Indole based multicomponent reactions towards

Issue in Honor of Prof. Sándor Antus
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Indole based multicomponent reactions towards functionalized
heterocycles
Janos Sapi* and Jean-Yves Laronze
UMR CNRS 6013 “Isolement, Structure, Transformations et Synthèse de Substances
Naturelles”, IFR 53 “Biomolécules”, Faculté de Pharmacie, Université de Reims-ChampagneArdenne, 51 rue Cognacq-Jay, F-51096 Reims Cedex, France
E-mail: [email protected]
Dedicated to Professor Dr. Sándor Antus on the occasion of his 60th birthday
(received 19 Jan 04; accepted 08 Apr 04; published on the web 13 Apr 04)
Abstract
This short review offers a non-exhaustive panorama of the indole ring implicated
multicomponent reactions, and simple functional group transformation-based approaches,
developed over the last thirty years for the synthesis of various biologically interesting indole
heterocyclic ring systems.
Keywords: Multicomponent reactions, indole derivatives, alkaloids, nitrogen heterocycles,
Mannich reaction, gramines, Ugi reaction, Petasis reaction, domino reactions, Yonemitsu
reaction, trimolecular condensation, Meldrum’s acid, Curtius rearrangement, β-substituted
tryptophan, tryptamine derivatives, β-carboline, spiro-oxindole derivatives, tetrahydro carbazole
derivatives
Contents
Introduction
1.
Mannich reaction-“Gramine chemistry”
2.
Multicomponent reactions involving isocyanides-Ugi reaction
3.
Multicomponent reactions with boronic acids-Petasis reaction
4.
Multicomponent reactions using dihydropyridines
5.
Multicomponent reactions combined with domino cyclisation
6.
Yonemitsu-reaction
6.1.1. Synthesis of β-substituted tryptophans
6.1.2. Synthesis of heterocycle-fused tryptamines
6.1.3. Preparation of spiro[pyrrolidinone-indolines]
6.1.4. Tetramolecular version of the Yonemitsu reaction
7.
Conclusions
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Introduction
Multicomponent reactions (MCR-s) have recently emerged as valuable tools in the preparation of
structurally diverse chemical libraries of drug-like heterocyclic compounds.1 The
multicomponent reaction story began as far back as 1850 by the publication of the Strecker
reaction,2 arriving nowadays at its apogee. During this one and a half century period, some
notable achievements include the discovery of the Biginelli,3 the Mannich,4 and the Passerini5
reactions culminating in 1959 when Ugi published6 probably the most versatile MCR based on
the reactivity of isocyanides.7 In view of the increasing interest for the preparation of large
heterocyclic compound libraries, the development of new and synthetically valuable
multicomponent reactions remains a challenge for both academic and industrial research teams.8
Although functionalized indole ring systems have been found frequently in biologically
active molecules, indole derivatives as MCR partners are rather under-represented. This review
offers a short and non-exhaustive summary of the synthesis of functionalized heterocyclic
systems by multicomponent strategies involving indole derivatives as reaction partners.
1. Mannich reaction-“Gramine chemistry”
The condensation of activated carbonyl compounds with in-situ formed iminium species, called
the Mannich reaction, provides β-amino carbonyl compounds.4 When such iminium species
undergo nucleophilic attack by indole derivatives, gramines can be prepared.9 From a preparative
point of view the generally unstable gramines are very important intermediates towards various
tryptamine, tryptophan, β-carboline,9,10 carbazole11 and other indole alkaloids.12 Additionally,
some gramine derivatives have been found to be potent 5-HT6 receptor ligands.13
Recently, Lévy et al. have successfully exploited the thermal instability of 2-substituted
gramines 2 for the in-situ generation of indole-2,3-quinodimethanes 3 which were engaged as
reactive dienes in Diels-Alder reactions to afford 1,2,3,4-tetrahydrocarbazoles (Scheme 1).14
R1
NH
N
CO 2Et
H
+
+
NH 2
2
R1
O
CHO
N
H
1a
CO 2Et
+
∆
R1
N
R1
O
O
N
O
N
N
O
H
3
CO 2Et
O
N
CO 2Et
H
4
Scheme 1
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In this process, in the absence of an amine component, a simple multicomponent approach
employing an equimolar mixture of ethyl 2-indolylacetate 1a, benzaldehyde and Nmethylmaleimide resulted in the formation of 4 in 74% yield.
