Amphoteric 2-(sulfonylamino)benzaldehydes, secondary amines and isocyanides in the multicomponent synthesis of elusive N-alkyl-2,3-diaminoindoles

Article abstract of DOI:10.1016/j.tetlet.2017.09.076

A novel interrupted Ugi reaction between ortho-sulfonylaminated aryl aldehydes, secondary amines, and isocyanides affords in good to high yields N-alkyl-2,3-diaminoindoles, providing access to a so far unexplored area of the indole chemical space. With only one single chemical operation, this novel reaction affords a broad gamma of substituted 2,3-diaminoindoles with five points of diversity. The success of this novel multicomponent transformation lies in presence of the amphoteric sulfonylamino group, which sequentially acts as a Br?nsted acids and as a nucleophile the lack of need for additional catalysts and the high atom economy, with the loss of only one molecule of water, renders this approach a very effective one.

Full text of DOI:10.1016/j.tetlet.2017.09.076

Accepted Manuscript
Amphoteric 2-(Sulfonylamino)Benzaldehydes, Secondary Amines and Isocya-
nides in the Multicomponent Synthesis of Elusive N-Alkyl-2,3-diaminoindoles.
Mariateresa Giustiniano, Sveva Pelliccia, Luca Sangaletti, Fiorella Meneghetti,
Jussara Amato, Ettore Novellino, Gian Cesare Tron
PII:
S0040-4039(17)31226-1
https://doi.org/10.1016/j.tetlet.2017.09.076
TETL 49346
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
29 August 2017
21 September 2017
25 September 2017
Please cite this article as: Giustiniano, M., Pelliccia, S., Sangaletti, L., Meneghetti, F., Amato, J., Novellino, E.,
Tron, G.C., Amphoteric 2-(Sulfonylamino)Benzaldehydes, Secondary Amines and Isocyanides in the
Multicomponent Synthesis of Elusive N-Alkyl-2,3-diaminoindoles., Tetrahedron Letters (2017), doi: https://
doi.org/10.1016/j.tetlet.2017.09.076
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Tetrahedron Letters
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Amphoteric 2-(Sulfonylamino)Benzaldehydes, Secondary Amines and
Isocyanides in the Multicomponent Synthesis of Elusive N-Alkyl-2,3-
diaminoindoles.
Mariateresa Giustiniano, *a,d Sveva Pelliccia,a,d Luca Sangaletti,b Fiorella Meneghetti,c Jussara Amato,a
Ettore Novellino,a and Gian Cesare Tron*b
a Dipartimento di Farmacia, Università di Napoli “Federico II”, via D. Montesano 49, 80131, Napoli, Italy.
b Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy.
c Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
d These authors contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel interrupted Ugi reaction between ortho-sulfonylaminated aryl aldehydes, secondary
amines, and isocyanides affords in good to high yields N-alkyl-2,3-diaminoindoles, providing
access to a so far unexplored area of the indole chemical space. With only one single chemical
operation, this novel reaction affords a broad gamma of substituted 2,3-diaminoindoles with five
points of diversity. The success of this novel multicomponent transformation lies in presence of
the amphoteric sulfonylamino group, which sequentially acts as a Brønsted acids and as a
nucleophile the lack of need for additional catalysts and the high atom economy, with the loss of
only one molecule of water, renders this approach a very effective one.
Received in revised form
Accepted
Available online
Keywords:
Multicomponent reactions
2-(sulfonylamino)benzaldehydes
Isocyanides
2009 Elsevier Ltd. All rights reserved.
Secondary Amines
N-alkyl 2,3-Diaminoindoles.
Nowadays, multicomponent reactions (MCRs)1 are considered
precious transformations both for organic and medicinal chemists
thanks to their intrinsic convergent nature, atom economy and
efficiency. MCRs telescope the access to complex biologically
active scaffolds, as exemplified by the four-component Ugi
reaction.2 This reaction, discovered in 1959, has served as a basis
for the development of related transformations that have
substantially expanded its scope and the area of the chemical
space it can target.3 The discovery of novel Ugi-related reactions
capitalizes on the use of functionalized starting reagents. These
can intercept intramolecularly the ephemeral nitrilium ion
generated by the reaction between an aldehyde, an amine and an
isocyanide, eluding termination by carboxylate attack.
Alternatively, functionalized reagents can exploit the carbenic
nature of isocyanide and engage it in formal [4+1]
cycloadditions.4 In all these cases, the net result is the switch
from a dipeptide structure to a drug-like heterocycle compound
(Figure 1).
Figure 1. Ugi reaction vs interrupted Ugi reactions.
These transformations are referred to as interrupted Ugi
reactions, a name coined by Sorensen in 2009.5
The final formation of a heterocycle replaces the amide-
generating Mumm rearrangement of the classic Ugi reaction as a
driving force for the reaction.

