N, N′ -Diarylsquaramides: General, high-yielding synthesis and applications in colorimetric anion sensing

Article abstract of DOI:10.1021/jo100104g

Zinc trifluoromethanesulfonate promotes efficient condensations of anilines with squarate esters, providing access to symmetrical and unsymmetrical squaramides in high yields from readily available starting materials. Efficient access to electron-deficient diaryl squaramides has enabled a systematic investigation of the colorimetric anion-sensing behavior of a p-nitro-substituted squaramide. Its behavior differs in dramatic and unexpected ways from that of structurally similar p-nitroaniline-based ureas, an effect that highlights the remarkable differences in acidity between the squaramide and urea functional groups. Computational studies illustrating the enhanced hydrogen bond donor ability and acidity of squaramides in comparison to ureas are presented.

Full text of DOI:10.1021/jo100104g

pubs.acs.org/joc
N,N0-Diarylsquaramides: General, High-Yielding Synthesis and
Applications in Colorimetric Anion Sensing
Ali Rostami, Alexis Colin, Xiao Yu Li, Michael G. Chudzinski, Alan J. Lough, and
Mark S. Taylor*
Department of Chemistry, Lash Miller Laboratories, University of Toronto 80 St George Street,
Toronto ON M5S 3H6, Canada
mtaylor@chem.utoronto.ca
Received January 21, 2010
Zinc trifluoromethanesulfonate promotes efficient condensations of anilines with squarate esters,
providing access to symmetrical and unsymmetrical squaramides in high yields from readily available
starting materials. Efficient access to electron-deficient diaryl squaramides has enabled a systematic
investigation of the colorimetric anion-sensing behavior of a p-nitro-substituted squaramide. Its
behavior differs in dramatic and unexpected ways from that of structurally similar p-nitroaniline-
based ureas, an effect that highlights the remarkable differences in acidity between the squaramide
and urea functional groups. Computational studies illustrating the enhanced hydrogen bond donor
ability and acidity of squaramides in comparison to ureas are presented.
Introduction
chemistry.4 The strong hydrogen bond donor ability of the
squaramide functional group has been exploited in the design of
anion receptors,5 self-complementary molecular recognition
motifs,6 and catalysts.7 The chemistry presented here represents
a significant improvement in efficiency, operational simplicity,
and generality over existing methods for the preparation of
aniline-derived squaramides. Ready access to this class of
compounds has enabled us to study the properties of diaryls-
quaramides as hydrogen bond donors and as colorimetric
sensors for anions. These properties differ significantly from
those of the well-characterized N,N0-diarylureas, providing
interesting opportunities for incorporation of electron-deficient
In this paper, we describe an efficient method for the pre-
paration of N,N0-diarylsquaramides (3,4-diaminocyclobutene-
1,2-diones) by Lewis acid catalyzed condensation of anilines
and squarate esters. Squaramides find application in numerous
contexts: they have been used as linkers for bioconjugation,1
as precursors to bis-aminoketenes,2 as scaffolds for crystal
engineering,3 and as emerging pharmacophores in medicinal
(1) Owen, R. M.; Carlson, C. B.; Xu, J.; Mowery, P.; Fassella, E.;
Kiessling, L. L. ChemBioChem 2007, 8, 68.
(2) Fu, N.; Allen, A. D.; Kobayashi, S.; Tidwell, T. T.; Vukovic, S.;
Arumugam, S.; Popik, V. V.; Mishima, M. J. Org. Chem. 2007, 72, 1951–
1956.
ꢀ
(5) (a) Prohens, R.; Tomas, S.; Morey, J.; Deya, P. M.; Ballester, P.;
Costa, A. Tetrahedron Lett. 1998, 39, 1063–1066. (b) Prohens, R.; Martorell,
ꢀ
(3) Liu, Y.; Lam, A. H. W.; Fowler, F. W.; Lauher, J. W. Mol. Cryst. Liq.
Cryst. 2002, 389, 39.
~
G.; Ballester, P.; Costa, A. Chem. Commun. 2001, 1456. (c) Pina, M. N.;
(4) (a) Gilbert, A. M.; et al. J. Med. Chem. 2000, 43, 1203–1214.
(b) Valgeirsson, J.; Nielsen, E. Ø.; Peters, D.; Mathiesen, C.; Kristensen,
A. S.; Madsen, U. J. Med. Chem. 2004, 47, 6948–6957. (c) Onaran, M. B.;
Comeau, A. B.; Seto, C. T. J. Org. Chem. 2005, 70, 10792–10802. (d) Merritt,
J. R.; et al. Bioorg. Med. Chem. Lett. 2006, 16, 4107–4110. (e) McCleland, B.
W.; et al. Bioorg. Med. Chem. Lett. 2007, 17, 1713. (f) Palovich, M. R.;
Weinstock, J.; Widdowson, K. L. WO200164208, Sep 7, 2001. (g) Palovich, M.
R.; Widdowson, K. L. WO02067919, Sep 06, 2002. (h) McCleland, B.; Palovich,
M. R.; Widdowson, K. L. WO200257230, Jul 25, 2002. (i) Palovich M. R.;
McCleland, B.; Bi, G.; Werner, M.; Widdowson, K. US 7,008,962, Mar 7, 2006.
(j) Busch-Petersen, J.; Palovich, M. R.; Widdowson, K. L. EP1812008, Aug 01,
2008. (k) Crew, A.; Li, A.-H.; Qiu, L.; Castelhano, A. L.; Dong, H.; Smith, A.;
Tardibono, L.; Zhang, T. WO 2006 034111, Mar 30, 2006. (l) Bluhm, H.; Gege,
Christian,; Hochg€urtel, M.; Taveras, A. WO 2008 109179, Sep 12, 2008.
ꢀ
Rotger, M. C.; Costa, A.; Ballester, P.; Deya, P. M. Tetrahedron Lett. 2004,
45, 3749–3752. (d) Frontera, A.; Morey, J.; Oliver, A.; Pina, M. N.;
~
~
ꢀ
Quinonero, D.; Costa, A.; Ballester, P.; Deya, P. M.; Anslyn, E. V. J. Org.
Chem. 2006, 71, 7185–7195. (e) Ambrosi, G.; Formica, M.; Fusi, V.; Giorgi,
L.; Guerri, A.; Micheloni, M.; Paoli, P.; Pontellini, R.; Rossi, P. Chem.;Eur.
J. 2007, 13, 702–712. (f) Ramalingam, V.; Domaradzki, M. E.; Jang, S.;
Muthyala, R. S. Org. Lett. 2008, 10, 3315–3318.
(6) Davis, A. P.; Draper, S. M.; Dunne, G.; Ashton, P. Chem. Commun.
1999, 2265–2266.
(7) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc.
2008, 130, 14416. (b) Cheon, C. H.; Yamamoto, H. Tetrahedron Lett. 2009,
50, 3555–3558. (c) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int.
Ed. 2009, 49, 153–156.
DOI: 10.1021/jo100104g
r
Published on Web 05/20/2010
J. Org. Chem. 2010, 75, 3983–3992 3983
2010 American Chemical Society

Rostami et al.
JOCArticle
SCHEME 1. Squaraines and Squaramide Monoesters as Byproducts of N,N0-Diarylsquaramide Formation
TABLE 1. Evaluation of Lewis Acid Catalysts for the Condensation of
3,5-Bis(trifluoromethyl)aniline and Diethyl Squarate
squaramides into arrays of colorimetric sensors for anion
identification.
