIII

Scheme XIV

Thus, when allyl (triphenylphosphoranylidine)acetate was subjected with indole-3-

carboxyaldehyde in refluxing diphenyl ether for 8 h (monitored by TLC). The

product crystallized out in the reaction mixture after cooling (Scheme XV).

121

CHO Ph 3 P

0

PhOPh, N 2 , 8h

2 3

4a 4b

Scheme XV

The solid compound, MP = 228-229 °C with strong IR absorption bands at 3386

cm - ' and 1764 cm-1 , indicating the presence of —NH of indole moiety and carbonyl

group of lactone respectively.

Its 'H NMR (400 MHz, CDC13) spectrum (Fig la) at 8 2.7-3.3 (6H, m) could be

attributed to protons of cyclohexane ring. One broad doublet and one doublet of

doublet were seen at 8 4.16 (1H, J = 4.3 & 8.9 Hz) and 4.45 (1H, J = 4.3 Hz) could

be attributed to methylene of CH2O- group. In addition to this one multiplet (2 H),

one triplet (2H, J = 6.0 & 10.1 Hz) and one doublet (1H, J = 7.3 Hz) were seen in

aromatic region at 8 7.1, 7.31 & 7.49 which could be attributed to aromatic

protons. One singlet was seen at 8 7.74 due to the presence of nitrogen proton.

HRMS data confirmed the elemental composition as C14H1302N (Observed: m/z

228.1032, calculated for [M+FI] I- = 228.1024).

Thus on the basis of mode of formation & spectral properties structure 4 was

assigned to it. The yield of the compound found was 59.80%. From our previous

experience (first section) it was expected to get two diastereomers 4a and 4b.

However the products could not be separated on TLC. HPLC analysis, however,

confirmed that both the expected diastereomers have been formed in 1:1 ratio.

122

Our analysis of products suggested that the cyclization takes place by both endo

and exo pathways. The former route gives the product with cis-ring junction (cis-

adduct), while the latter will give the product with trans-ring junction (trans-

adduct) (Fig II).

endo

exo

Fig II

Fig 1 a

1 23

5

PhOPh H H2C/

3a

CHO Ph3P_

xylene 4

To confirm the geometry of the intermediate diene we also carried out the

synthesis of 4 in a stepwise manner. Thus indole-3-carboxyaldehyde was

condensed with allyl (triphenylphosphoranylidine)acetate in refluxing xylene to get

Wittig product 3 (Scheme XVI).

Scheme XVI

Based on the mode of formation & spectral properties mentioned below, allyl (2E)-

3-(1H-indole-3-yl)acrylate (3a) was assigned to the compound. The high coupling

constant (15.9 Hz) of the vinyl protons indicated trans geometry of the product

(MP = 61-62°C, yield = 88.50%).

IR (v.): 3296 cm'(NH), 1672cm'(CO).

'HNMR (CDC13, 300 MHz): (Fig 2a)

8 4.78

5 5.35 & 5.45

d (J = 5.4 Hz)

2 X dd (J = 1.2, 10.2 & 17.4 Hz)

2H

2H

C132-CH=CH2

CH2-CH=C132

8 6.0 m 1H CH2-CH=CH2

8 6.56 d (J = 15.9 Hz) 1H CH=CH-CO

8 7.30 m 2H ArH (C-2, C-5)

8 7.45 m 2H ArH (C-6, C-7)

8 7.95 d (J = 6.6 Hz) 1H ArH (C-4)

8 8.01 d (J = 15.9 Hz) 1H CH=CH-CO

8 8.88 brs 1H NH

124

' 3C NMR (CDC13) (Fig 2b): 5 65.02 (t, CH2-CH=CH2), 112.08 (d, CH2-CH=CH2),

112.54 (d, CH=CH-00), 113.34 (s), 118.10 (t, CH2-CH=CH2), 120.41 (d, C AJH),

121.55 (d, CAJH), 123.34 (d, CAJH), 125.28 (s), 129.51 (d, CAiH), 132.58 (d,

137.26 (s), 139.15 (d, CH=CH-00), 168.35 (s, CO).

