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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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