Squaric acid is a suitable building-block in 4C-Ugi reaction: Access to original bivalent compounds

Article abstract of DOI:10.1016/j.tetlet.2011.11.077

The 4C-Ugi reaction requires an acidic component as one of the building-blocks. We report here the first use of squaric acid for this reaction to access original symmetrical compounds. The scope and conditions of the reaction were explored.

Full text of DOI:10.1016/j.tetlet.2011.11.077

Tetrahedron Letters 53 (2012) 458–461
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Squaric acid is a suitable building-block in 4C-Ugi reaction: access
to original bivalent compounds
Karen Aknin, Marion Gauriot, Jane Totobenazara, Noemie Deguine, Rebecca Deprez-Poulain, Benoit Deprez,
⇑
Julie Charton
INSERM U761 Biostructures and Drug Discovery, Lille F-59000, France
Faculté de Pharmacie, Université Lille Nord de France, Lille F-59000, France
Institut Pasteur de Lille, IFR 142, Lille F-59021, France
PRIM, Lille F-59000, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The 4C-Ugi reaction requires an acidic component as one of the building-blocks. We report here the first
use of squaric acid for this reaction to access original symmetrical compounds. The scope and conditions
of the reaction were explored.
Received 18 October 2011
Revised 7 November 2011
Accepted 15 November 2011
Available online 22 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Squaric acid
4C-Ugi reaction
Bivalent compounds
During the past decade, isocyanide based multicomponent reac-
tions(IMCR)gainedsignificantinterestwithinthescientificcommu-
nity as an efficient, convenient, time-saving, and atom-economical
approach to rapidly generate chemical diversity. IMCRs are easily
performed using readily available starting materials and tolerate a
variety range of functional groups. Variations and subsequent trans-
formations provide access to a fairly large number of unique struc-
tures that would otherwise require lengthy preparations.1,2
The Ugi reaction usually refers to the reaction between an amine
(usually a primary amine; less often ammonia, or a secondary
amine), a carbonyl compound (aldehyde or ketone), an isocyanide,
and a carboxylic acid.3 Carboxylic surrogates like carbonic4 or thio-
carbonic acids, thiocarboxylic acids,5 hydrazoic acid,6 isocyanic7 and
isothiocyanic acids, phenol,8 and thiophenol were also successfully
used in Ugi-type reaction.9 Squaric acid is a diacid that exhibits two
acidic hydroxyl groups with pKa values of 0.54 and 3.48, respec-
tively, as well as two highly polarized carbonyl groups.10 This struc-
ture provides not only unique versatile proton acceptor carbonyl
groups11 but also binding sites to metal ions.12 Since the work of Co-
hen13 in 1959, many examples of the use of squaric template (Fig. 1)
have been described particularly in the fields of bioorganic and
medicinal chemistry.14 Medicinal chemists use squaric template
as either a linker, or a precursor of acidic or metal binding func-
tions.15 We have ourselves developed rapid parallel synthesis proce-
dures to access bioactive squaramides, inhibitors of aggrecanase.16
Other teams have disclosed squaramides with various biological
activities such as kinase inhibition,17 CXCR2 or vitronectin receptor
modulation,18 potassium channel blockade.19
Interestingly, squaric acid could also be useful for the synthesis of
dimeric bioactive compounds. The design of symmetrical bivalent
ligands20 has already been successfully applied to various pharma-
cological targets such as GPCRs, channels, and transporters.21
Herein we report the first use of squaric acid as the acid compo-
nent in the 4C-Ugi reaction. This allows the rapid access to a variety
of original symmetrical squaramides in moderate to good yields.
The reaction is a double 4C-Ugi reaction that uses the two acidic
functions of squaric acid to give squaramides of general formula A
(Fig. 2) as a mixture of four diastereoisomers. A proposed mecha-
nism of this reaction, which may be considered as a Ugi-Smiles
extension,22 is presented in Scheme 1.
The 4C-Ugi reaction with squaric acid was examined with benzy-
lisocyanide, p-toluidine, and p-chlorobenzaldehyde (Table 1) to opti-
mize reaction conditions. Methanol and isopropanol, that are
classical for Ugi reaction, were selected as solvents. We varied both
concentrations and temperature. Amine, aldehyde, isocyanide, and
squaric acidwere used in1:1:1:0.5proportions. A one-potsequential
procedure was used. First, pre-formation of theimine was performed
by mixing the aniline and the aldehyde for 45 min. Then squaric acid
was added to form the iminium intermediate. After 10 min, isocya-
nide wasfinallyadded. Themixture wasreactedovernight. Theprod-
uct was obtained by a simple work-up as it precipitates. Under these
reaction conditions, the synthesized dimer 1 is a mixture of the meso
isomer1aandtheracemate1b(Table 1). Theexistence ofconformers
⇑
Corresponding author. Tel.: +33 3 20964928; fax: +33 3 20964709.
E-mail address: julie.charton@univ-lille2.fr (J. Charton).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.077