2
Although the first example of an intramolecular interception
of a nitrilium ion can be traced back to 1969,6 the most famous
and versatile example of an Ugi interrupted reaction remains the
Groebke–Blackburn–Bienaymé multicomponent reaction, where
a 2-aminopyridine reacts with an isocyanide and an aldehyde in
the presence of a catalytic amount of protic or Lewis acids to
give fused 3-aminoimidazoles.7 Subsequently, other
transformations, which can be considered interrupted Ugi
reactions, emerged from the literature.8 In our opinion, however,
this attractive subclass of Ugi isocyanide chemistry is still an
underexplored territory, which can still lead to the identification
of novel multicomponent transformations. For this reason, we
became interested in the study of novel interrupted Ugi reactions,
and, in particular, we envisioned the possibility to synthesize
elusive N-alkyl-2,3-diaminoindoles,9 starting from an amphoteric
sulfonyl amino arylaldehyde, a secondary amine, and an
isocyanide according to Scheme 1. In this case, the carbonyl
component bears an aromatic electrophilic aldehyde and a
sulfonamide at the ortho position, which could act as internal
nucleophile, intercepting the nitrilium ion to give 2,3-dialkyl
diaminoindoles. With this in mind, when we tested this reaction
using 2-[(4-tolylsulfonyl)amino]benzaldehyde 1, tert-butyl
isocyanide 2 and diethylamine 3 mixed in dry dichloromethane at
room temperature overnight, we were pleased to observe the
formation of a single new spot, which revealed to be the desired
N-alkyl-2,3-diaminoindoles 4, obtained in 85 % yield.
Figure 2. Building blocks used.
Scheme 1. Three-component-four-center reaction between 2-
tolylsulfonylamino benzaldeyde, tert-butylisocyanide and
diethylamine.
It is important to note that despite the massive presence of
indole nucleus in biologically active compounds, 2,3-
diaminoindoles derivatives are still a rare class of compounds,
probably due to the lack of a straightforward synthetic
approach.10
Taking advantage of this novel interrupted Ugi
multicomponent reaction, a library of N-alkyl-2,3-diaminoindoles
has been prepared with the aim to investigate scope and
generality. Different ortho-sulfonylaminated aryl aldehydes (1, 5-
12) were readily prepared by the corresponding commercially
available anthranilic acids in three easy steps following literature
reported procedures.11 Distinctive isocyanides (2, 13-19) and
secondary amines (3, 20-24) were also chosen in order to give a
clear picture of this novel multicomponent transformation
(Figure 2).
Figure 3. Synthesized compounds.