2. MCR-s involving isocyanides-Ugi reaction
Despite the importance of Ugi-type reactions in the synthesis of heterocyclic compounds, only
scant attention has been paid to the incorporation of indoles as multicomponent reaction partners.
For example, the indole nucleus has a secondary role in a recently published preparation of
pyrrolo[2,1-a]isoquinoline derivatives. Mironov et al. have found a new MCR between
isoquinoline 5, geminal diactivated olefins 6, and isocyanides 7, for the synthesis of dihydro10H-pyrrolo[2,1-a]isoquinolines (Scheme 2).15 From a mechanistic point of view, the key step is
the formation of zwitterion 8, which was attacked by isocyanide affording the final product 9.
N
N
N
Ph
Ph
R= 5-indolyl
Ph
5
CN
CN
N
+
C
NC
CN
N
R
N
C
NC
7
CN
R
6
8
9
N
H
Scheme 2
The β-carboline core is a frequently occurring structural motif in natural products and
biologically active substances. For the preparation of a pentacyclic β-carboline structure
Dömling et al. proposed an Ugi-type reaction condensing tryptophan 10 with phthalic dialdehyde
11 and isocyanide 12. Spontaneous Pictet-Spengler cyclization of the Ugi-intermediate 13,
followed by D-ring oxidation afforded the pentacycle 14 (Scheme 3).7a
CO2H
CO2H
HN
NH2
NH
N
10
H
H
CHO CN
12
CONHtBu
N
O
N
N
+
CO2H
OHC
13
H
14
CHO
11
Scheme 3
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A modified version of the Ugi four component reaction, using bifunctional aldehyde acid 15,
tryptamine 16, and isocyanide 17 as starting materials, has been worked out by Zhang et al. for
the synthesis of various, including indole containing, polycyclic lactams 18 (Scheme 4).16
NH2
N
CHO
HN
H
+
O
16
CO2H
N
CN
15
17
N
O
H
18
Scheme 4
3. MCR-s with boronic acids-Petasis reaction
In the ‘90-s, a new synthetic method, involving vinyl boronic acids as nucleophiles in Mannich
type reactions was developed by Petasis for the preparation of various allylamines.17 Later on,
this approach was extended to the preparation of non-natural amino acids. Thus, a trimolecular
condensation involving diverse 3-indolyl boronic acids 19, glyoxalic acid 20, and a chiral amine
21 allowed the preparation of N-substituted-indolylglycines 22 (Scheme 5) with excellent
diastereoselectivity (de>99%).18
Ph
Ph
HN
NH2 21
B(OH)2
CO2H
+
R
19
N
CO2H
Ts
CHO
R
N
Ts
20
22
Scheme 5
4. Multicomponent reactions using dihydropyridines
For a long time, calcium channel antagonist dihydropyridines have been attractive targets for
multicomponent approaches (Hantzsch reaction,19 1882). The high diversity, the ready access
and the reactivity of the enamine appendage make them versatile intermediates for further
synthetic transformations. Thus, Lavilla et al. have developed recently a dihydropyridine-based
multicomponent approach for the preparation of new pyridine annulated tetrahydroquinoline
derivatives through a lanthanide catalyzed formal [4+2] cycloaddition. When N-tryptophyl
dihydropyridine 23 was reacted with anilines 24 and ethyl glyoxalate 25 under InCl3 mediated
catalysis, the indoloquinolizidine derivative 26 was isolated as a 4:1 mixture of epimers on the
aminoester moiety (Scheme 6). The observed diastereoselectivity was rationalized by a
preferential attack of the dihydropyridine from the less hindered face of the imine, whereupon
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final cyclisation of indole onto the intermediate iminium species takes place with total
stereocontrol leading to trans-indoloquinolizines.20
CO2Et
CHO
N
+
25
N
NH2
N
N
H
H
EtO2C
O
CN
23
O
CN
NH
24
26
CO2Et
CO2Et
Scheme 6
5. Multicomponent reactions combined with domino cyclisation
Domino reactions21 involving the formation of several chemical bonds in one sequence without
isolating the intermediates, have proven to be economically and environmentally favourable
procedures for the preparation of complex molecules. A successful combination of domino
reactions with the multicomponent approach tends towards the ideal organic synthesis concept.
