Towards a facile and convenient synthesis of highly functionalized indole derivatives based on multi-component reactions

Article abstract of DOI:10.1039/c4ob00166d

A library of potentially bioactive compounds through the novel 1H-indole-methyl-isocyanide and MCRs has been described. A flexible and efficient synthesis affording great complexity and diversity is achieved with moderate to good yields with no need for protection and deprotection steps. This journal is The Royal Society of Chemistry 2014.

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Towards a facile and convenient synthesis of highly
functionalized indole derivatives based on Multi-
Component Reactions
Cite this: DOI: 10.1039/x0xx00000x
Constantinos G. Neochoritisa and Alexander Dömlinga*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
MCRs are valuable tools that give us the opportunity to access
complex and diverse scaffolds with potential bioactivity.(6) Despite
the importance of Ugiꢀtype reactions in the synthesis of heterocyclic
compounds, only scant attention has been paid to the incorporation
of indoles as multicomponent reaction partners. Recently the Ugiꢀ4C
reactions of indoleꢀcarboxaldehydes and their postꢀUgi
A library of potentially bioactive compounds through the
novel
1H-indole-methyl-isocyanide and MCRs has been
described. A flexible and efficient synthesis affording great
complexity and diversity is achieved, with moderate to good
yields with no need for protection and deprotection steps.
In 1869, Adolf von Baeyer proposed the structure of one of the most transformations was reported.(7) In continuation of our interest in
important heterocyclic compounds(1): indole. Indole is isocyanide based MCRs, we envisaged using “Mannichꢀtype”
unambiguously the king of heterocycles: An
electronꢀrich heteroatomic system with enhanced
reactivity in electrophilic aromatic substitutions,
especially in Cꢀ3 position (enamine type). The
importance of indole is recognized both by the
isocyanides from electronꢀrich heterocycles, such as indole, for the
construction of scaffolds which otherwise their skeleton would be
accessible via lengthy sequential synthesis. In past, we reported Ugi
reactions with a tryptophan derived isocyanide and subsequent
PictetꢀSpengler reactions(8ꢀ9) but herein we report the first “gramineꢀ
number of publications (more than 80000 publications in 114 years) type” isocyanide and its employment in various MCRs giving access
and with its presence in pharmaceuticals, agrochemicals, organic to unique drugꢀlike indole scaffolds. To the best of our knowledge
electronics, in addition to the vast of natural products alkaloids 1Hꢀindoleꢀmethylꢀisocyanide 2 has never been mentioned before in
containing indole moieties. Alkaloids like gramine, strychnine and literature and thought to be the most suitable precursor. It could be
lysergic acid (LSD), aminoacids and other bioactive compounds like synthesized from the corresponding formamide 1 by dehydration,
tryptophan, tryptamine and serotonin and pharmaceuticals like whereas the latter could be synthesized from the readily available
vincristine, delavirdine and yohimbine (fig. 1) are just very few indoleꢀ3ꢀcarboxaldehyde via a reductive amination reaction (scheme
examples showing why chemists have this continuous interest in 1).
employing the indole core in the compounds.(2ꢀ5)
Scheme 1. Retrosynthetic analysis of 1Hꢀindoleꢀmethylꢀisocyanide 2
The reductive amination of indoleꢀ3ꢀcarboxaldehyde with
formamide(10) led to the desired formylated compound 1 in 49%
yield, affording also the indole benzyl alcohol 3 in a 30% isolated
yield (scheme 2). After quite some experimentation, we “revived” an
old but nevertheless very useful reaction: The LeuckartꢀWallach
reaction.(11) This, rather abandoned in modern synthetic chemistry,
reaction is a oneꢀstep reductive amination but suffers from some
serious practical problems such as prolonged reaction times, high
temperatures and compatibility issues with substituted
benzaldehydes. Nevertheless, decreasing the concentration of the
indoleꢀ3ꢀcarboxaldehyde with certain specific
Fig 1. Selected examples of indoleꢀcontaining compounds
