Synthesis of unsymmetrical mono- and bissquaramides with (3-aminopropyl)triethoxysilane (APTES) or dopamine moieties

Article abstract of DOI:10.1055/s-0032-1317546

A simple and efficient synthesis of unsymmetrical mono- and bissquaramides derivatives and their corresponding methyltrialkyl ammonium salts was achieved in moderate yields from diethyl squarate via sequencial reactions. Copyright

Full text of DOI:10.1055/s-0032-1317546

2830▌
LETTER
lSetyternthesis of Unsymmetrical Mono- and Bissquaramides with (3-Amino-
propyl)triethoxysilane (APTES) or Dopamine Moieties
Unsymmetrical Mono- and Bissquaramides
Kenia A. López, M. Nieves Piña, Jeroni Morey*
Department of Chemistry, University of the Balearic Islands, Crta. de Valldemossa Km 7.5, 07122 Palma de Mallorca, Balearic Islands, Spain
Fax +34971173426; E-mail: jeroni.morey@uib.es
Received: 08.10.2012; Accepted: 17.10.2012
agents because of their bifunctional nature and the nucleo-
Abstract: A simple and efficient synthesis of unsymmetrical mo-
philicity of the NH2 group which will be beneficial for the
no- and bissquaramides derivatives and their corresponding methyl-
coupling with the squarate molecule. On the other hand,
trialkyl ammonium salts was achieved in moderate yields from
the most widely used substrates for the synthesis of mod-
ular squaramides are mono- or dialkoxysquarate [dimeth-
yl (1a), diethyl (1b), or diisopropyl squarate (1c)]
derivatives by amine condensation (Scheme 1). Usually
this reaction is carried out in organic media or buffer
aqueous solution, in high yield at room temperature for
several hours with a slight excess of the amine, to generate
the corresponding symmetrical squaramide 3 (R1 = R2).
diethyl squarate via sequencial reactions.
Key words: squaramides, bissquaramides, modular synthesis, am-
monium iodide salt, receptors
Squaric acid (3,4-dihydroxi-3-cyclobutene-1,2-dione),
also known as ‘quadric acid’, and its derivatives have at-
tracted considerable attention since the parent compound
was first reported in 1959 by Cohen and co-workers.1 A
squaric acid derivative, the squaramide, has been recog-
nized to offer the potential to act as a hydrogen-bond do-
nor, hydrogen-bond acceptor, or both hydrogen-bond
donor–acceptor. The ability of squaramides to act as hy-
drogen-bond donors to anionic species has been also in-
vestigated.2 In this way, some abiotic squaramide
receptors have been reported to successfully bind carbox-
ylate anions working in water, a highly competitive medi-
um for hydrogen bonding. In spite of the large capacity
that squaramides have to behave as hydrogen-bond do-
nors and acceptors, these binding units have not been used
in conjunction with magnetic iron nanoparticles as new
hybrid nanomaterials with potential to be employed for
establishing intermolecular noncovalent forces, for exam-
ple, in supramolecular chemistry or for bioconjugation.
For us, squaramide tetraalkylammonium salts are very im-
portant binding units due to their high ability to favorably
interact with several oxoanions as nitrate, sulfate,3 and
carboxylates, for example, as acetate, benzoate, oxalate,
tartrate, trimesoate, tricarballate, citrate, and folates.4
O
O
O
O
O
O
R3NH2
R2NH2
R1O
OR1
R2HN
OR1
R2HN
NHR3
1
2
3
1a R1 = Me
1b R1 = Et
1c R1 = i-Pr
R2 = alkyl, aryl
R3 = alkyl, aryl
Scheme 1 General route of the synthesis of squaramides
Although it is possible to synthesize unsymmetrical squa-
ramides 2 when the reaction is carried out with one equiv-
alent of a primary or secondary amine, symmetrical
squaramides 3 may also be produced. To minimize this
undesired side reaction, the reaction is usually carried out
in diethyl ether, as in this medium, the formation of dis-
quaramides is disfavored, due to the precipitation of the
mixed squaramate 2. Accordingly, for the introduction of
a second different alkylamine or arylamine, it suffices to
dissolve the mixed squaramate 2 in an alcoholic solvent,
typically ethanol or methanol, and to add another equiva-
lent of a different alkylamine or arylamine. Other solvents
such as dichloromethane, chloroform, dimethyl sulfoxide,
or even aqueous basic buffer solution, can be used.