The multiplicities of carbon signals mentioned were obtained from DEPT 135

experiment.

The trans unsaturated ester upon, refluxing in diphenyl ether for 8 h under nitrogen

atmosphere, followed by chromatography yielded two diastereomeric y-lactones

4a-b in 64.00% (Product ratio = 1:1).

rupotth n, RP-05-30, kat61A

Fig 2a

125

u^a E4. 3, Itr- 05- 30 13C tOIV.

Fig 2b

After successful application of tandem Wittig reaction and Diels-Alder reaction for

the construction of furano tetrahydrocarbazole we thought of synthesizing the

methyl substituted furano tetrahydrocarbazole by using same methodology

(Scheme XVII). Thus, crotyl (triphenylphosphoranylidine)acetate (previously used

in sec. I) was treated with indole-3-carboxyaldehyde in refluxing diphenyl ether for

8 h (monitor by TLC).

cH3 CHO

Ph 3P

0

PhOPh, N2, 8h

2 H

Scheme XVII

1 26

5 4

2 H 5

CHO 0,...../\„.„-Ns CH3 6

N H xylene reflux

6

The solid compound, MP = 210-211 °C with strong IR absorption bands at 3253 -t cm-1 and 1705 cm , confirmed the presence —NH of indole moiety and carbonyl

group of lactone in the molecule. Its NMR spectrum had one multiplet (3H, 4 X

d) was seen at 8 1.42- 1.55 indicating presence of a methyl group. One multiplet at

8 2.1-3.3 (5H) could be attributed to protons of cyclohexane ring. One multiplet

seen at 8 4.46 (2H) could be attributed to methylene proton of CH2O- group. In

addition to this one multiplet (4 H) was seen in aromatic region at 8 7.1-7.45 which

could be attributed to aromatic protons. One singlet was seen at 8 7.8 could be due

to the presence of nitrogen proton.

HRMS data confirmed the elemental composition as C i5H 15 02N (Observed: m/z

264.1015, calculated for [M+H] + = 264.1000).

Thus on the basis of mode of formation & spectral properties structure 6 was

assigned to it. We failed to separate the diastereomers by column chromatography.

HPLC analysis also could not properly resolve all the four diastereomers (Yield =

61.20%).

In this reaction sequence also Wittig reaction and Diels Alder reaction was

achieved in one pot. So, we planned the reaction sequence in a stepwise manner.

Initially crotyl (triphenylphosphoranylidine)acetate was condensed with indole-3-

carboxyaldehyde to get the unsaturated Wittig product which was then subjected to

the intramolecular Diels-Alder reaction (Scheme XVIII).

Scheme XVIII

127

Based on the mode of formation & spectral properties mentioned below, (2E)-but-

2-en-l-y1(2E)-3-(1H-indo1-3-ypacrylate (5) was assigned to the Wittig product.

The high coupling constant (16.2 Hz) of the vinyl protons indicated trans geometry

of the product (MP = 109-110 °C, yield = 86.40%).

IR (vmax): 3286 cm-I (NH), 1691cm-1 (CO)

1 H NMR (CDC1 3 , 300 MHz): (Fig 3a)

8 1.77 d (J = 6.3 Hz) 3H CH3

8 4.70 d (J = 6.3 Hz) 2H Q112-CH=CH-

8 5.7 m 1H CH2-CH=CH-

8 5.9 m 1H CH2-CH=CH-

8 6.53 d (J = 16.2 Hz) 1H CH=CH-CO

8 7.25 m 2H ArH (C-2, C-5)

8 7.43 m 2H ArH (C-6, C-7)

8 7.94 m 1H ArH (C-4)

8 7.98 d (J = 16.2 Hz) 1H CH=CH-CO

8 8.88 brs 1H NH

13C NMR and DEPT 135 (CDC13) (Fig 3b): 8 17.8 (q, CH 3), 65.03 (t, CH2-

CH=CH2), 111.18 (d, CH2-CH=CH), 113.03 (d, CH2-CH=CH), 113.49 (s), 120.45

(d, CH=CH-CO), 121.60 (d, CAIH), 123.31 (d, CAIH), 125.47 (d, CAIH), 129.11 (d,

CJJH), 125.29 (s), 131,21 (d, CA,H), 137.17 (s), 138.67 (d, CH=CH-CO), 168.33 (s,

CO).