Results and Discussion
A. Development of a Lewis-Acid-Promoted Condensation
of Anilines with Squarate Esters. Our interest in the squar-
amide group is focused on the development of arylamine-
based oligomers and polymers composed of this functional
group for applications in anion sensing and transport. For
this purpose, we required a high-yielding method for the
preparation of N,N0-diarylsquaramides. Condensations of
aliphatic amines with squarate esters are generally straight-
forward: these reactions proceed at room temperature in
high yields, a feature that underlies their application in
complex bioconjugation reactions.1 In contrast, the addi-
tions of anilines to squarates are much more sluggish and
generate squaraine isomers 2 as byproducts under more
forcing conditions (Scheme 1).8 It has been proposed that
the squaraine isomers are the thermodynamically favored
products of these condensation reactions. Previous solu-
tions to this problem have resorted to use of the reactive
electrophile 3,4-dichlorocyclobutene-1,2-dione, a toxic, low-
boiling, and moisture-sensitive species.9 Recently, the copper-
catalyzed arylation of N,N0-dimethylsquaramide has been
achieved, but this method has not been successfully applied to
targets bearing acidic squaramide N-H groups.10
We set out to test whether a suitable Lewis acid catalyst
could promote the condensation of anilines with squarate
esters, suppressing the formation of squaraine byproducts.
To the best of our knowledge, Lewis acid catalysis of
squaramide synthesis has not been investigated to date.
The low-yielding condensation of 4-bromoaniline with a
squarate ester mediated by stoichiometric triethylaluminum,
reported in the patent literature, is the closest existing
precedent. The reaction chosen for evaluation of catalyst
candidates is shown in Table 1. The use of 3,5-bis-trifluoro-
methylaniline as the nucleophile was motivated by two
factors: first, this electron-deficient aniline is a particularly
challenging substrate that represents a stringent test for
catalyst efficiency; second, the trifluoromethyl groups pro-
vided a convenient spectroscopic “handle” for analysis of
product distributions by 19F NMR.
entry
Lewis acid
none
BF3 OEt2
SnCl4
ZnCl2
Sc(OTf)3
Mg(OTf)2
Cu(OTf)2
Zn(OTf)2
1aa (%)
3aa (%)
1
2
3
4
5
6
7
8
10
25
70
10
85
30
75
80
10
10
5
0
0
15
5
0
3
aProduct distribution determined by 19F NMR of the crude reaction
mixture with R,R,R-trifluorotoluene as a quantitative internal standard.
Under the conditions studied, the squaraine isomer 2a was not observed.
showed more promising results; in particular, metal trifluoro-
methanesulfonates (triflates) were efficient promoters of the
desired condensation reaction (entries 5-8).11 Both scandium-
(III) and zinc(II) triflates provided high activity and selectivity,
and the substrate scope was investigated using the latter catalyst.
The optimized reaction conditions provide access to a
variety of sterically and electronically diverse N,N0-diaryl-
squaramides (Table 2). These include electron-deficient tar-
gets (1a, 1g, 1h) and an ortho- substituted variant (1g). The
procedure is operationally simple, and the products are
obtained in high yields by precipitation, without resort to
column chromatography. This zinc-catalyzed condensation
represents a significant improvement over existing protocols
in terms of scope, yield, and convenience and bodes well for
the incorporation of the squaramide group into more com-
plex architectures.
The results of experiments using a variety of Lewis acid
catalysts are summarized in Table 1. The condensation pro-
ceeded sluggishly in the absence of a Lewis acid catalyst (entry 1).
A modest improvement in yield was obtained using boron
trifluoride diethyl etherate as catalyst (entry 2). In contrast,
catalysts capable of two-point binding to dicarbonyl compounds
Squaramides bearing two distinct N-aryl substituents are
accessible through a simple modification of this method
(Table 3). The room-temperature coupling of diethyl squarate
with anilines yields the squaramide monoesters in good yields.
These serve as the substrates for a second condensation under
€
(8) (a) Schmidt, A. H. Synthesis 1980, 961–994. (b) Ehrhardt, H.; Hunig,
S.; Putter, H. Chem. Ber. 1977, 110, 2506–2523. (c) Neuse, E. W.; Green,
€
B. R. Polymer 1974, 15, 339–345.
(9) Lunelli, B. Tetrahedron Lett. 2007, 48, 3595–3597.
(10) Ramalingam, V.; Bhagirath, N.; Muthyala, R. S. J. Org. Chem. 2007,
72, 3976–3979.
(11) Under the optimal conditions, the squaraine isomer 2a was not
produced in detectable amounts. We have verified this point by independent
synthesis and characterization of 2a.
3984 J. Org. Chem. Vol. 75, No. 12, 2010

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TABLE 2. Preparation of Symmetrically Substituted
N,N0-Diarylsquaramides by Zn(OTf)2-Catalyzed Condensation
entry
Ar
product
yielda (%)
1
2
3
4
5
6
7
8
3,5-(CF3)2C6H3
C6H5
4-t-BuC6H4
4-BrC6H4
4-(OCH3)C6H4
3-(OCH3)C6H4
2-(NO2)C6H4
2-pyridyl
1a
1b
1c
1d
1e
1f
80
99
97
99
94
90
98
90
1g
1h
aIsolated yield of pure product on 0.1-0.55 mmol scale.
TABLE 3. Preparation of Unsymmetrically Substituted N,N0-Diaryl
Squaramides by Zn(OTf)2-Catalyzed Condensation
FIGURE 1. Solid-state structures (ORTEP) of the hydrogen-
bonded complexes of 1a and DMSO (top); 1i and DMSO (bottom).
based hydrogen bonds to a common acceptor. The average
Nsquaramide-Osulfoxide distances in this structure are 2.768(4)
A, similar to those observed in cocrystals of N,N -bis-
0
˚
˚
(nitrophenyl)ureas with DMSO (2.854(2) A). Squaramide
1i derived from 2,4-dimethylaniline (Figure 1, bottom) forms
a cocrystal with DMSO, with average Nsquaramide-Osulfoxide
distances of 2.83 A; Etter and co-workers observed that
˚
ortho-substituted ureas generally do not cocrystallize with
hydrogen-bond acceptors.
The latter observation appears to be consistent with previous
experimental and computational studies by Costa and co-
workers suggesting that hydrogen bonds of squaramide donors
with anions are stronger than those of their urea counterparts.14
Our own computational studies on the DMSO complexes of N,
N0-diphenylurea and N,N0-diphenylsquaramide (Figure 2) fol-
low this trend, in agreement with the experimental data: the
computed gas-phase energy of interaction of N,N0-diphenyl-
squaramide with DMSO (B3LYP, 6-311Gþþ**) is 2.3 kcal/
mol greater than that of N,N0-diphenylurea.15 The calculations
predict Nsquaramide-Osulfoxide distances that are slightly shorter
than the predicted Nurea-Osulfoxide distances, (2.951 and 2.957
entry
Ar1
Ar2
product
yielda (%)
1
2
3
4
5
6
7
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
C6H5
4a
4b
4c
4d
4e
4f
91
93
97
99
85
93
91
4-(OCH3)C6H4
2-(OCH3)C6H4
3-(OCH3)C6H4
3,5-(CF3)2C6H3
4-t-BuC6H4
4-(OCH3)C6H4
4g
aIsolated yield of pure product on 0.2-0.4 mmol scale.
the previously developed reaction conditions. Unsymmetrical
N,N0-diarylsquaramides of this type have previously been
synthesized in moderate yields, often relying on chlorocyclo-
butenedione intermediates.
˚
A, respectively). They also predict larger N-H---O angles for
the squaramide-sulfoxide complex than for the urea-squar-
amide complex (165° vs 156°).