The aim of this communication is to present the prepara-
tion, via modular synthesis under mild experimental con-
ditions, of several unsymmetrical mono- and
bissquaramides with dopamine or triethoxysilane amine
ready to be coupled to iron nanoparticles.
Scheme 2 depicts the preparation of simple squaramides 5
and 7 with APTES moieties. Our synthetic plan starting
from the parent compound squaramide 4 readily provides
the desired products from the condensation of the
diethoxysquarate 1b with the N,N-dimethyl-1,3-diamino-
propane in diethyl ether in good yield.6 The introduction
of this amine compound provides an excellent binding
unit, and more specifically the corresponding trimethylal-
kyl ammonium iodide salt.
Dopamine (3,4-dihydroxyphenylethylamine) and (3-ami-
nopropyl)triethoxysilane (APTES) are the linkers most
frequently used to tie iron nanoparticles to another com-
pound through the Fe–O bond. It has been demonstrated5
that chatecols form strong bonds with metal oxide
nanoparticles. Aminosilanes are widely used as coupling
SYNLETT 2012, 23, 2830–2834
Advanced online publication: 13.11.2012
The preparation of the unsymmetrical ethoxysilane
squaramide 5 is readily achieved by combination of
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317546; Art ID: ST-2012-D0862-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Unsymmetrical Mono- and Bissquaramides
2831
O
O
squaramide 4 with the corresponding commercially pri-
mary amine, APTES. To avoid hydrolysis7 of the alkyl-
triethoxysilane group, we preferably use anhydrous
ethanol as solvent as we observed exchange of ethoxy
groups, ethoxy for hydroxy, under standard conditions in-
volving extended periods of reaction, typically 12 hours,
at a high pH value.
O
O
i
N
N
N
EtO
N
N
H
H
H
4
Si(OEt)3
5
ii
The unsymmetrical squaramide 8 was obtained by con-
densation of squaramide 4 with dopamine in moderate
yield (Scheme 3). To minimize the ready but undesirable
formation of the dopaquinone (DOQ),8 an excess of solid
sodium dithionite (1.5 equiv) was added9 to prevent the
oxidation of the catechol moiety of the dopamine. To gen-
erate the amine from the commercially dopamine hydro-
chloride salt, an excess of solid of sodium carbonate (4
equiv) was added, and the reaction mixture was protected
from air and light, maintaining the experimental assembly
under an argon atmosphere in the dark.
O
O
O
O
iii
I
N
H
N
H
N
EtO
N
N
I
H
6
Si(OEt)3
7
Scheme 2 Synthesis of unsymmetrical aliphatic monosquaramides 5
and 7. Reagents and conditions: i) APTES, EtOH, r.t., 56%; ii) MeI,
acetone, DMF, 90 °C, 80%; iii) APTES, EtOH, r.t., 85%.
O
O
O
O
HO
HO
i
To obtain the unsymmetrical trimethylalkyl ammonium
squaramide iodide salts 710 and 9, the squaramide 6 was
initially formed by methylation of 4 with methyl iodide11
in acetone–DMF. In fact, the preparation of squaramide
ammonium iodide salt 9 from 8 by direct methylation is
also possible, without protecting the aromatic hydroxyl
group, because the pH is not appropriate for the formation
of the dimethoxy ether of the catechol residue of the do-
pamine.
N
H
N
EtO
N
N
H
H
8
4
N
ii
iii
O
O
O
O
HO
HO
iv
The preparation of unsymmetrical bissquaramides can
proceed in two ways. One consists of modifying the pre-
viously synthesized the squaramate–squaramide 10
(Scheme 4). Alternatively, the commercially available di-
ethyl squarate 1b can be used as a starting material, to in-
troduce the different substitution by a sequential modular
synthesis (Scheme 5 and Scheme 6).