Following this idea, a three component condensation domino Knoevenagel-hetero Diels-Alder
pathway was worked out by Tietze et al. for the preparation of indole alkaloid derivatives (30
and 34, respectively) of the Corynanthe (Scheme 7) and Valesiachotamine (Scheme 8) groups.22
In both reactions, high diastereoselectivity was observed and the configuration of the newly
formed stereogenic centres can be reversed by changing the tosyl group (27a) at the indole
nitrogen into hydrogen (27b) or vice-versa.23
N
N
N
Cbz
N
H
CHO
Ts
27a
+
EDDA,rt
(((
O
Cbz
N
H OBn
N
H
Ts
Pd-C,H2
O
H
29
Ts
OBn
O
H
30
O
H
H
O
N
O
N
N
N
N
N
O
O
O
Corynanthe type
28
Scheme 7
N
N
N
Cbz
N
H
CHO
H
+
27b
EDDA,rt
H
OBn
O
R1
N
H OBn
N
H
H
(((
O
Cbz
Pd-C,H2
H
H
H
R2
H
O
O
31
O
32
33 R 1: O; R2: CHO
34 R 1: H2; R2: CH2OH
Dihydroantirhine
O
LiAlH4
Scheme 8
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With an aim towards constructing the central isoquinoline based tricyclic core of the
anticancer alkaloids manzamine (Scheme 9), Markó et al. have proposed a novel cascade anionic
polycyclisation method.24
N
N
H
H
OH
N
R1
N
N
H
R2
N
H
manzamine A
Scheme 9
Their procedure is situated somewhere on the borderline between multicomponent and
domino reactions. Substituted gramines 35, in the presence of t-BuOK reacted with acrolein and
functionalized β-keto phosphonates via a multicomponent condensation, followed by base
catalyzed polycyclisation cascade of 36 to afford highly substituted decahydro-isoquinoline type
compounds 37 (Scheme 10). This highly chemo- and diastereoselective process allowed the
control of up to four chiral centres.
R1
H
O
CHO
O
NH
DBU
N
MeO
R1
O
N
R2
N
R2
P
H
35
O
R1
N
R2
N
H
MeO
36
t-BuOK
H
37
R1: Allyl, PMB
R2: H, Et, Bu,
Cl
( )2
( )4
Scheme 10
6. Yonemitsu-reaction
Meldrum’s acid 31 appears to be an attractive reagent in organic syntheses owing to its high
acidity, steric rigidity and high reactivity.25
In 1978, Yonemitsu et al. found a new multicomponent reaction (Scheme 11) by reacting
indole 38, Meldrum’s acid 31 with different aldehydes.26 Subsequent decarboxylative ethanolysis
of adducts 39 led to various ethyl 3-substituted indolyl-propionates 40, used as intermediates in
the synthesis of complex indole alkaloids.27
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R1
CHO
R
+
N
38
MeCN
rt
O
O
N
H
O
O
R1
R
O
O
H
O
R1
R
EtOH-pyridine
Cu,∆
CO2Et
N
H
39
"Reims group"
O
31
R:H MeO Br CN PhthNCH2
x y
v w
z
functional group
transformations
non-natural tryptophans,
tryptamines,
indole heterocycles
40
Yonemitsu et al.
carbazoles
R1:Me i-Pr 3-pentyl chexyl Ph 2,5-(MeO)2Ph Et Pr n-Bu s-Bu, 3,4-(OCH2O)Ph H
a b
c
d
e
f
g h i
j
k
l
Scheme 11
6.1. Synthesis of β-substituted tryptophans
Tryptophan is an important essential amino acid present in various biologically active peptides.
Its replacement by conformationally constrained β-substituted analogs has been used commonly
in peptide-receptor affinity studies.
When, at beginning of the ’90-s, we were interested in the preparation of non-natural βsubstituted tryptophan derivatives for the synthesis of modified CCK-4 analogs28, the Yonemitsu
reaction attracted our attention. Stable, high-yield isolated products with the readily cleavable
dioxanedione appendage seemed to be valuable intermediates for our purposes.