B. Hydrogen Bonding of N,N0-Diarylsquaramides with
Neutral Acceptors: Solid-State and Computational Studies.
Ready access to a range of diarylsquaramides, including
electron-deficient derivatives, has enabled us to carry out
detailed studies of their hydrogen bond donor abilities.
Recrystallization of squaramide 1a from methyl sulfoxide
(DMSO) resulted in the formation of a cocrystal in which the
squaramide group donates two hydrogen bonds (Figure 1).
While cocrystals of this type involving ureas have been
studied in depth,12 information regarding the hydrogen-
bonding of squaramides in the solid state is limited.3,13 This
structurally characterized complex provides a unique oppor-
tunity for the direct comparison of urea- and squaramide-
C. Colorimetric Anion Sensing by Nitro-Substituted N,N0-
Diarylsquaramides. The 4-nitroaniline-derived squaramides
4e, 4f, and 4g provide an opportunity to exploit the intra-
molecular charge-transfer properties of the 4-nitroaniline
chromophore for colorimetric anion sensing. The selective
detection and quantification of anions is an area of ongoing
~
(14) (a) Garau, C.; Frontera, A.; Ballester, P.; Quinonero, D.; Costa, A.;
Deya, P. M. Eur. J. Org. Chem. 2005, 179–183. (b) Quinonero, D.; Prohens,
ꢀ
~
ꢀ
R.; Garau, C.; Frontera, A.; Ballester, P.; Costa, A.; Deya, P. M. Chem. Phys.
Lett. 2002, 351, 115–120.
(15) Calculations were carried out using Gaussian 03, Revision C.02:
Frisch, M. J. et al. Gaussian, Inc., Wallingford, CT, 2004. The calculated gas-
phase interaction energies were estimated by subtracting the energy of the
complex from the sum of the energies of the individual fragments, correcting
for vibrational zero-point energies of each species but not for the basis set
superposition error. See the Supporting Information for details, estimates of
the enthalpies and free energies of interaction, and for the full reference to the
Gaussian 03 software package.
~
(12) Etter, M. C.; Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panun-
to, T. W. J. Am. Chem. Soc. 1990, 112, 8415–8426.
(13) The structure of a nitrate-squaramide complex has been reported:
~
Rotger, C.; Soberats, B.; Quinonero, D.; Frontera, A.; Ballester, P.; Benet-
Buchholz, J.; Deya, P. M.; Costa, A. Eur. J. Org. Chem. 2008, 1864–1868.
ꢀ
J. Org. Chem. Vol. 75, No. 12, 2010 3985

Rostami et al.
JOCArticle
FIGURE 2. Structures and DFT-calculated energies of interaction (gas phase, B3LYP/6-311þþG**) of squaramide-DMSO and urea-DM-
SO hydrogen-bonded complexes. See the text and the Supporting Information for details of the calculations.
SCHEME 2. Sequential Deprotonations of Bis(4-nitrophenyl)-
urea as the Basis for Colorimetric Anion Sensing
possible (Scheme 2): formation of a hydrogen-bonded complex
(observed with a variety of anions in acetonitrile solvent);
deprotonation of one urea N-H group (observed with basic
anions such as acetate, hydroxide, and fluoride in DMSO
solvent and with fluoride in acetonitrile solvent); and depro-
tonation of both urea N-H groups (observed with excess
hydroxide or fluoride in DMSO solvent). The behavior of
many of the urea-based receptors that display anion-induced
color changes can likely be understood in the context of such
proton transfer reactions. In contrast, squaramides that show
significant color changes in the presence of anions have not
been reported to date: existing colorimetric and fluorescent
sensors that employ squaramides are based on indicator dis-
placement schemes, in which a squaramide recognition group
is used in cooperation with an added dye indicator.5b,d
We chose to study nitro-substituted squaramide 4e in detail
and to compare its anion-induced colorimetric properties with
those of N,N0-bis(dinitrophenyl)urea.19 Simple UV-vis spec-
tra of 4e in the absence of anions suggested immediately that its
properties differ significantly from those of electron-deficient
diarylureas: the absorption spectrum of 4e in DMSO is red-
shifted by more than 100 nm relative to its spectrum in
acetonitrile (Figure 3). A conventional solvatochromic effect
seemed unlikely, as bis(4-nitrophenyl)urea is reported to show
comparatively minor changes in its absorption spectrum indu-
ced by changes in solvent polarity. Instead, this spectral change
appeared to be consistent with deprotonation of one squar-
amide N-H group, suggesting that DMSO is able to promote
ionization of 4e, without addition of base.
and active research,16 and molecules that signal the presence of
anions through color changes are of significant interest.17
A
large number of urea-based receptors that display anion-
induced color changes have been developed, several of which
are derivatives of 4-nitroaniline.18 Detailed studies of the beha-
vior of electron-deficient N,N0-diarylureas have been carried
out by the groups of Fabbrizzi and Gunnlaugsson,18b,f,k
demonstrating that three types of interaction with anions are
~
(16) (a) Bianchi, A., Bowman-James, K., García-Espana, E., Eds. Supramo-
lecular Chemistry of Anions; Wiley-VCH: New York, 1997. (b) Sessler, J. L.,
Gale, P. A., Cho, W.-S., Eds. Anion Receptor Chemistry; Royal Society of
Chemistry: Cambridge, UK, 2006. (c) Beer, P. D.; Gale, P. A. Angew. Chem., Int.
Ed. 2001, 40, 486–516. (d) Caltagirone, C.; Gale, P. A. Chem. Soc. Rev. 2009, 38,
520–563.
(17) For a pioneering example of the colorimetric sensing of fluoride:
Black, C. B.; Andrioletti, B.; Try, A. C.; Ruiperez, C.; Sessler, J. L. J. Am.
Chem. Soc. 1999, 121, 10428–10439.
(18) (a) Kwon, J. Y.; Yun Jung Jang, Y. J.; Kim, S. K.; Lee, K.-H.; Kim, J.
S.; Yoon, J. J. Org. Chem. 2004, 69, 5155–5157. (b) Boiocchi, M.; Del Boca,
ꢁ
L.; Gomez, D. E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. J. Am. Chem.
Soc. 2004, 126, 16507–16514. (c) Vasquez, M.; Fabbrizzi, L.; Taglietti, A.;
To test this hypothesis, UV-vis spectra of 4e in aceto-
nitrile/DMSO mixtures were obtained (Figure 3), resulting
in a clean interconversion of the two absorption bands at 377
and 485 nm. This observation is consistent with an equilib-
rium between 4e and [4e - H]- that favors ionization as the
DMSO content of the solvent increases. The hydrogen-
bond-accepting ability of DMSO, which is greater than that
of acetonitrile (the values of β for DMSO and acetonitrile are
0.76 and 0.40, respectively),20 likely promotes the ionization
reaction. Spectra of 4e in DMSO are concentration-depen-
dent: as the concentration increases, a signal corresponding
ꢁ
ꢁ
Pedrido, R. M.; Gonzalez-Noya, A. M.; Bermejo, M. R. Angew. Chem., Int.
Ed. 2004, 43, 1962–1965. (d) Jose, D. A.; Kumar, D. K.; Ganguly, B.; Das, A.
Org. Lett. 2004, 6, 3445–3448. (e) Thiagarajan, V.; Ramamurthy, P.;
Thirumalai, D.; Ramadrishnan, V. Org. Lett. 2005, 7, 657–660. (f) Esteban-
ꢁ
Gomez, D.; Fabbrizzi, L.; Lichelli, M. J. Org. Chem. 2005, 70, 5717–5720.