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molar ratios of the formamide and formic acid using microwave
assistance (accelerated LeuckartꢀWallach), gave us access to the
important intermediate 1 in 71% yield reducing also the reaction
time to 3 minutes (scheme 2). Typical dehydrating conditions with
POCl3 and Et3N afforded the novel 1Hꢀindoleꢀmethylꢀisocyanide.
Table 1. Survey on reactions Ugiꢀ4C, Ugiꢀtetrazole and UgiꢀSmiles
Entry
R1
R2
Acid
component
Product
(% yield)
Scheme 2. The LeuckartꢀWallach reaction and synthesis of the
isocyanide 2
1
2
3
5
6
7
Cl
Br
H
CN
Br
H
formic acid
formic acid
formic acid
TMSꢀazide
TMSꢀazide
TMSꢀazide
4a (85)
4b (82)
4c (74)
5a (88)
5b (80)
5c (71)
H
OMe
Cl
Next, the isocyanide 2 was successfully employed in various multiꢀ
component reactions, based on the rapid and easy access to
biologically relevant compounds that can give, such as the Ugi
reactionꢀ4 component,(6a) Ugiꢀtetrazole,(6b) Ugiꢀβꢀlactam,(6c) Ugiꢀ
Smiles,(6d) Ugiꢀ4 componentꢀ5 centers(6e) and Passeriniꢀ3
component(6f) (fig. 2). Various aldehydes, amines and acids were
used in order to illustrate the diversity of these drugꢀlike compounds,
which could be obtained assembling the indole moiety.
H
3ꢀClꢀC6H4
F
8
9
10
Cl
H
OMe
Br
H
CN
pꢀnitroꢀphenol
pꢀnitroꢀphenol
pꢀnitroꢀphenol
6a (35)
6b (41)
6c (45)
In addition, an Ugiꢀ4C reaction was performed with three different
indole moieties(12), giving access to a trisꢀindole alkaloidꢀlike
structure which would otherwise have been very difficult to
synthesize in a linear approach (scheme 3). Thus unprotected
tryptamine, protected indole aldehyde 7, the protected indole
isocyanide 8 (for synthesis see supporting information) and formic
acid combined to give the trisꢀindole compound 9 in 70% yield.
Fig 2. MultiꢀComponent Reactions of the novel isocyanide
Both Ugiꢀ4C and Ugiꢀtetrazole reactions gave very good results
using electron withdrawing and donating groups on the amine and
aldehyde components (table 1). Scaffolds like 4 illustrate the
flexibility and complexity that in a oneꢀstep can be achieved,
whereas compounds 5 combine two of the most bioactive rings such
as the indole and tetrazole ring. UgiꢀSmiles reactions (6a-c) gave
lower yields but still demonstrate the versatility of the reaction.
Scheme 3. Synthesis of a trisꢀindole alkaloidꢀlike compound
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isocyanomethylindole will find application in natural product
synthesis.
Furthermore, amino acids were thought to be useful for assembling
with the new isocyanide. To investigate that, Ugi 4Cꢀ5 center and
Ugiꢀlactam reactions were performed with βꢀamino acids (10a-c)
and αꢀamino acids (11a-c) respectively giving good yields. For
compounds (11a-b) diastereoselectivities of 1:2 were observed. Both
the complexity that these kinds of reactions ensure and the formation
of bioactive rings such as a lactam are of great importance (table 2).
Finally, a Passerini reaction (12a-c), performed with different
substituents on the aldehyde and acid moiety, giving access to more
scaffolds (table 2).
Acknowledgements
This work was supported partially by grants from NIH
(1R21GM087617ꢀ01A1, 1P41GM094055ꢀ01, and 1R01GM09708201).
Notes and references
a Constantinos G. Neochoritis, Alexander Dömling*
Department of Drug Design, University of Groningen, A. Deusinglaan 1,
9713 AV Groningen, The Netherlands, a.s.s.domling@rug.nl
Table 2. Survey on reactions Ugi 4Cꢀ5CR, Ugiꢀlactam and Passerini
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A novel indole isocyanide was synthesized, through the
accelerated LeuckartꢀWallach reaction, which was subsequently
employed in the most important multiꢀcomponent reactions
leading to possible bioactive compounds. The new derivatives
expand the indole chemical space, combining both the
necessary complexity and diversity. The examples presented
herein illustrate the generality and the broad scope of using this
isocyanide in MCR chemistry. The 3ꢀaminomethyindole
fragment is abundant in multiple natural products and thus it
can be predicted that MCRs involving our new 3ꢀ
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