Consistent with Yonemitsu’s report26, indoles 38 with various alkyl-, or arylaldehydes and
Meldrum’s acid 31 smoothly gave the condensation products 39 (Scheme 11) (75-95 %).29
Condensation with paraformaldehyde led to a mixture of normal adduct 39l and its
hydroxymethyl counterpart 41 which could be quantitatively converted into 39l under
microwave irradiation (Scheme 12).30
O
38x
+
R
O
(CH2O)x
O
31
O
+
O
N
O
HO
R
O
N
O
H
H
39l
Et3N
MW
41
Scheme 12
Solvolysis of 39 with alcohols gave a diastereomeric mixture of acid esters 42 (Scheme 13).
For the transformation of the carboxylic acid function into carbamate, the well-known domino
acylazide 43 formation-Curtius rearrangement-benzylalcohol mediated solvolysis of the
isocyanate intermediate 44 procedure was utilized. Separation of the diastereomeric carbamates
45 (syn/anti), followed by classical deprotection completed the synthesis of β-substituted
tryptophans 46 (syn/anti).31
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O
R1
R
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R1
R
O
CO2Et
NH
O
O
N
N
H
39
47
HBr-AcOH,∆ or
HCl,∆
R3OH,∆
R1
CO2R2
DPPA
Et3N,∆
CO2H
3-indolyl
O
H
R1
CO2R2
∆
3-indolyl
CON3
R1
3-indolyl
R:H, Br
R2:Et
CO2R2
N
C
42
43
R1:Me i-Pr 3-pentyl chexyl Ph 2,5-(MeO)2Ph
a b
c
d
e
f
44
O
R:H
R2:t-Bu
BnOH,∆
R1
R
CO2R2
NH-R3
N
H
45 R 2:t-Bu R3:CO2Bn
46 R 2:H R3:H
1.separation
2.Pd-C, H2
3.TFA orBBr3
Scheme 13
When the Curtius rearrangement was carried out in an acid medium, 4-substituted 1-oxotetrahydro-β-carboline derivatives 47 were isolated in 40-68 % overall yield (Scheme 13.).32 The
1-Oxo-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ester 47 (R:H) core is considered as a
rigid pseudopeptide analog of tryptophan and could represent a valuable scaffold for the
synthesis of futher functionalized polycyclic systems of biological interest.
6.2. Synthesis of heterocycle-fused tryptamines
The tetrahydro-β-carboline core, present in numerous alkaloids (Vinca-, Rauwolfia-, Harmanalkaloids) and synthetic products with valuable biological properties, is accessible from
tryptamine via the well-known Pictet-Spengler33 and Bischler-Napieralski reactions. Some 3,4annulated (tetrahydro)-β-carbolines were reported to be potent benzodiazepine antagonists or
tyrosine kinase inhibitors.34 Heterocycle fused tryptamines are considered as useful precursors
for the preparation of functionalized, conformationally restricted serotonin and melatonin
analogs.
A multicomponent pathway, using masked nucleophile containing aldehydes, was proposed
for the preparation of new 3,4-heterocycle fused (tetrahydro)-β-carbolines. Following a
chemoselective deprotection, an internal nucleophilic ring opening of the Meldrum’s acid moiety
could be envisaged and the resulting carboxylic acid function was to be relayed toward the
targeted tryptamine and β-carboline compounds.
In a preliminary study,35 the trimolecular adducts 49 were prepared by using Cbz (CO2Bn)
masked 2-hydroxy- 48a or 2-aminoacetaldehydes 48b,c as aldehyde partners (Scheme 14).
Deprotection of 49 and subsequent internal nucleophilic attack allowed the isolation of furanone
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50a (90 %), and pyrrolidinone 50b (80 %), as sole products. In both cases, we observed the
exclusive formation of 3,4-trans disubstituted ring systems, resulting from a decongested
transition state in which the bulky indole ring, being remote from the Meldrum’s acid moiety,
favours an equatorial attack. Conversion of the carboxylic acid function to amine followed the
classical pathway providing heterocycle-fused trans tryptamines 51a or 51b.