K. Aknin et al. / Tetrahedron Letters 53 (2012) 458–461
459
O
O
O
O
O
O
O
O
O
N
O
R
R
R''
R
HO
OH RO
OR'
N
OH
N
N
NH2
R'
squaramic acid
R' R'''
R'
squaramide
squaric acid
squarate
(squaryl diamide)
Figure 1. Squaric-based templates.
O
R3
O
R4
R3
O
O
R4
O
O
H
N
R1
H
N
N
R2
N
R2
N+
C
NH2
+
+
+
R1
R3
R1
R2
R4
HO
OH
O
(RS, meso) + (RR/SS)
Figure 2. Double 4C-Ugi.
O
O
HO
OH
O
O
R3
R3
R3
pKa1 = 0.54
pKa2 = 3.48
NH2
R2
N+
+
+
H
H
H
N
H
O
HO
O
R2
R2
R1 N+
C
R3
R1
O
O
Mumm-type
rearrangement
H
N
N
R3
O
O
O
R3
H
R1
R1
N+
R2
N
O
N
R2
NH
R2
HO
OH
HO
O
O
pKa =2-3
O
O
O
N
O
N
R3
R3
N+
R1
O
O
R3
H
R1
R3
H
N
NH
R2
N
N
R2
H
N
R1
O
R2
R2
O
R1
O
Scheme 1. Proposed mechanism of the double 4C-Ugi reaction using squaric acid.
was evidenced by LC–MS-TOF-MS and NMR. In solution we observed
the splitting and broadening of several resonances in the 1H NMR
spectraatroomtemperature. Ithasalreadybeenreportedthatthere-
stricted rotation around the C–N bonds of squaramides lead to a mix-
ture of anti/syn conformers.23,24
mediate is critical.26 Less basic amines like anilines gave the
expected compounds in better yields than more basic aliphatic
amines (Table 2). Already observed with carboxylic acids, this
behavior is even more pronounced with the more acidic squaric
acid (pKa values of 0.54 and 3.48, significantly lower than the aver-
age carboxylic acid). The high acidity of squaric acid is favorable for
the reaction with anilines and aromatic aldehydes for which the
very low basicity of the Schiff base formed is highly detrimental
for the obtention of the iminium ion.
The lower yields obtained with aliphatic amines could be due to
incomplete formation of the imine. Indeed, the equilibrium amine/
imine could be displaced in favor of the amine by protonation of
the latter by squaric acid. Such equilibrium displacement may
not be encountered for anilines since (1) the corresponding imines
are conjugated and (2) anilines are less basic.27,28
The best yield was obtained using methanol as the solvent, at
room temperature, with a squaric acid concentration of 0.1 M (con-
centration corresponding to the measured solubility of squaric acid
in methanol). When the reaction was carried out in more concen-
trated (0.5 M) or more diluted (0.05 M) medium, yield decreased.
Same results were obtained at higher temperature (50 °C) or when
using isopropanol as the solvent. We next applied our best condi-
tions (Table 1, entry 1) to explore the scope of the reaction (Table 2).
The reaction tolerated aromatic, benzyl-, and aliphatic isocya-
nides providing the desired products in moderate to good yields
(2–5, 55–73%). Influence of the amine component was assessed
using aliphatic and aromatic amines (2, 11–15, 25–73%). Aliphatic
amines like butylamine and cyclopropanemethylamine provided
the desired compounds in lower yields of 25% (14) and 42% (15),
respectively. In this reaction, the formation of the iminium inter-
For the carbonyl component, the scope is as expected for a ‘clas-
sical’ 4C-Ugi reaction. Aliphatic or aromatic aldehydes give the de-
sired compounds in good yields (Table 2). Aliphatic ketones are
slightly less reactive and arylketone, described as the least reactive
carbonyl component for 4C-Ugi reaction, did not yield compound 7.