The trans ester 5 upon, refluxing in diphenyl ether for 8 h under nitrogen

atmosphere, followed by chromatographic separation yielded two diastereomeric y-

lactones 6a-d in 62.80%.

128

tip) 14, RP-05-52,

1

8.5 8:0 7,6 70 6.6 6.0 6,6 53 4.6 4.0 35 3.0 25 2.0 ppm

Fig 3a

170 •160 160 140 130 120 110 100 90 80 70 09 60 40 30 20 ppm

Fig 3b

129

PhOPh, N2, reflux 8h 2

In the similar manner we thought of making gem-dimethyl substituted

tetrahydrocarbazole. Thus prenyl (triphenylphosphoranylidine)acetate was treated

with indole-3-carboxyaldehyde in refluxing diphenyl ether for 8 h (monitored by

TLC). The reaction mixture got decomposed during heating and we didn't get

cyclised product (Scheme XIX). Therefore we thought of separating the Wittig

product and then carry out the cycloaddition reaction to get the desired product.

Scheme XIX

Thus indole-3-carboxyaldehyde was condensed with prenyl (triphenyl

phosphoranylidine)acetate in refluxing xylene to get the Wittig product. The

mixture was subjected to column chromatography using ethyl acetate and hexanes

(3:7) as an eluent to give yellow solid compound (Scheme )0C).

CHO HC 3 Ph3PTh,

CH3 0

xylene reflux

Scheme XX

Based on the mode of formation & spectral properties mentioned below, (3-methyl

but-2-en- 1 -y1(2E)-3-(1H-indo1-3-yl)acrylate 8 was assigned to the compound. The

high coupling constant (15.9 Hz) of the vinyl protons indicated trans geometry of

the product (MP = 92-93 °C, Yield = 87.60%).

IR (vmax): 3310 crn -l (NH), 1710 cm-1(C0).

130

1 H NMR (CDC13, 300 MHz): (Fig 4a)

S 1.79 s 314 CH3

8 1.82 s 314 CH3

8 4.78 d (J = 7.2 Hz) 214 CH_2-CH=

8 5.49 d (J = 7.2 Hz) 1H CH2-CH

8 6.54 d (J = 15.9 Hz) 1H CH=CH-CO

8 7.27 m 2H ArH (C-2, C-5)

8 7.43 m 2H ArH (C-6, C-7)

8 7.92 m 1H ArH (C-4)

8 7.98 d (J = 15.9 Hz) 1H CH=CH-CO

8 8.85 brs 1H NH

13 C NMR and DEPT 135 (CDC13) (Fig 4b): 8 18.09 (q, CH3), 25.82 (q, CH3), 61.29

(t, CH2-CH=), 111.97 (d, CH2-CH=), 112.96 (d, CH=CH-CO), 113.40 (s), 118.92

(d, CASH), 120.43 (d, CASH), 121.47 (d, C ASH), 123.28 (d, C ASH), 125.2 (s), 137.25

(s), 138.73 (d, CH=CH-CO), 139.02 (s), 168.76 (s, CO).

The trans ester was then heated in refluxing diphenyl ether for 8 h under nitrogen

atmosphere (monitored by TLC). It was showing the disappearance of starting

material but there were no other spot observed in the TLC and the reaction mixture

was getting dark black in colour (Scheme XXI).

PhOPh

N2, 8h reflux

Scheme XXI

131

—r -

7.5 7.0 CS

CS 8.0 6.0 5.5

11

17pcizh k.2.; RP—'05-2m, Rg461.. 3

Fig 4a

I r RP-n-2a, 13c 3M11

00 160 . 150 140 130 120 110 100 aa BO 70 60 60 40 30 20 p

Fig 4h

132

102 10b

Bn

CHO Ph3P

1N.