(g) Boiocchi, M.; Boca, L. D.; Esteban-Gomez, D.; Fabbrizzi, L.; Licchelli,
ꢁ
M.; Monzani, E. Chem.;Eur. J. 2005, 11, 3097–3104. (h) Gunnlaugsson, T.;
Kruger, P. E.; Jensen, P.; Tierney, J.; Paduka-Ali, H. D.; Hussey, G. M. J. Org.
Chem. 2005, 70, 10875–10878. (i) Pfeffer, F. M.; Seter, M.; Lewcenko, M.;
Barnett, N. W. Tetrahedron Lett. 2006, 47, 5241–5245. (j) Evans, L. S.;
Gale, P. A.; Light, M. E.; Quesada, R. Chem. Commun. 2006, 965–967.
(k) Gunnlaugsson, T.; Glynn, M.; Tocci, G. M.; Kruger, P. E.; Pfeffer, F. M.
Coord. Chem. Rev. 2006, 250, 3094-3117 and references cited therein.
(19) The nitro-substituted squaramides 4f, 4g ,and 1g displayed qualita-
tively similar anion-responsive behavior as 4e: photographs of 4f, 4g, and 1g
in the presence of acetate, tosylate, and fluoride in DMSO are included in the
Supporting Information.
(20) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 3rd
ed.; Wiley-VCH: Weinheim, 2003.
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FIGURE 3. Absorption spectrum of squaramide 4e (4.0 ꢀ 10-5 M)
as a function of solvent composition, varying from pure acetonitrile
(MeCN; triangle markers) to pure methylsulfoxide (DMSO; circle
markers).
FIGURE 5. Changes in the absorption spectrum of 4e (1.4 ꢀ
10-5 M, acetonitrile) upon addition of tetrabutylammonium fluor-
ide (0-3.0 equiv).
from those observed in DMSO. Fabbrizzi and co-workers
have found that bis(4-nitrophenyl)urea forms spectroscopi-
cally observable hydrogen bonds with weakly basic anions
such as acetate and dihydrogenphosphate in acetonitrile and
is deprotonated to form the monoanion only by 2 equiv of
the strong base fluoride (Scheme 2). In analogy to these
results, addition of tetrabutylammonium fluoride resulted
first in the formation of a species presumed to be the
hydrogen-bonded complex, followed by deprotonation
upon addition of 2 equiv of anion to generate the red-shifted
band corresponding to [4e - H]- (Figure 5). The require-
ment for 2 equiv of fluoride to effect deprotonation has been
observed previously and is consistent with the formation of
the stable bifluoride anion HF2- as the driving force for the
proton-transfer reaction.
However, in contrast to the reported behavior of the urea,
squaramide 4e also underwent deprotonation in the presence
of relatively poorly basic anions, including acetate, dihydro-
genphosphate, and even p-toluenesulfonate in acetonitrile.
The spectral changes accompanying acetate and dihydrogen
phosphate addition reached a maximum upon addition of 1
equiv of anion (Figure 6), consistent with a deprotonation
rather than a hydrogen-bonding interaction. Deprotonation
by p-toluenesulfonate was more complex and did not appear
to reach saturation before the formation of the hydrogen-
bonded complex [4e---OTs]- began to intervene (see below),
but a significant fraction of the deprotonated form [4e - H]-
was clearly evident. This latter result implies that the pKa of 4e
in acetonitrile is similar to that of p-toluenesulfonic acid in this
solvent, a striking illustration of the enhanced acidity of the
N-H groups of squaramides relative to ureas (see the follow-
ing section for more discussion). The increased acidity of
squaramides in comparison to ureas has been invoked to
explain the strong anion-complexing properties of the former,
but experimental support for this contention has been lacking.
It is clear that the prospect of proton transfer should be
considered carefully in the context of developing new colori-
metricsensorsbased onelectron-deficientsquaramide groups.
Further unexpected observations emerged from studies invol-
ving the addition of excess quantities of tetrabutylammonium
p-toluenesulfonate to a solution of 4e in DMSO. The spectral
FIGURE 4. Changes in absorption spectrum of squaramide 4e
(4.0 ꢀ 10-5 M, DMSO) upon addition of tetra-n-butylammonium
fluoride (TBAF, 80 equiv).
to the neutral, protonated form becomes progressively more
pronounced (see the Supporting Information). Stabilization
of the neutral form by self-association through hydrogen
bonding to the dicarbonyl moiety at higher concentrations is
likely responsible for this effect. Finally, addition of excess
acetic acid to dilute solutions of 4e in DMSO caused the
disappearance of the absorption feature characteristic of
[4e - H]- and the appearance of that corresponding to its
neutral form (data not shown).
Addition of basic anions known to deprotonate bis(4-
nitrophenyl)urea in DMSO (AcO- and H2PO4-) did not
elicit significant changes in the spectrum of 4e, providing
additional evidence that 4e exists predominantly in its de-
protonated form even in the absence of bases. However,
addition of excess tetrabutylammonium fluoride, a base
known to promote a second deprotonation of bis(4-
nitrophenyl)urea, resulted in the formation of an intense
blue color attributable to the dianion [4e - 2H]2-(Figure 4).
Given that squaramide 4e exists in its neutral, protonated
form in acetonitrile, we anticipated that its colorimetric
sensing properties in this solvent might differ significantly
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FIGURE 6. (a) Changes in the absorption spectrum of 4e (1.4 ꢀ
10-5 M, acetonitrile) upon addition of tetrabutylammonium acet-
ate. (b) Absorption intensity of 4e at 459 nm as a function of added
acetate in acetonitrile.
FIGURE 7. (a) Changes in the absorption spectrum of 4e (4.0 ꢀ
10-5 M, DMSO) upon addition of tetrabutylammonium p-tolue-
nesulfonate (Bu4NOTs). (b) Absorption intensity of 4e at 395 nm as
a function of added Bu4NOTs in DMSO.
feature corresponding to [4e - H]- was gradually replaced
by a new absorption peak centered at 395 nm, accompanied
by a readily perceived color change from pink to yellow
(Figure 7). This behavior appeared to be consistent with
protonation of [4e - H]- by addition of excess tosylate, a
counterintuitive result in light of the observations discussed
above and those of Fabbrizzi and co-workers. Indeed,
although proton transfer has been documented for several
classes of anion receptors, including pyrroles,21 anilines,22
amides,23 and sulfonamides,24 we are unaware of reports
of reversal of proton transfer equilibria in the presence of
excess anion: rather, formation of a hydrogen-bonded com-
plex is often favored at relatively low anion concentration,
followed by deprotonation at higher anion concentrations.23
Proton transfer to [4e - H]- in the presence of excess anion
can, however, be rationalized in terms of the preferential
stabilization of the protonated form of 4e over that of
[DMSO þ H]þ by formation of a strong, doubly hydrogen-
bonded complex with tosylate. In DMSO, this behavior is
unique to tosylate: addition of excess acetate, hydrogen
sulfate, dihydrogen phosphate, chloride, bromide, and io-
dide resulted in the persistence of the pink color characteri-
stic of [4e - H]-.
1H NMR studies in DMSO-d6 provided strong support for
the “re-protonation” hypothesis: in the presence of 1 equiv of
tetrabutylammonium tosylate, the chemical shifts corre-
sponding to the N-H groups of 4e underwent significant
broadening, consistent with chemical exchange to form [4e -
H]-.25 Adding 10-30 equiv of tosylate resulted in the
reappearance of two sharp, distinct N-H signals (Figure
8). Despite the isosbestic point apparent in Figure 7a, the
changes in absorption at 395 nm as a function of tosylate
concentration follow a sigmoidal curve that cannot be
accurately modeled by a 1:1 binding isotherm (Figure 7b).