460
K. Aknin et al. / Tetrahedron Letters 53 (2012) 458–461
Table 1
Optimization of the synthesis of 1a and 1b
Cl
Cl
O
H
C
NH2
O
O
N+
O
O
H
N
H
N
+
+
+
N
N
HO
OH
O
O
Cl
1a (meso) + 1b (SS + RR)
Entry
Solventa
T (°C)
[squaric acid] (M)
Yieldb (%)
1
2
3
4
5
6
MeOH
MeOH
MeOH
MeOH
iPrOH
iPrOH
20
20
20
50
20
50
0.1
0.05
0.5
0.1
0.1
0.1
69
42
44
33
21
40
a
Measured solubility of squaric acid in MeOH: 0.09 M or in iPrOH: 0.02 M.
Yield of the mixture of diastereoisomers.
b
Table 2
Synthesis of symmetrical squaramides 1–15 via 4C-Ugi reaction
O
N
O
R3
R4
R3
R4
O
H
N
R1
H
N
N
R2
R1
R2
O
Compd
R1-
R2-
R3-
R4-
H-
Yielda
69
Cl
1
O2N
2
3
4
5
H-
H-
H-
H-
73
55
68
58
O2N
O2N
O2N
F
O
6
7
H-
45
0
Me-
H-
8
60b
4025
32
9
10
H-
H-

K. Aknin et al. / Tetrahedron Letters 53 (2012) 458–461
461
Table 2 (continued)
Compd
R1-
R2-
R3-
R4-
H-
Yielda
O2N
O
11
12
13
14
54
64
55
25
42
O2N
O2N
O2N
O2N
Cl
H-
H-
H-
H-
15
a
Yield of diastereoisomer mixture.
Purified by flash chromatography.
b
Bramlett, D. R.; Miller, T. L.; Tasse, R. P.; Zaleska, M. M.; Moyer, J. A. J. Med.
Chem. 1998, 41, 236; (f) Kinney, W. A.; Lee, N. E.; Garrison, D. T.; Podlesny, E. J.,
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Chem. 1992, 35, 4720.
In conclusion, we report the first use of squaric acid as a compo-
nent of the 4C-Ugi reaction. We describe a new, simple, and effi-
cient application to the one-pot direct access to original squaric-
based symmetrical compounds using mild reaction conditions
and a straightforward purification process. The access to squaramic
acids via a ‘mono-4C-Ugi’ reaction is currently under investigation
in our laboratory.
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Acknowledgments
We are grateful to the institutions that support our laboratory
(Inserm, Université de Lille2 and Institut Pasteur de Lille, Région
Nord-Pas de Calais, EC).
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.077.
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24. In our case, raising the temperature (up to 80 °C) in the NMR experiments did
not allow coalescence of the signals.
25. Typical procedure for the preparation of symmetrical squaramides (9 as example):
p-toluidine (2 equiv) is added to cyclohexanone (2 equiv) in (1.5 mL) MeOH.
After stirring 45 min at room temperature, squaric acid (0.25 mmol, 1 equiv) in
solution in MeOH (1 mL) is added and the mixture is stirred 5 min. Benzyl
isocyanide (2 equiv) is finally added and the reaction is stirred overnight at
room temperature. The precipitate is filtrated and washed with diethyl ether to
give the desired compound 9 as a white solid (72 mg, 40%). 1H NMR (300 MHz,
DMSO-d6) d 8.62 (br s, 2H, NH), 7.22–7.32 (m, 10H, Har), 7.00–7.08 (m, 8H,
Har), 4.24 (d, J = 5.4 Hz, 4H, 2CH2), 2.29 (br m, 10H, 2 CH3 + 2CH2), 1.85 (br m,
4H, 2CH2), 1.28–1.39 (m, 12H, 6CH2). trLC–MS = 3.70 min. 13C NMR (75 MHz,
DMSO-d6) d 180.9, 171.1, 139.7, 137.8, 136.6, 129.1, 128.6, 127.7, 127.2, 69.9,
43.4, 34.3, 24.4, 22.8, 21.2. Purity 97%. MS (ESI+) m/z = 723 [M+H]+. HRMS:
calcd for C46H50N4O4, (MH+) 723.3910, found 723.3915.
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hydrolysis when adding squaric acid. Unfortunately, the yield could not be
improved by this way.
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