PhOPh, N2, reflux 10h Fi

9 2

0

NBn

After successfully synthesizing furanotetrahydrocarbazoles we thought of

preparing pyrrolotetrahydrocarbazole by using amide functionality Wittig reagent

(previously prepared in sec.I). Thus, when previously prepared N-allyl-N-benzy1-2-

(triphosphoranylidene)acetamide was condensed with indol-3-carboxyaldehyde in

refluxing diphenyl ether for 8 h (monitored by TLC), it gave y-lactam via Wittig

reaction and DieIs-Alder reaction in one pot. Again, we could see only one spot of

the product on the TLC (Scheme XXII).

Scheme XXII

IR spectrum of the solid compound 10 (MP = 235-236 °C) had strong bands at 3267

cm-' and 1650 cm -i due to the presence of —NH of indole moiety and carbonyl

group of lactone respectively. It's 1 1-1 NMR (300 MHz, CDC13) spectrum (Fig 5a)

had three multiplets at 8 2.35-3.5 (8H) which could be attributed to protons of six

membered ring and of the lactam ring. One doublet of doublet (21-1, 14.7 Hz) at 8

4.35 & 4.60 [4.56] could be attributed to benzylic methylene protons. In addition to

this one multiplet (9 H) was seen in aromatic region at 8 7.1-7.6 which could be

attributed to indole aromatic protons and benzene protons. One singlet was seen at

8 7.4 due to the presence of nitrogen proton of indole moiety (Yield = 65.00 %,

HPLC ratio = 1:1).

133

:,.-..trps$11 10, R8-.07-24 R43-,466

r ' • 1 '• • • "T"-"---

3:6 .3..A 3.2 2.8 2.6

I

-e,

8.0 7.5 7.0 6.6 5.5 &O 4.5 44 2.5

2.0 ppm

HRMS data confirmed the elemental composition as C211-1200N2 (Observed: m/z

339.1476, calculated for {M+Nar = 339.1473).

Thus on the basis of mode of formation & spectral properties 10 was assigned to it.

Fig 5a

We have also carried out the synthesis of 10 in a stepwise manner. Thus indole-3-

carboxyaldehyde was condensed with N-allyl-N-benzyl-2-(triphenylphosphoran-

ylidene)acetamide in refluxing xylene to get the Wittig product and then carried

cycloaddition reaction in refluxing diphenyl ether (Scheme XXIII).

Bn

Ph3P_ CHO 5 PhOPh

NBn

H H2C7

7 2 N2, reflux

9

xylene, N 2 , reflux

1 0

Scheme XXIII

134

Based on the mode of formation & spectral properties mentioned below, allyl (2E)- 3-(1H-indole-3-yl)acrylate (9) was assigned to the compound. The yield of was

found to be 74.50%. The high coupling constant (15.6 Hz) of the vinyl protons

indicated trans geometry of the product. Yield = 74.50%, MP = 176-178 °C, IR (vmax): 3168 cni l (NH), 1620 cm-I (CO)

'HNMR (DMSO-d6, 400 MHz):

8 4.10

8 4.62 [4.74]

brs

s

2H

211

CH2-CH=CH2

CH2Ph

8 5.20 m 211 CH2-CH=CH2

8 5.85 m 111 CH2-CH=CH2

8 6.80 d (J = 15.6 Hz) 111 CH=CH-CO

8 7.10-7.50 m 911 Ar-H

8 7.80 m 211 CH=CH-CO & Ar-H (C-4)

811.66 2 X brs 1H NH

The trans unsaturated amide upon, refluxing in diphenyl ether for 8 h under

nitrogen atmosphere, followed by chromatography yielded two diastereomers in 66.80%.

After successful application of tandem Wittig reaction and Diels-Alder reaction for

the construction of pyrrolo tetrahydrocarbazole we thought of synthesizing a

methyl substituted pyrrolo tetrahydrocarbazole using same methodology (Scheme

XXIV). Thus, treatment of N-crotyl-N-benzy1-2-(triphenylphosphoran-

ylidene)acetamide, (previously used in sec. I) with indole-3-carboxyaldehyde in

refluxing diphenyl ether for 8 h yielded the desired product, as indicated by TLC.