X-CO2Bn
CHO
X-CO2Bn
O
48a-c
X
O
O
+
38x
+
O
O
N
31
4
O
Pd-C
H2
O
O
X
H
H
49
X: O, NH, NBn
a b
c
R
O
Indole
3
N
H
50 R: CO2H
1.DPPA, Et3N
2.BnOH,∆
3.Pd-C, H2
51 R: NH2
Scheme 14
It was then interesting to investigate whether a chiral aldehyde, possessing the same type of
masked nucleophile, could control the trimolecular condensation step. For this purpose, 2,3-Oisopropylidene-D-glyceraldehyde (-)-52, as a chiral template, was reacted with indole 38x and
Meldrum’s acid 31 affording condensation product (-)-53 as the sole diastereomer (Scheme 15)
(75 %).
38x
O
O
+
31
CHO
52
OTBDMS
OH
O
O
O
(S)
(S)
O
(S)
HCl
O
O
N
N
53
O 1.TBDMSCl
imidazole
(S)
2.DPPA,Et3N
CO2H
3.BnOH,∆
4.Pd-C,H2
O
NH2
N
H
H
H
O
O
54
55
Scheme 15
As expected, a subsequent deprotection-spontaneous cyclization sequence gave the
corresponding lactone acid (-)-54, enabling the complete diastereocontrol of the two newly
created stereocenters.36 Transformation of (-)-54 into furan fused chiral tryptamine (+)-55 was
performed by the classical manner.
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Continuing our program, we sought to investigate the chemoselectivity of the internal ring
opening of the Meldrum’s acid unit by using Garner’s aldehyde37 56, an orthogonally protected
bifunctional chiral aldehyde. In the event, trimolecular condensation of Garner’s aldehyde 56
with indole 38x, and Meldrum’s acid 31 provided the corresponding adduct (-)-57 (90 %) in high
(de >90%) diasteroselectivity (Scheme 16).
Depending on the reaction conditions, chemoselective internal O- or N-nucleophilic ring
closures were observed. Careful isopropylidene deprotection of (-)-57 followed by esterification
allowed the isolation of diastereomerically pure pyranone-fused tryptamine derivative (-)-58.
Deprotection of (-)-57 in refluxing methanol-HCl provided diastereomerically pure lactam
ester (-)-59, as a result of a full deprotection, selective internal N-nucleophile ring closure
sequence, followed by esterification of the carboxylic acid moiety (Scheme 16).
O
O
N Boc
CHO
56
O
Boc
N
O
O
MeO2C
O
(R)
1.p-TsOH,MeOH
O
+
38x
N
+
31
H
NH-Boc
2.CH2N2
O
N
57
H
1.MeOH-HCl
2.Et3N
58
TFA
OTBDMS
H
N
HO
H
N
O
CO2Me
N
1.TBDMSCl
imidazole
2.KOHaq.
3.DPPA,Et3N
4.BnOH,∆
O
NH-R
N
H
H
59
60 R:CO2Bn
Pd-C
H2
61 R:H
Scheme 16
Simple functional group transformations completed the synthesis of chiral pyrrolidinonefused tryptamine (-)-61.38 In both series, the chirality of the Garner’s aldehyde ensured a
complete and predictible control of the two newly created stereocentres.
6.3. Preparation of spiro[pyrrolidinone-indolines]
In 1983 Bailey et al. successfully applied the Yonemitsu reaction to 2-substituted indoles
(Scheme 17). They found that 1,2-dimethylindole 62 reacted with aldehydes and Meldrum’s acid
31 giving rise to the expected trimolecular products 63.39
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O
O
O
O
+
∆
+
O
CH3
N
62
HCOH
O
CH3
O
CH3
N
O
CH3
31
63
Scheme 17
Although our initial investigations to reproduce Bailey’s results failed, multicomponent
reactions between 2-substituted indoles 1, benzaldehyde and Meldrum’s acid 31 were carried out
in the presence of one equivalent of triethylamine affording stable, crystalline adduct salts 64 in
60-78 % yield.40 It is noteworthy that 64 are obtained stricto sensu in tetramolecular reaction
processes (Scheme 18).