aminobenzaldeydes with the 2-aminobenzaldeyde we observed
the formation of a plethora of spots even with secondary
amines.13 This means that the sulfonamide moiety is the key
group for the success of this multicomponent transformation
driving the reaction toward the formation of a single final
product. Indeed, its weak acidity can still favor the protonation of
the hemiaminal, facilitating the formation of the iminium ion
with the simultaneous formation of the sulfonamide anion,
nucleophilic enough to intercept the transient nitrilium ion. We
therefore propose the following mechanism: the oxo- function A
and the amine B condense to form the hemiaminal form C, which
loses a molecule of water to form the iminium ion D with the
concomitant formation of the sulfonamide anion. Now, two
different reaction mechanisms are possible: the iminium ion
could be directly attacked by the isocyanide to form a nitrilium
ion E which is in turn attacked by the sulfonamide nitrogen to
give the cyclic intermediate F, which rearranges to form a
substituted 2,3-dialkyl diaminoindole G upon a 1,3-H shift.
Alternatively, the isocyanide carbon could also react according to
its carbenic nature with the enamine tautomer H in a [4+1]
cyclization giving, after a tautomeric shift, the desired N-alkyl-
2,3-diaminoindole (Scheme 2).
Figure 3. Synthesized compounds (continue).
As shown in Figure 3, we synthesized twenty-one (25-44)
variously decorated N-alkyl-2,3-diaminoindoles with a yield
range of 27-92 %. In particular, we observed that the reaction
was complete overnight (ca. 16 h) when either electron
withdrawing substituents or no substituents were present on the
aromatic rings of ortho-sulfonylaminated aryl aldehydes, while in
the presence of electron donating groups the reactions was slower
requiring 48-72h to be completed. Increasing the temperature as
well as changing the solvent was detrimental for the success of
this transformation. Interestingly, when an electron-withdrawing
group was present on the benzenesulfonamide ring (11) the
reaction was very fast (2 h) while, on the contrary, in the
presence of an electron-donating group (12) the reaction was
sluggish requiring again 48-72 h to go to completion. We can
speculate that the change in acidity of the sulfonamide group can
dramatically influence the velocity of formation of the iminium
ion.
N-alkyl-2,3-diaminoindole derivatives appear to be stable on
chromatographic conditions and they can be crystalized in
methanol without sign of decomposition. In Figure 4, we report
the X-ray crystal structure of compound 32 (see supporting
information for a full discussion).
Scheme 2. The proposed reaction mechanism
In conclusion, we reported a novel three component-four-
center reaction which allows, for the first time, the synthesis of
until now elusive N-alkyl-2,3-diaminoindole derivatives where
both amino groups are substituted. The reaction requires ambient
temperature simple mixing equimolar amount of sulfonyl amino
arylaldehyde, a secondary amine, and an isocyanide in
dichloromethane. This newly discovered reaction is in perfect
agreement with the fundamentals of multicomponent reactions,
exhibiting an extraordinary atom economy (only one molecule of
water is lost during the process) and a high bond forming
efficiency, since two new C-N bonds and one C-C bond are
formed in the one-pot process. The sensible choice of the
sulfonamide group gives the right balance between acidity,
needed to promote the formation of the iminium ion, and
nitrogen nucleophilicity, necessary to intercept the nitrilium ion.
We hope that this work can draw new interest towards the
interrupted Ugi reactions, which have the potential to be
powerful tools to gain access to unexplored regions of the
chemical space not easily accessible by the two-component
chemistry.
Figure 4. ORTEP view of 32 and the relative arbitrary atom
numbering scheme (thermal ellipsoids at 40% probability).
Before proposing a mechanism for this reaction, we carried
out some more different experiments. We evaluated whether in
the presence of an aliphatic primary amine (e.g.
phenylethylamine) and an aromatic amine (e.g. aniline) we could
obtain the same results. In this case anyway we were not able to
observe the formation of the desired products, but only the
formation of the imine intermediates, which were isolated in 75
and 69 % yield, respectively. It is possible to rationalize these
results by considering the lesser acidity of N-sulfonyl-2-
aminobenzaldeydes compared with that of a carboxylic acid (pKa
7.9 vs 5.0),12 which cannot protonate and activate the imino
group. On the other hand, when secondary amines are used, the
subsequent iminium ion is already a much better electrophile
with respect to the imine formed by primary aliphatic amines and
anilines. Additionally, when we replaced the N-sulfonyl-2-
Acknowledgments
Financial support from University of Naples Federico II and
University of Piemonte Orientale, Novara, is acknowledged. M.
G. acknowledges AIRC (MFAG 18793).

4
References and notes
Supplementary Material
Experimental procedure, spectroscopic data, copies of 1H and 13
spectra (PDF).
C
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.

Leave this area blank for abstract info.
Amphoteric 2-(Sulfonylamino)Benzaldehydes,
Secondary Amines and Isocyanides in the
Multicomponent Synthesis of Elusive N-alkyl
2,3-Diaminoindoles.
Mariateresa Giustiniano,a*† Sveva Pelliccia,a† Luca Sangaletti,b Fiorella Meneghetti,c Jussara Amato,a Ettore
Novellino,a and Gian Cesare Tronb*

6
-
-
One pot synthesis of N-alkyl 2,3-diaminoindoles
The sulphonamide group intercepts the nascent
nitrilium ion
-
No transition metals required