Dimerization or oligomerization of the “free” squaramide
(21) (a) Camiolo, S.; Gale, P. A.; Hursthouse, M. B.; Light, M. E.; Shi, A.
J. Chem. Commun. 2002, 758–759. (b) Gale, P. A.; Navakhun, K.; Camiolo,
S.; Light, M. E.; Hursthouse, M. B. J. Am. Chem. Soc. 2002, 124, 11228–
11229. (c) Camiolo, S.; Gale, P. A.; Hursthouse, M. B.; Light, M. E. Org.
Biomol. Chem. 2003, 1, 741–744. (d) Gale, P. A. Acc. Chem. Res. 2006, 39,
465–475.
(22) Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.; Pfeffer, F. M.; Hussey,
G. M. Tetrahedron Lett. 2003, 49, 8909–8913.
(23) Costero, A. M.; Banuls, M. J.; Aurell, M. J.; Ward, M. D.; Argent, S.
Tetrahedron 2004, 60, 9471–9478.
(25) At the relatively high concentrations of 4e (1.0 ꢀ 10-4 M) required
for accurate 1H NMR results, it exists predominantly in the neutral form (see
the Supporting Information for the concentration-dependent ionization of
4e in DMSO).
(24) Caltagirone, C.; Bates, G. W.; Gale, P. A.; Light, M. E. Chem.
Commun. 2008, 61–63.
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FIGURE 8. Changes in the 1H NMR spectrum of 4e (DMSO-d6, 1.0 ꢀ 10-4 M) upon addition of tetrabutylammonium p-toluenesulfonate
(0-30 equiv).
would give rise to such behavior and is consistent with our
observations of concentration-dependent ionization of 4e
discussed in a preceding paragraph.
In acetonitrile, similar behavior was observed: the addi-
tion of 1 equiv of p-toluenesulfonate resulted predominantly
in deprotonation, and addition of excess tosylate resulted in
the formation of the hydrogen-bonded complex. The forma-
tion of analagous hydrogen-bonded complexes was not
observed upon addition of excess tetrabutylammonium
acetate or dihydrogenphosphate.
Electron-deficient squaramide 4e thus differs from N,N0-
FIGURE 9. Photographs of 4e (2 ꢀ 10-4 M in DMSO) in the
bis(4-nitrophenyl)urea in the following ways: (1) 4e under-
goes spontaneous ionization to its conjugate base in dilute
presence of (left to right, 2 ꢀ 10-2 M): Bu4NOTs; no analyte;
Bu4NOAc; Bu4NF.
DMSO solution; (2) 4e is deprotonated by the weakly basic
anions acetate and phosphate, even in the relatively poorly
hydrogen-bond-accepting solvent acetonitrile; (3) in both
DMSO and acetonitrile, the presence of excess tosylate
results in the protonation of [4e - H]- to form the 4e---
OTs complex, accompanied by a color change from pink to
yellow. Properties (1) and (2) above arise from the enhanced
acidity of squaramides relative to ureas, a property that has
not been exploited to date in colorimetric sensing applica-
tions. Property (3) appears to reflect the ability of squar-
amides to form strong hydrogen bonds to sulfonate anions,
and represents a unique behavior that can be exploited for
colorimetric sensing. Certain properties are shared between
the urea and squaramide, including their propensity for
undergoing two sequential deprotonations in the presence
of the strong base fluoride: in the case of squaramide 4e, this
double deprotonation gives rise to a characteristic blue color.
Photographs accompanying the treatment of DMSO solu-
tions of squaramide 4e with tosylate, acetate, and fluoride
are shown in Figure 9. Given the significant differences in
behavior between the squaramides described here and the
well-explored colorimetric ureas, the former appear to hold
significant promise as elements of arrays of colorimetric
sensors for anion identification.
D. Computational Investigation of the Acidity of Squar-
amides. The profound differences between the colorimetric
anion-sensing properties of electron-deficient squaramide 4e
and those of the well-explored electron-deficient ureas ap-
pear to be a reflection of the significantly higher acidity of
the N-H groups of squaramides relative to ureas. The high
acidity of squaramides has previously been invoked to
explain their strong anion-complexing properties,14b but
our observations represent, to the best of our knowledge,
the first experimental data supporting this contention. Re-
cently,
a
N,N0-bis-trifluoromethanesulfonyl-substituted
squaramide has been exploited as a Brønsted acid catalyst
for Mukaiyama aldol and Michael reactions. The low pKa
of the squaramide group was proposed as a basis for the
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SCHEME 3. DFT-Calculated Gas-Phase Acidities for
N,N0-Diphenylurea and N,N0-Diphenylsquaramide
exceptional activity of this organocatalyst. The acidity of
squaramides also underlies their application as mimics of the
phosphate group in oligodeoxynucleotides.26
The clear importance of the acidity of the squaramide
group to a wide range of emerging applications led us to
pursue this issue in more detail. The high propensity for self-
association of squaramides, even in good hydrogen-bond
acceptor solvents such as DMSO (see the previous section),
complicates experimental determinations of pKa. We thus
undertook a computational comparison of the gas-phase
acidities of N,N0-diphenylsquaramide and the analogous
urea. The question of the aromaticity of squarate anions has
been addressed in a number of computational studies, and its
effect on the pKa of squaric acid is well-documented.27 While
calculations suggest that the aromatic character of squar-
amides increases upon hydrogen bond donation, we are una-
ware of any quantitative studies (experimental or com-
putational) of the acidity of squaramides.
FIGURE 10. DFT-calculated highest occupied molecular orbitals
for the conjugate bases of (top) N,N0-diphenylurea and (bottom) N,
N0-diphenylsquaramide.
shows considerable delocalization of electron density into
the cyclobutenedione ring. This delocalization of charge is
manifested in a lengthening of the CdC π bond, from 1.40 to
˚
1.43 A, upon deprotonation of the squaramide. Presumably
this unique feature of the squaramide-derived anion is at
least partially responsible for the pKa differences implied by
our experimental study described previously.
Conclusions
The gas-phase free energy changes for the reactions depi-
cted in Scheme 3 were calculated using density functional
theory (B3LYP/6-311þþG**), by geometry optimizations
of both the neutral and charged species, followed by fre-
quency calculations. N,N0-Diphenylurea was chosen as the
reference compound for comparison to the corresponding
squaramide. The B3LYP functional with this basis set has
been shown to provide useful correspondence with experi-
mental gas-phase acidity data.28 A value of 6.28 kcal/mol
was employed for the gas-phase Gibbs free energy G of the
proton Hþ at 298K (where T is the Kelvin temperature and
S the gas-phase entropy).29 The calculated free energy of
proton loss from N,N0-diphenylsquaramide is 18 kcal/mol
lower than the corresponding quantity for N,N0-diphenylurea
at this level of theory, a trend that is in agreement with the
experimental results presented in the preceding section.
Depictions of the highest occupied molecular orbitals
(HOMO) of the conjugate bases of diphenylsquaramide
and diphenylurea, shown in Figure 10, reveal significant
differences between the two systems. While the HOMO
density for the conjugate base of N,N0-diphenylurea is
localized largely on the nitrogen atom and the adjacent aryl
group, the conjugate base of N,N0-diphenylsquaramide
Zinc triflate catalysis provides a general and high-yielding
method for the preparation of useful diaryl squaramides
from commercially available and easily handled squarate
esters. It is applicable to the synthesis of both symmetrically
and unsymmetrically substituted variants and represents a
significant improvement over existing methods for the pre-
paration of these important compounds. Diarylsquaramides
display distinct behavior as colorimetric anion sensors be-
cause of their enhanced acidity in comparison to ureas, a
property that is evident from the experiments described here
and from our computational studies. The unusual observa-
tion that certain anions promote the “re-protonation” of the
squaramide monoanion also appears to be a unique property
of the diarylsquaramide system.