135

CHO ph3p

Bn CH3

PhOPh, IN12 , 10h

2

1 1

12

Scheme XXIV

Based on the mode of formation & spectral properties mentioned below, structure

12 was assigned to the compound. MP = 241-242 °C, yield = 62.20%,

IR (vmax): 3172 cm-1 (NH), 1630 cm-1 (CO)

1 HNMR (CDC13, 300 MHz):

8 1.22-1.4 EE

E

EE

Ecn

3H CH3

8 2.0-3.5 7H 3-H2, 3a-H, 4-H, 10-H2,

10a-H

8 5.55 2H C1-1_2-Ph

8 7.1 1H ArH

8 7.3 7H ArH

8 7.5 1H ArH

8 8.0 1H NH

HRMS data confirmed the elemental composition as C22H220N2 (Observed: m/z

331.1808, calculated for [M+H] + = 331.1810).

HPLC analysis could not properly resolve all four diastereomers.

136

We have also carried out the synthesis 12 in a stepwise manner. Thus indole-3-

carboxyaldehyde was condensed with N-crotyl-N-benzyl-2-(triphenylphosphoran-

ylidene)acetamide in refluxing xylene to give the Wittig product and then carrying

out cycloaddition reaction on the intermediate in refluxing diphenyl ether (Scheme

XXV).

CHO

Bn

Ph3P_ PhOPh

NBn N2, reflux

12

2

Xylene, N 2 , reflux

11

Scheme XXV

Based on the mode of formation & spectral properties mentioned below, (2E)-N-

benzyl-N-[(2Z)-but-2-en-l-y1]-3-(1H-indo1-3-y1)acrylamide was assigned to the

compound. The coupling constant (J = 15.2 Hz) of the vinyl protons indicated the

trans geometry of the product.

MP = 145-146°C, yield = 70.00%

IR (vmax): 3203 cm'(NH), 1670 cm -1 (CO)

1 H NMR (DMSO-d6, 400 MHz):

8 1.67 d ( J = 6.3 Hz) 3H CH3

8 4.01 [4.11] brs 2H CH2-CH=CH-

8 4.6 [4.71] s 2H CH2Ph

8 5.5 m 1H CH2-CH=CH-

8 5.7 m 1H CH2-CH=CH-

8 6.77 [6.90] d (J = 15.2 Hz) 1H CH=CH-CO

8 7.0-7.6 m 9H ArH

8 7.8 m 2H CH=CH-CO, Ar-H (C-4)

811.6 2 X brs 1H • NH

137

The trans unsaturated amide 11 was then heated in refluxing diphenyl ether under

nitrogen atmosphere. After column chromatography the yield of diastereomeric y-

lactams (12) was found to be 65.20%.

When N-prenyl-N-benzyl-2-(triphenylphosphoranylidene)acetamide was subjected

to tandem Wittig reaction and Diels Alder reaction with indole-3-carboxyaldehyde

in refluxing diphenyl ether (Scheme XXVI) it gave mixture of diastereomers

(Yield = 61.40 %, HPLC = 1:1).

Bn CH 3

CHO Ph 3 13 ----

CH3

O

PhOPh, N2 , reflux 10h

2

441, NBn + N

N 14 H3C CH 3 H H H

H 3C CH 3

14a 14b

Scheme XXVI

The solid compound, MP = 245-246°C with strong IR absorption bands at 3292 - cm and 1674 cm I , confirmed the presence —NH of indole moiety and carbonyl

group of lactone in the molecule. Its I H NMR (300 MHz, CDC13) spectrum (Fig

6a) had two singlets at 8 1.20 (3H) and 1.40 (3H) indicating the presence of gem-

dimethyl group. One multiplet (6H) seen at 8 2.30-3.40 could be attributed to

protons of six membered ring and lactam ring. One doublet of doublets was seen at

8 4.55 (2H, J = 14.7 Hz) which could be attributed for benzylic methylene group.