N
H
N
EtO
N
N
I
H
H
9
6
N
I
Scheme 3 Synthesis of unsymmetrical aliphatic monosquaramides 8
and 9. Reagents and conditions: i) dopamine, EtOH, Na2CO3,
Na2S2O4, pH 7, r.t., 40%; ii) MeI, acetone, DMF, 90 °C, 80%; iii)
MeI, acetone, DMF, 90 °C, 50%; iv) dopamine, EtOH, Na2CO3,
Na2S2O4, pH 7, r.t., 50%.
Some time ago, we reported the preparation of mixed
bissquaramate 10.12 From this compound the bissqua-
ramides 11 and 14 can be obtained by two different routes
O
O
O
O
O
O
O
O
I
ii
N
N
N
H
N
N
H
N
N
N
H
N
N
H
H
H
H
H
N
11
N
I
Si(OEt)3
O
Si(OEt)3
13
O
O
O
i
O
N
H
N
H
N
N
H
iii
N
10
O
O
O
O
O
O
O
O
I
iv
N
N
N
N
N
H
N
N
H
N
H
N
N
H
H
H
H
H
14
12
N
N
I
HO
HO
OH
OH
Scheme 4 Synthesis of unsymmetrical aliphatic bissquaramides 11 and 14. Reagents and conditions: i) APTES, EtOH, r.t., 98%; ii) MeI, ace-
tone, DMF, 90 °C; iii) dopamine, EtOH, Na2CO3, Na2S2O4, pH 7, r.t., 70%; iv) MeI, acetone, DMF, 90 °C, 17%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2830–2834

2832
K. A. López et al.
LETTER
(Scheme 4). The synthetic approach and experimental amine in a 2:1 mixture (v/v) of chloroform and
conditions are similar to the ones described above. It is acetonitrile.
worth mentioning that in the methylation of
bissquaramide triethoxysilane 11, the compound obtained
was not the expected squaramide 13. In fact, the best way
to obtain the squaramide functionalized with both groups
The appropriate choice of solvents in this step was impor-
tant, because in this mixture the reactants were soluble
while the reaction products were insoluble, preventing the
undesired formation of the squaramide resulting of the
– triethoxysilane and tetraalkyl ammonium iodide – con-
double attack of the first amine. A 63% yield of material
sists in initially preparing the iodide ammonium tetraalkyl
of adequate purity by 1H NMR spectroscopy was thus ob-
squarate and then adding the (3-aminopropyl)triethoxysi-
tained. Finally, the condensation of 16 with dopamine hy-
drochloride produced the desired bissquaramide 17 in
good yield (77%).
lane as described above for the preparation of squaramide
9 from 8.
Schemes 5 and 6 show the synthetic approaches for the
An analogous process was followed to obtain the unsym-
preparation of bissquaramides 18 and 22, with a long
metrical bissquaramide 22. Just as in the preparation of
chain (6 and 12 methylene groups) from the commercial
bissquaramide 18, the key step was the condensation of
the 3-(dimethylamino)-1-propylamine with bissquara-
mate 19 to obtain unsymmetrical mixed bissquaramate 20.
In this case, the experimental conditions were similar: a
diethoxysquarate 1b13 and 1,6-diaminohexane (1,6-hexa-
methylenediamine) or 1,12-diaminododecane (dodeca-
methylenediamine) in methanol. The key step for the
synthesis of the bissquaramide 1814 (with 6 methylene
groups) is the preparation of the intermediate unsymmet-
O
O
O
O
O
O
O
rical mixed bissquaramate 16. This process is carried out
by condensation of a slight molar excess of the symmetri-
cal bissquaramide 15 with 3-(dimethylamino)-1-propyl-
i
2
N
H
1b
H
N
O
O
O
O
O
O
O
O
O
i
2
19
N
O
H
1b
O
O
O
ii
ii
O
O
NH
O
N
H
N
O
15
O
O
H
H
H
N
N
N
iii
H
N
NH
O
N
O
O
20
OH
16
O
O
HO
O
iii
N
N
H
H
HO
HO
O
O
H
H
N
N
N
N
H
N
H
iv
O
O
OH
H
N
21
iv
N
NH
O
O
HO
HO
O
O
17
N
O
O
N
H
HO
H
N
H
N
H
H
H
N
N
N
I
H
N
N
NH
I
O
O
22
18
O
O
Scheme 6 Synthesis of unsymmetrical bissquaramides 21 and 22. Re-
agents and conditions: i) 1,12-diaminedodecane, MeOH, r.t., 80%; ii)
3-(dimethylamine)-1-propylamine, CHCl3, r.t., 66%; iii) dopamine,
MeOH, Na2CO3, Na2S2O4, pH 7, r.t., 92%; iv) MeI, DMF, 153 °C,
32%.