Experimental Section
Representative experimental procedures (synthesis of 1a, 1b, 3b,
and 4a) and full characterization data for 1a-h, 3b-c, and 4a-g.
General Procedure A: Preparation of Symmetrically Substi-
tuted N,N0-Diarylsquaramides. 3,4-Bis(3,5-bis(trifluoromethyl)-
phenylamino)cyclobut-3-ene-1,2-dione (1a). To a stirred solu-
tion of 3,4-diethoxycyclobut-3-ene-1,2-dione (diethyl squarate,
96 μL, 0.65 mmol, 1.0 equiv) and zinc trifluoromethanesulfo-
nate (45 mg, 0.13 mmol, 20 mol %) in toluene/NMP 19:1 (1 mL)
was added 3,5-bis(trifluoromethyl)benzenamine (218 μL, 1.4
mmol, 2.1 equiv). The solution was heated to 100 °C and stirred
for 12 h. Upon cooling to room temperature, pale yellow crystals
were obtained, isolated by filtration, and further washed with
(26) (a) Sato, K.; Seio, K.; Sekine, M. J. Am. Chem. Soc. 2002, 124,
12715–12724. (b) Seio, K.; Miyashita, T.; Sato, K.; Sekine, M. Eur. J. Org.
Chem. 2005, 5163–5170.
(27) (a) West, R.; Niu, N.-Y.; Powell, D. L.; Evans, M. V. J. Am. Chem.
~
Soc. 1960, 82, 6204–6205. (b) Quinonero, D.; Garau, C.; Frontera, A.;
Ballester, P.; Costa, A.; Deya, P. M. Chem.;Eur. J. 2002, 8, 433–438.
ꢀ
toluene to give 1a (NMP solvate 1a NMP, 330 mg, 80% yield):
3
(28) (a) Burk, P.; Koppel, I. A.; Koppel, I.; Leito, I.; Travnikova, O.
Chem. Phys. Lett. 2000, 323, 482–489. (b) Marino, T.; Russo, N.; Tocci, E.;
Toscano, M. Int. J. Quantum Chem. 2001, 84, 264–268.
IR (powder) 3473 (br), 1800 (w), 1673 (m), 1552 (m), 1446 (m),
1362 (m), 1269 (s), 1168 (m), 1120 (s), 1029 (m) cm-1; 1H NMR
(400 MHz, DMSO-d6): δ 10.6 (2H, s), 7.88 (4H, s), 7.70 (2H, s),
(29) Liptak, M. D.; Shields, G. C. J. Am. Chem. Soc. 2001, 123, 7314–7319.
3990 J. Org. Chem. Vol. 75, No. 12, 2010

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2.7 (3H, s), 2.2 (m, 3H), 1.8 (m, 3H); 13C NMR (100 MHz,
DMSO-d6) 183.7, 165.6, 140.2, 131.1 (q, JC-F = 33 Hz), 122.7
(q, JC-F = 272 Hz), 118.9, 115.6, 16.9; HRMS (EI) calcd for
C20H8F12N2O2 536.0394, found m/z 536.0391.
(m), 1443 (s), 1206 (m), 1155 (m) cm-1; H NMR (400 MHz,
DMSO-d6) δ 9.9 (2H, s), 7.26 (4H, m), 6.96 (2H, dd, J = 8.0,
2.1 Hz), 6.66 (2H, dd, J = 8.0, 2.1 Hz); 13C NMR (100 MHz,
DMSO-d6) δ 181.5, 165.5, 160.1, 139.7, 130.2, 110.5, 109.0,
104.1, 55.1; HRMS (EI) calcd for C18H16N2O4 324.1110, found
m/z 324.1111.
1
3,4-Bis(phenylamino)cyclobut-3-ene-1,2-dione (1b). To a stir-
red solution of 3,4-diethoxycyclobut-3-ene-1,2-dione (81.3 μL,
0.55 mmol, 1.0 equiv) and zinc trifluoromethanesulfonate
(40 mg, 0.11 mmol, 20 mol %) in toluene/DMF 19:1 (1 mL)
was added aniline (92.6 μL, 1.15 mmol, 2.1 equiv). The solution
was heated to 100 °C and stirred for 12 h. When the solution was
cooled to room temperature, a white precipitate was observed
and isolated by decanting the solvent. The solid was further
washed with methanol (3 ꢀ 5 mL), and each time it was shaken
vigorously and centrifuged to remove the methanol yielding
1b as a white solid (138 mg, 0.52 mmol, 99% yield). The zinc
content of the isolated product was 0.02% as analyzed by ICP-
MS: IR (powder) 3134 (br), 1795 (w), 1666 (m), 1598 (m), 1534
3,4-Bis(2-nitrophenylamino)cyclobut-3-ene-1,2-dione (1g).
Synthesized on 0.1 mmol scale according to general procedure A,
the product was centrifuged, washed with pentane (3 ꢀ 5 mL),
and isolated as a red solid (69 mg, 98% yield): IR (powder) 3478
(br), 1785 (w), 1719 (w), 1605 (m), 1494 (m), 1433 (m), 1393 (m),
1249(s), 1034(m);1H NMR (400 MHz, DMSO-d6) δ10.6(2H, s),
8.16 (2H, dd, J = 8.4, 1.5 Hz), 7.77 (2H, ddd, J = 8.4, 7.4, 1.5
Hz), 7.58 (2H, dd, J =8.4, 1.5Hz), 7.4(2H, ddd, 8.5, 7.4, 1.5 Hz,);
13C NMR (100 MHz, DMSO-d6) δ 183.6, 166.3, 139.4, 134.8,
131.9, 125.5, 125.5, 124.8; HRMS (ESI) [M þ H]þ calcd for
C16H11N4O6 355.0673, found m/z 355.0682.
(s), 1448 (s) cm-1; the H NMR spectrum was in agreement
3,4-Bis(pyridin-2-ylamino)cyclobut-3-ene-1,2-dione (1h).
Synthesized on 0.1 mmol scale according to general procedure
A, the product was centrifuged, washed with methanol (3 ꢀ
5 mL), and isolated as a pale yellow solid (45 mg, 90% yield): IR
(powder) 3196 (w), 1797 (m), 1686 (m), 1605 (m), 1563 (m), 1475
1
with the previously reported spectrum:2 1H NMR (400 MHz,
DMSO-d6) δ 7.50 (4H, d, J = 7.3 Hz), 7.38 (4H, app t, J =
7.4 Hz), 7.90 (2H, app t, J = 7.4 Hz); 13C NMR (100
MHz, DMSO-d6) δ 181.5, 165.6, 138.5, 129.3, 123.2, 118.4;
HRMS (EI) calcd for C16H12N2O2 264.0899, found m/z
264.0896.
1
(m), 1362 (s), 1309 (s), 1148 (m), 772 (s) cm-1; H NMR (400
MHz, DMSO-d6) δ 11.6 (2H, s), 8.34 (2H, d, J = 5.0 Hz), 7.86
(2H, dd, J = 8.0, 1.9 Hz), 7.70 (2H, br s), 7.12 (2H, dd, J = 8.0,
5.0 Hz); 13C NMR (100 MHz, DMSO-d6) δ 183.4, 165.5, 151.4,
147.7, 139.4, 118.8, 112.7; HRMS (EI) calcd for C14H10N4O2
266.0804, found m/z 266.0806.