In addition to this one multiplet (9 H) was seen in aromatic region at 8 7.10-7.60

which could be attributed to indole protons and benzene protons. One singlet was

seen at 8 7.9 due to the presence of nitrogen proton. The structure was further

confirmed by its I3C NMR and DEPT 135 spectra (Fig 6b). Thus, peaks at 24.07

(q) and 27.12 (q) could be assigned to the two carbons of methyl groups. Peak at

138

NBn

I patre 1 £i?-;1742, CX

22.27 (t) could be attributed to methylene carbon attached to indole ring. Peak at

45.45 (t) could be assigned to methylene carbon of lactam ring. Peak at 46.79 (t)

could be attributed to benzylic methylene carbon. Peaks at 41.09 (d) and 48.59 (d)

were assigned to methine carbon of CH-CH group. Peaks at 110.67 (d), 118.42 (d),

119.59 (d) and 121.81 (d) could be attributed to aromatic methine carbons of

indole ring. Peaks at 127.62 (d), 128.11 (d), and 128.79 (d) could be assigned to

benzene methine carbons. The quaternary carbon appearing 33.9 (s), 108.62 (s),

127.27 (s), 136.21 (s), 136.66 (s), 141.68 (s) which could be attributed to saturated

carbon and aromatic carbons. The lactam carbonyl carbon appeared at 175.34 (s)

as expected.

HRMS data confirmed the elemental composition as C23H240N2 (Observed: m/z

367.1784, calculated for [M+Na] + = 367.1784). (Yield = 61.40%, product ratio:

1:1).

Thus on the basis of mode of formation & spectral properties structure 14 was assigned to it.

•?".'" I r • r*—

8.6 8A 1.6 Y TO "6,6 6,0 5,5 5.0 4.5 4.0 3,6 am 2,6 2:0 1.6 1,6 6.6

Fig 6a

139

CHO Ph3P-

14

Bn

CH3

xylene, reflux NBn

PhOPh

reflux

pat re 9, g:?-07 - 1.2 195

13G HO 30 140 130 120 110 1 .00 90 80 70 60 SO 40 30 rppm

Fig 6b

We also carried out the synthesis of 14 in a stepwise manner (Scheme XXVII).

13

Scheme XXVII

Based on the mode of formation & spectral properties mentioned below, (2E)-3-

(1H-indo1-3-y1)-N-(3-methylbut-2-en-l-y1)acrylamide 13 was assigned to the

compound. The high coupling constant (15.3 Hz) of the vinyl protons indicated

trans geometry of the product (MP = 152-153 °C, yield = 69.70%).

IR (v.): 3172 cm -I (NH), 1629 cm -1 (C0).

140

1H NMR (CDC13, 300 MHz):

S 1.65

8 1.75

s

s

3H

3H

CH3

CH3

8 4.13 [4.20] d (J= 6.3 Hz) 2H CH - CH=

8 4.60 [4.65] s 2H C112Ph

8 5.30 brs 11-1 CH2-CH=

8 6.90 [6.95] d (J =15.3 Hz) 1H CH=CH-CO

8 7.10-7.90 m 10H ArH

8 8.10 [8.15] d (J = 15.3 Hz) 1H CH=CH-CO

89.10 2 X brs 1H NH

13C NMR and DEPT.135 (CDC13): S 18.0 (q, CH 3), 25.8 (q, CH3), 44.0 [44.2] (t,

CH2-CH=), 45.0 [45.2] (t, CH2Ph), 111.0 (d, CH2-CH=), 112.0 (d, CH=CH-CO),

113.40 (s), 119.12 (d, C ivil), 123.0 (d, CArll), 125.2 (s), 126.65-128.87 (d, CAIN),

137.20 (s), 138.7 (d, CH=CH-00), 139 (s), 168.99 (CCO).

The trans ester 13 upon, refluxing diphenyl ether for 6 h, followed by

chromatography separation yielded two diastereomers in 63.30%.