Et3NH O
Ph
Ph
+ CHO
R
N
+
O
CO2t-Bu
H
t-BuOH
∆
O
O
R
N
H 1
O
Ph
O
CO2H
R
N
H
64
65
DPPA
Et3N
∆
+ Et3N
O
O
Ph
31
R
CON3
C
H
67
66
∆
BnOH,∆
CO2t-Bu
Ph
N H
N
O
R
CO2t-Bu
Ph
Ph
CO2t-Bu
N H
O
N
BnOH, Et3N
∆
NHCO2Bn
R
N
H
68b-d
R
N
O
H
CO2t-Bu
∆
N
N
Ph
CO2t-Bu
CO2Et
68a
H
69
R: CO2Et Me Ph SMe
a
b c d
Scheme 18
When in situ formed azides 66, prepared via the well-known path from 65, were heated in
toluene, a diastereomeric mixture of spirocyclic pyrrolidinone-indolines 68 was isolated via 67
resulting from a Curtius rearrangement, followed by a thermal spirocyclisation process.
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Indoline-2-one (oxindole) 70 also proved to be a reactive nucleophile under modified
Yonemitsu conditions. Condensation of 70 with aromatic aldehydes, Meldrum’s acid 31 and
triethylamine afforded adduct salts 71 in moderate yields. A successful application of the
previous domino process on 72 allowed the isolation of functionalized spiro-oxindole derivatives
73.41 It is important to note that the spiro-oxindole core is present in various alkaloids, for
example horsfiline or spirotyprostatines, of biological interest.
R1
+
N
R1
O
O
O
N
O
t-BuOH
∆
CO2H
N
O
H
H
70
72
1.DPPA, Et3N,∆
2.∆
71
+ Et3N
O
CO2t-Bu
R1
O
O
CO2t-Bu
O
H
O +
Et3NH O
R1
CHO
N H
31
R1:Ph 2,5-(MeO)2Ph 2-NO2-Ph
e
f
l
4-F-Ph
m
N
H
O
O
73
Scheme 19
6.4. Tetramolecular version of the Yonemitsu reaction
When a mixture of ethyl 2-indolylacetate 1a, Meldrum’s acid 31 and two equivalents of
benzaldehyde were heated in a Dean-Stark trap or with a microwave apparatus, functionalized
tetrahydrocarbazole derivatives 74 were obtained (Scheme 20). This four-component reaction
was expanded to other substituted indoles and arylaldehydes with different substitution patterns.
Mechanistically, the pivotal Knoevenagel adduct could react with different in situ formed
intermediates affording the tetramolecular compounds 74.
Toward combinatorial utilisation, the reversibility of this process was also studied by using
benzaldehyde and 4-fluorobenzaldehyde combined with mass spectral analytical methods.
Treatment of salt 64 (R: CH2CO2Et) with 4-fluorobenzaldehyde led to a mixture of
nonfluorinated 75 and monofluorinated 76 carbazoles, while the reaction of 1a with 31,
benzaldehyde and 4-fluorobenzaldehyde gave a mixture of all possible tetrahydrocarbazoles 7578 (Scheme 21). This reaction seems to be the first step towards the development of a
combinatorial version of the Yonemitsu reaction.
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Ar
O
O
Ar
N
+ CHO
R1
R2
Ar
or
O
O
+
Dean-Stark,∆
or MW
O
Ar
Ar
N
R1
1a: R1: H; R2: CO2Et
62:
CH3; CH3
O
R2
R1
74
O
Ar
or
CHO
O
+ Ar
Ar
N
O
O
R2
+ CHO
O
N
N
R2
R1
O
Ar O
O
R1
31
O
O
R2
Ar: C6H5; 2,5-(MeO)2C6H3; 2-NO2-C6H4
Scheme 20
Et3NH
O
Ph
O
O
N
O
F
H
Ar1 O
O
N
O
CO2Et
64
O
Ar2
CO2Et
H
Ph
1a
CHO +
F
N
CHO
∆
H
CO2Et
75 Ar1=Ar2=C6H5
76 Ar1=C6H5; Ar2=4-F-C6H4
77 Ar1=Ar2=4-F-C6H4
78 Ar1=4-F-C6H4; Ar2=C6H5
O +
O
O
O
31
CHO
Scheme 21
7. Conclusions
This short review describes the main synthetic methods that have been published in the field of
indole based multicomponent reactions during the last three decades. In spite of some recent
progress, particularly concerning the Yonemitsu reaction, multicomponent methodology with the
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indole ring system as a reaction partner remains to be further explored for the construction of
various biologically important heterocyclic compounds.
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