3,4-Bis(4-tert-butylphenylamino)cyclobut-3-ene-1,2-dione (1c).
Synthesized on 0.55 mmol scale according to general procedure
A, the productwas centrifuged, washedwithmethanol(3ꢀ 5 mL)
and isolated as a pale yellow solid (194 mg, 97% yield): IR
(powder) 3149 (br), 2951, 1790 (m), 1661 (m), 1598 (m), 1522
(s), 1428 (s), 1360 (s) cm-1; 1H NMR (400 MHz, DMSO-d6): δ
9.8 (2H, s), 7.40 (8H, m), 1.3 (18H, s); 13C NMR (100 MHz,
DMSO-d6) δ 181.3, 165.3, 145.7, 135.9, 126.0. 118.2, 34.0, 31.1;
HRMS (EI) calcd for C24H28N2O2 376.2151, found m/z
376.2141.
General Procedure B: Preparation of Squarate Monoesters.
3,4-Bis(4-bromophenylamino)cyclobut-3-ene-1,2-dione (1d).
Synthesized on 0.55 mmol scale according to general procedure
A, the product was centrifuged, washed with methanol (3 ꢀ
5 mL), and isolated as a pale yellow solid (210 mg, 99% yield): IR
(powder) 2942 (br), 1797 (m), 1657 (m), 1599 (m), 1528 (m), 1426
(s), 1399 (s), 1226 (m), 815 (s), 747 (s) cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 9.9 (2H, s), 7.55 (4H, d, J = 9.0 Hz), 7.42 (4H, d,
J = 9.0 Hz); 13C NMR (100 MHz, DMSO-d6) partial (signal
corresponding to CdO was not observed) δ 165.5, 137.8, 132.1,
120.6, 115.3; HRMS (EI) calcd for C16H10N2O2Br2 419.9109,
found m/z 419.9100. Anal. Calcd for C16H10N2O2Br2: C, 45.53;
H, 2.39; N, 6.64. Found: C, 45.45; H, 2.53; N, 6.66.
3-(4-Bromophenylamino)-4-ethoxycyclobut-3-ene-1,2-dione
(3b). To a stirred solution of 3,4-diethoxycyclobut-3-ene-1,2-
dione (0.88 mL, 6.0 mmol, 1.2 equiv) and zinc trifluorometha-
nesulfonate (181 mg, 0.5 mmol, 10 mol %) in ethanol (15 mL)
at room temperature was added 4-bromoaniline (860 mg,
5.0 mmol, 1.0 equiv). After the solution was stirred for 1 h,
a white precipitate was formed, which was centrifuged to
remove the ethanol. The solid was further washed with
ethanol (3 ꢀ 5 mL), and each time it was centrifuged to
remove the ethanol yielding 3b as a white solid (1040 mg,
3.5 mmol, 70% yield): IR (powder) 3240 (w), 1790 (m), 1696
(m), 1603 (m), 1562 (m), 1501 (m), 1426 (s), 816 (m) cm-1; 1H
NMR (400 MHz, DMSO-d6) δ 10.82 (1H, s), 7.53 (2H, d, J =
8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 4.80 (2H, q, J = 7.0 Hz), 1.44
(3H, t, J = 7.0 Hz); 13C NMR (100 MHz, DMSO-d6) δ 187.5,
183.8, 178.5, 169.3, 137.4, 131.8, 121.4, 116.0, 69.6, 15.5;
HRMS (EI) calcd for C12H10BrNO3 294.9844, found m/z
294.9845. Anal. Calcd for C12H10BrNO3: C, 48.67; H, 3.40;
N, 4.73. Found: C, 47.95; H, 3.39; N, 4.62.
3-(4-Nitrophenylamino)-4-ethoxycyclobut-3-ene-1,2-dione (3c).
Synthesized on 2.0 mmol scale according to general procedure B,
the product was isolated as an orange solid (450 mg, 86% yield):
IR (powder) 3296 (w), 1802 (m), 1711 (m), 1620 (m), 1590 (m),
1504 (m), 1405 (m), 1297 (s), 1183 (s), 1097 (s), 986 (m) cm-1; 1H
NMR (400 MHz, DMSO-d6) δ 11.22 (1H, s), 8.23 (2H, d, 9.1 Hz),
7.59(2H, d, 9.1 Hz), 4.79(2H, q, 7.0Hz), 1.44 (3H, (2H, t, 7.0 Hz);
13C NMR (100 MHz, DMSO-d6) δ 187.0, 184.7, 179.9, 169.3,
144.3, 142.4, 125.2, 118.9, 70.1, 15.5; HRMS (ESI) [M þ H]þ for
C12H11N2O5 calcd 263.0662, found m/z 263.1. Anal. Calcd for
C12H10N2O5: C, 54.97; H, 3.84; N, 10.68. Found: C, 54.77; H,
3.82; N, 10.62.
3,4-Bis(4-methoxyphenylamino)cyclobut-3-ene-1,2-dione (1e).
Synthesized on 0.55 mmol scale according to general proce-
dure A, the product was centrifuged, washed with methanol (3
ꢀ 5 mL), and isolated as a pale yellow solid (180 mg, 94%
yield): IR (powder) 3113 (br), 1797 (w), 1661 (m), 1610 (w),
1554 (s), 1507 (s), 1451 (s), 1244 (m), 1178 (m), 1026 (m) cm-1
;
1
the H NMR spectrum was in agreement with the previously
reported spectrum:30 1H NMR (400 MHz, DMSO-d6) δ 9.7
(2H, s), 7.40 (4H, d, J = 8.7 Hz), 6.96 (4H, d, J = 8.7 Hz), 3.8
(6H, s); 13C NMR (100 MHz, DMSO-d6) δ 181.6, 164.9, 155.4,
131.6, 119.9, 114.3, 55.1; HRMS (EI) calcd for C18H16N2O4
324.1110, found m/z 324.1106. Anal. Calcd for C18H16-
N2O4: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.15; H, 5.06;
N, 8.63.
3,4-Bis(3-methoxyphenylamino)cyclobut-3-ene-1,2-dione (1f).
Synthesized on 0.1 mmol scale according to general procedure
A, the product was centrifuged, washed with methanol (3 ꢀ
5 mL), and isolated as a pale yellow solid (59 mg, 90% yield): IR
(powder) 3007 (br), 1772 (w), 1646 (m), 1618 (m), 1598 (m), 1555
€
(30) Grunefeld, J.; Zinner, G. Arch. Pharm. (Weinheim) 1985, 318, 1062–
1070.
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General Procedure C: Preparation of Unsymmetrically Sub-
stituted N,N0-Diarylsquaramides.
(m), 1598 (m), 1524 (s), 1430 (s), 1166 (m), 1148 (m), 820 (m), 768
(m) cm-1; H NMR (400 MHz, DMSO-d6) 9.91 (2H, s), 7.54
1
(2H, d, J = 9.0 Hz), 7.46 (2H, d, J = 9.0 Hz), 7.26 (2H, m), 6.95
(1H, dd, J = 8.0, 1.5 Hz), 6.66 (1H, dd, J = 8.0, 1.5 Hz), 3.80
(3H, s); 13C NMR (100 MHz, DMSO-d6) δ 181.7, 181.6, 165.7,
165.2, 160.1, 139.6, 137.9, 132.1, 132.1, 130.2, 115.1, 110.6,
109.1, 104.2, 55.1; HRMS (EI) calcd for C17H13BrN2O3
372.0110, found m/z 372.0104.