Scheme 5 Synthesis of unsymmetrical bissquaramides 17 and 18. Re-
agents and conditions: i) 1,6-diaminehexane, EtOH, r.t., 91%; ii) 3-
(dimethylamine)-1-propylamine, CHCl3–MeCN, r.t., 63%; iii) dopa-
mine, MeOH, Na2CO3, Na2S2O4, pH 7, r.t., 77%; iv) MeI, DMF,
153 °C, 30%.
Synlett 2012, 23, 2830–2834
© Georg Thieme Verlag Stuttgart · New York

LETTER
Unsymmetrical Mono- and Bissquaramides
2833
March’s Advanced Organic Chemistry. Reactions,
Mechanisms, and Structure, 5th ed.; John Wiley and Sons:
New York, 2001, 1517–1518.
slight excess of 19 in chloroform. The bissquaramide 21
was synthesized by condensation of 20 and dopamine hy-
drochloride in methanol in good yield (77%) as a white
solid. Finally, the ammonium salts 18 and 22 are obtained
by methylation with methyl iodide in DMF.
(8) Morey, J.; Saá, J. M. Tetrahedron 1993, 49, 105.
(9) Caravajal, G. S.; Leyden, D. E.; Quinting, G. R.; Maciel, G.
E. Anal. Chem. 1988, 60, 1776.
(10) Delgado, E.; Rotger, M. C.; Costa, A.; Piña, M. N.; Jiménez,
H. R.; Alarcón, J.; García-España, G. Chem. Commun. 2012,
48, 2609.
(11) MeI is volatile and reported to be a potent carcinogen.
(12) Piña, M. N.; Rotger, M. C.; Costa, A.; Ballester, P.; Deyà, P.
M. Tetrahedron Lett. 2004, 45, 3749.
(13) Caution: This compound has been found, in some
individuals, to be irritating upon contact with the skin.
(14) Typical Procedure for the Synthesis of Unsymmetrical
Bissquaramide
In summary, unsymmetrical mono- and bissquaramides,
with catechol or ethoxysilane groups, have been synthe-
sized by modular condensation under mild conditions in
moderate to high yields for each synthetic step, with the
added advantage that no chromatography is required. Re-
peated washing of the crude reaction material with organ-
ic solvent yields material of high purity as indicated by
spectroscopic analysis.
Reaction of Diethyl Squarate 1b with 1,6-Diaminehexane
A solution of 1,6-diaminehexane (0.35 g, 3 mmol) in ethanol
(50 mL) was added drop-wise to a stirred solution of 1b (1.5
g, 8.8 mmol) in ethanol (10 mL). The reaction mixture was
stirred overnight at room temperature under an atmosphere
of argon. The resulting white solid 15 was isolated by
centrifugation after decanting the supernatant and washed
with ether (3 × 10 mL) and cold ethanol (3 × 10 mL). Finally,
the precipitate 15 was dried under vacuum; yield: 0.99 g
(91%). m.p. = 163–164 °C. 1H NMR (300 MHz, DMSO-d6)
δ = 8.81 (br, J = 5.6 Hz, NH), 8.60 (br, J = 5.6 Hz, NH), 4.65
(q, J = 7 Hz, 4 H), 3.45 (q, J = 6.1 Hz, 2 H), 3.27 (q, J = 6.6
Hz, 2 H), 1.50 (m, J = 6.3 Hz, 4 H), 1.36 (t, J = 6.3 Hz, 6 H),
1.28 (m, 4 H) ppm. 13C NMR (75 MHz, DMSO-d6): δ =
190.32, 182.99, 177.90, 177.35, 173.58, 173.20, 69.69,
44.63, 44.30, 31.20, 30.69, 26.24, 16.57 ppm. IR (KBr):
3284, 2944, 1804, 1703, 1598, 1517, 1461, 1388, 1340,
1288, 1106, 1043, 1009, 817 cm–1. HRMS–ES(+): m/z calcd
for C18H24N2O6Na: 387.1533; found: 387.1532.