Conclusion:

We have successfully synthesized the furano and pyrrolo tetrahydrocarbazoles

using tandem Wittig-Diels-Alder reaction.

141

Experimental section:

Expt. 2.2.1: General procedure for tandem Wittig-Diels-Alder reaction

A solution of indol-3-carboxyaldehyde (1 mmol) & substituted allyl (triphenyl

phosphoranylidine)acetate/N-allyl-N-benzy1-2-(triphenylphosphoranylidene)

acetamide (1.5 mmol) in diphenyl ether (10 mL) was refluxed under nitrogen

atmosphere for 8 h. The crude mixture was subjected to column chromatography

over silica gel using hexanes to remove diphenyl ether first and further elution with

30-40% ethylacetate and hexanes to afford diastreomeric y-lactones/lactams.

Expt. No

Substrate Product Nature Yield

(%)

2.2.1.1 CHO O

Solid

(m.p. 228-229°C)

59.80% 0 * 0

2.2.1.2 CHO

H 0 Solid

(m.p. 210-211 °C) 61.20%

le el H

CH 3 I 0

H

2.2.1.3 CHO

H ° NBn

Solid

(m.p. 235-236°C) 65.00% 0 O I 0

H

2.2.1.4

CHO 0 H °

NBn

Solid

(m.p. 241-242°C) 62.20% I 0 01

H H CH3

2.2.1.5 CHO

H ° NBn

H

Solid

(m.p. 245-246°C) 61.40% le O N H H 3c CH 3

0

H

142

Expt. 2.2.2: General procedure for the preparation of substituted allyl indole

acrylate/acrylamide

A solution of indole-3-carboxyaldehyde (1 mmol) & substituted allyl (triphenyl

phosphoranylidine)acetate/acrylamide (1.5 mmol) in xylene (10 mL) was refluxed

for 8 h. The crude mixture was subjected to flash column chromatography over

silica gel using hexanes to remove xylene first and further elution with 30-40%

ethyl acetate and hexanes to afford - yellow solid which was recrystallised from

hexanes and ethyl acetate.

Expt. No

Substrate Product Nature Yield

(%)

2.2.2.1

CHO Solid

(m.p. 61-62°C) 88.5% 0 I 1 N

H I I 0

N H2C.- H

2.2.2.2

CHO Solid

(m.p. 109-110°C) 86.4% 0 1

N el 1 N H3C "-......

2.2.2.3

CHO Solid

(m.p. 245-246°C) 87.6%

0 I 0 • N

I ..„..-

H H3C CH3

2.2.2.4

Solid

(m.p. 92-93 °C) 74.5% 0 CHO

1 1 H i H2 ;.-----/

NBn

H

2.2.2.5

CHO Solid

(m.p. 145-146°C) 70%

4p 1 el I NBn

H3C /

2.2.2.6

CHO Solid

(/1.1). 152-153 °C) 69.7%

0 I NBn el 1 / H

N

H3C CH3

143

Expt. 2.2.3: General procedure for the preparation furano and pyrrolo

tetrahydrocarbazole from substituted allyl indole acrylamide/acrylamide.

Substituted allyl indole acrylamide/acrylamide was refluxed in diphenyl ether (10

mL) for 8 h under nitrogen atmosphere. The crude mixture was purified by flash

column chromatography over silica gel using hexanes to remove diphenyl ether

first and further elution with 30-40% cthyl acctatc and hcxancs to afford furano

and pyrrolo tetrahydrocarbazole.

Expt. No

Substrate Product Yield (%)

2.2.3.1

64% 0 14111 .----./ H2O/ S i O

2.2.3.2 H

62.80% 0 I N

H H3C

S i O H

CH3

2.2.3.3 O H CI

NBn

H 66.80%

14110 ,.._.,,../NBn

N F12%- - H

0 411 H

2 .2.3.4 NBn

H

65.20% le I / NBn

cH, S i

1 0 " H3C

2.2.15

O H 0

63.30% 10 1 NBn

H H3C CH3

14101 IIII N H

H3C 0-13

NBn

H

144

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