Reaction of 15 with 3-(Dimethylamine)-1-propylamine:
A solution of 3-(dimethylamine)-1-propylamine (115 L,
0.9 mmol) in ethanol (50 mL) was added dropwise to a
stirred solution of 15 (0.5 g, 1.37 mmol) in a mixture of
ethanol (10 mL) and acetonitrile (5 mL). The reaction
mixture was stirred overnight at room temperature under an
atmosphere of argon. After this period, a white precipitated
was collected from the reaction mixture by centrifugation,
washed with ether (3 × 5 mL) and with cold acetonitrile (3 ×
5 mL) to give 16; yield: 24 mg (63%). m.p. = 183–185 °C.
1H NMR (300 MHz, DMSO-d6): δ = 8.79 (br, J = 5.6 Hz, 1
H), 8.58 (br, J = 5.6 Hz, 1 H), 7.32 (br, 1 H), 4.63 (q, J = 6.9
Hz, 2 H), 3.47 (t, J = 6.1 Hz, 4 H), 3.32 (t, J = 6.9 Hz, 2 H),
2.25 (t, J = 6.9 Hz, 2 H), 2.12 (s, 6 H), 1.65 (m, J = 7.5 Hz,
2 H), 1.51 (m, 4 H), 1.36 (t, J = 6.9 Hz, 3 H), 1.27 (m, 4 H)
ppm. 13C NMR (75 MHz, DMSO-d6): δ = 189.85, 182.96,
182.53, 177.51, 176.89, 173.05, 172.67, 168.33, 69.20,
56.40, 45.36, 44.22, 43.88, 43.63, 42.00, 31.19, 30.73,
30.38, 28.85, 25.65, 16.30 ppm. IR (KBr): 3171, 2942, 1803,
1703, 1639, 1584, 1518, 1432, 1357 cm–1. HRMS–ES(+):
m/z calcd for C21H32N4O5Na: 443.2270; found: 443.2276.
Reaction of 16 with Dopamine: To a mixture of sodium
carbonate (400 mg, 3.6 mmol) and sodium dithionite (200
mg, 0.59 mmol) was added methanol (10 mL). A solution of
dopamine hydrochloride (0.17 g, 0.88 mmol) in methanol (5
mL) was added drop-wise to the stirred mixture.
Acknowledgment
This work was supported by Ministerio de Economía y Competiti-
vidad ref. CTQ 2011-27152, Fondos FEDER grant and Conselleria
d’Educació, Cultura i Universitats, Govern de les Illes Balears.
Grant FPI09-45692991-H was selected under an operational pro-
gram co-financed by the European Social Fund.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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Ballester, P.; Costa, A.; Deyà, P. M. Chem. Phys. Lett. 2002,
351, 115. (b) Prohens, R.; Tomas, S.; Morey, J.; Deyà, P. M.;
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P. M.; Ballester, P.; Costa, A. J. Org. Chem. 1996, 61, 9394;
and references therein.. (d) Quiñonero, D.; Frontera, A.;
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P. M. Tetrahedron Lett. 2000, 41, 2001.
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Ballester, P.; Benet-Buchholz, J.; Deyà, P. M.; Costa, A.
Eur. J. Org. Chem. 2008, 1864; and references cited therein..
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Quiñonero, D.; Costa, A.; Ballester, P.; Deyà, P. M.; Anslyn,
E. V. J. Org. Chem. 2006, 71, 7185. (b) Quiñonero, D.;
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Immediately, a solution of 16 (0.25 g, 0.59 mmol) in
methanol (55 mL) and DMSO (10 mL) was added into the
above solution drop-wise too. The pH of the mixture was
adjusted to 7 by adding 2 drops of 1 M NaOH. The reaction
mixture was stirred for 2 h at room temperature under an
atmosphere of argon and in the absence of light. After this
(7) (a) Dopamine, like catecholamines, can be oxidized in the
presence of either oxygen at a high pH value or other
oxidants to the corresponding ortho-quinones, see: Hawley,
M. D.; Tatawawadi, S. V.; Piekarski, S.; Adams, R. N. J. Am.
Chem. Soc. 1967, 89, 447. (b) Smith, M. B.; March, J. In
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2830–2834

2834
K. A. López et al.
LETTER
at 153 °C for 12 h, after which it was cooled to room
period, the solution was filtered and the resulting solution
was stirred overnight in the same conditions. The product
was obtained by evaporating the solvent under vacuum. The
white solid 17 was washed with cold methanol (5 × 10 mL)
and acetone (2 × 10 mL); yield: 0.24 g (77%). m.p. = 243–
245 °C. 1H NMR (300 MHz, DMSO-d6): δ = 8.79 (br, J = 5.6
Hz, 1 H), 8.70 (br, J = 5.6 Hz, 1 H), 7.70 (br, 2 NH), 7.38 (br,
2 NH), 6.64 (dd, J = 8.2, 4.2 Hz, 2 H), 6.48 (d, J = 7.9 Hz, 1
H), 3.49 (t, J = 6.6 Hz, 8 H), 2.67 (t, J = 6.7 Hz, 2 H), 2.49
(t, J = 7.2 Hz, 2 H), 2.26 (s, 6 H), 1.72 (m, J = 5.9 Hz, 2 H),
1.52 (m, 4 H), 1.31 (m, 4 H) ppm. 13C NMR (75 MHz,
DMSO-d6): δ = 183.45, 168.84, 146.10, 144.66, 130.21,
120.36, 117.10, 116.49, 56.11, 45.82, 44.88, 44.06, 37.43,
31.51, 28.66, 26.30 ppm. IR (KBr): 3170, 2931, 1799, 1641,
1582, 1432, 1357 cm–1. MALDI–TOF/TOF(+): m/z calcd for
C27H37N5O6Na: 550.2636; found: 550.2646.
temperature. 30 mL of acetone were added and the solution
was placed in an ice-cold water bath to obtain the product.
The resulting brown solid was isolated by centrifugation
after decanting the supernatant and purified by washing with
cold methanol (3 × 10 mL) and cold acetone (3 × 10 mL).
Finally, the precipitate 18 was dried under vacuum; yield:
0.19 g (30%). m.p.= 229–231 ºC. 1H NMR (300 MHz,
DMSO-d6): δ = 8.77 (br, 1 H), 8.68 (br, 1 H), 7.41 (br, 4 NH),
6.63 (dd, J = 7.9, 3.5 Hz, 2 H), 6.47 (d, J = 8.1 Hz,1 H), 3.64
(t, 2 H), 3.47 (m, 6 H), 3.10 (s, 9 H), 2.65 (t, J = 7.1 Hz, 2 H),
1.97 (m, 1 H), 1.82 (m, 1 H), 1.50 (m, 4 H), 1.30 (m, 4 H)
ppm. 13C NMR (75 MHz, DMSO-d6): δ = 182.21, 167.79,
145.08, 143.74, 129.31, 119.33, 116.06, 115.48, 54.38,
54.19, 44.86, 43.17, 36.41, 30.65, 25.41 ppm. IR (KBr):
3171, 1800, 1645, 1583, 1434, 1384, 1357, 1284, 1116, 617
cm–1. MALDI–TOF/TOF(+): m/z calcd for C28H40N5O6:
542.2973; found: 542.3003.
Reaction of 17 with MeI: Methyl Iodide (0.24 mL, 3.80
mmol) was added via syringe to a solution of 17 (0.50 g, 0.95
mmol) in DMF (7 mL). The mixture was heated under reflux
Synlett 2012, 23, 2830–2834
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