3-(3,5-Bis(trifluoromethyl)phenylamino)-4-(4-nitrophenyl-
amino)cyclobut-3-ene-1,2-dione (4e). Synthesized on 0.4 mmol
scale according to general procedure C, the product was recrys-
tallized from DMSO and isolated as yellow crystals (DMSO
3-(4-Bromophenylamino)-4-(phenylamino)cyclobut-3-ene-1,2-
dione (4a). To a stirred solution of 3-(4-bromophenylamino)-4-
ethoxycyclobut-3-ene-1,2-dione 3b (59 mg, 0.2 mmol, 1.0 equiv)
and zinc trifluoromethanesulfonate (70 mg, 0.02 mmol, 10 mol
%) in toluene/DMF 19:1 (1 mL) was added aniline (20.1 μL,
0.22 mmol, 1.1 equiv). The solution was heated to 100 °C and
stirred for 12 h. Upon cooling to room temperature, a white
precipitate was observed and was isolated by decanting the
solvent. The solid was further washed with methanol (3 ꢀ
5 mL), and each time it was shaken vigorously and centrifuged
to remove the methanol yielding 4a as a white solid (63 mg, 0.52
mmol, 91% yield): IR (powder) 3138 (br), 1794 (m), 1667 (m),
solvate 4e DMSO, 178 mg, 85% yield): IR (powder) 3481 (br),
3
1801 (w), 1675 (m), 1554 (m), 1447 (m), 1365 (m), 1272 (s), 1124
1
(s), 1029 (m) cm-1; H NMR (400 MHz, d7-DMF-d7) δ 10.6
(2H, s), 8.31 (2H, d, J = 9.0 Hz), 8.19 (2H, s), 7.84 (1H, s), 7.75
(2H, d, J = 9.0 Hz), 2.59 (6H, s); HRMS (EI) calcd for C18H9
F6N3O4 445.0497, found m/z 445.0494. Anal. Calcd for
(C18H9F6N3O4 C2H6OS): C, 45.89; H, 2.89; N, 8.03. Found:
C, 45.74; H, 3.03; N, 7.48.
3
3-(4-tert-Butylphenylamino)-4-(4-nitrophenylamino)cyclobut-
3-ene-1,2-dione (4f). Synthesized on a 0.4 mmol scale according
to general procedure C, the product was isolated as a yellow
solid (136 mg, 93% yield): IR (powder) 3113 (br), 2962 (w), 1795
(m), 1666 (m), 1595 (m), 1537 (s), 1507 (s), 1431 (s), 1330 (s), 1107
(m) cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.34 (1H, s), 10.03
(1H, s), 8.24 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.36
(4H, m); 1.22 (9H, s); 13C NMR (100 MHz, DMSO-d6) δ 183.2,
181.5, 167.2, 164.2, 146.7, 144.8, 142.1, 135.5, 125.9, 125.3,
118.9, 118.2, 34.0, 31.1; HRMS (EI) calcd for C20H19N3O4
365.1376, found m/z 365.1375.
1
1598 (m), 1532 (s), 1393 (s), 1075 (m), 737 (s) cm-1; H NMR
(400 MHz, DMSO-d6) δ 9.90 (2H, s), 7.55 (2H, d, J = 9.0 Hz),
7.45 (4H, m), 7.38 (2H, app t, J = 7.4 Hz), 7.10 (1 H, app t, J =
7.4 Hz); 13C NMR (100 MHz, DMSO-d6) δ 181.8, 181.6, 165.8,
165.2, 138.4, 137.9, 132.1, 129.3, 123.4, 120.5, 118.5, 115.1;
HRMS (EI) calcd for C16H11N2O2Br 342.0004, found m/z
341.9995.
3-(4-Bromophenylamino)-4-(4-methoxyphenylamino)cyclobut-
3-ene-1,2-dione (4b). Synthesized on a 0.2 mmol scale according
to general procedure C, the product was isolated as a pale yellow
solid (70 mg, 93% yield): IR (powder) 3007 (br), 1792 (m), 1663
(m), 1595 (m), 1537 (s), 1450 (s), 1246 (m), 1218 (m), 1026 (m)
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 9.8 (2H, s), 7.56 (2H, d,
J = 9.0 Hz), 7.44 (2H, d, J = 9.0 Hz), 7.38 (2H, d, J = 9.0 Hz),
6.94 (2H, d, J = 9.0 Hz), 3.78 (3H, s); 13C NMR (100 MHz,
DMSO-d6) partial (signal corresponding to CdO was not
observed) δ 181.1, 165.8, 164.6, 155.8, 138.1, 132.1, 131.5,
120.4, 120.3, 114.9, 114.5, 55.3; HRMS (EI) calcd for
C17H13N2O3Br 372.0110, found m/z 372.0119. Anal. Calcd for
C17H13N2O3Br: C, 54.71; H, 3.51; N, 7.51. Found: C, 54.35; H,
3.44; N, 7.25.
3-(2-Methoxyphenylamino)-4-(4-bromophenylamino)cyclo-
but-3-ene-1,2-dione (4c). Synthesized on a 0.4 mmol scale ac-
cording to general procedure C, the product was isolated as a
pale yellow solid (133 mg, 97% yield): IR (powder) 3477 (w),
2962 (w), 1785 (m), 1671 (m), 1610 (m), 1539 (m), 1478 (s), 1436
(s), 1251 (m), 1112 (m), 1005 (m), 743 (s) cm-1; 1H NMR (400
MHz, DMSO-d6) δ 10.39 (1H, s), 9.48 (1H, s), 7.68 (1H, d, J =
7.6 Hz), 7.56 (2H, d, J = 9.0 Hz), 7.46 (2H, d, J = 9.0 Hz), 7.1
(2H, J = 6.0 Hz), 6.96 (1H, m), 3.92 (3H, s); 13C NMR (100
MHz, DMSO-d6) δ 181.8, 181.6, 165.7, 165.4, 149.0, 138.0,
132.1, 132.1 126.9, 124.6, 120.6, 120.6, 115.1, 111.4, 55.9;
HRMS (EI) calcd for C17H13BrN2O3 372.0110, found m/z
372.0104.
3-(4-Methoxyphenylamino)-4-(4-nitrophenylamino)cyclobut-
3-ene-1,2-dione (4g). Synthesized on a 0.2 mmol scale according
to general procedure C, the product was isolated as a pale green
solid (61 mg, 91% yield): IR (powder) 3134 (br), 1795 (m), 1668
(m), 1605 (m), 1547 (s), 1509 (s), 1438 (s), 1350 (m), 1297 (m),
1
1251 (m), 1178 (m), 1115 (m), 1019 (m) cm-1; H NMR (400
MHz, DMSO-d6) δ 10.2 (2H, s), 8.24 (2H, d, J = 9.0 Hz), 7.64
(2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz), 6.96 (2H, d, J =
9.0 Hz), 3.79 (3H, s); 13C NMR (100 MHz, DMSO-d6) partial
(signals corresponding to CdO and CdC were not observed) δ
167.8, 156.1, 141.7, 131.2, 125.6, 120.7, 118.1, 114.5, 55.3;
HRMS (EI) calcd for C17H13N3O5 339.0855, found m/z
339.0860.
Acknowledgment. We gratefully acknowledge funding from
NSERC (Discovery Grants Program), Merck Research Labo-
ratories (Canadian Academic Development Program), the
Canadian Foundation for Innovation, the Ontario Research
Foundation, and the University of Toronto (Connaught Fund).
Supporting Information Available: Full experimental details
and a comprehensive list of Lewis acids tested for the reaction
shown in Table 1 and NMR spectral data (1H and 13C) for 1a-h,
3b-c, and 4a-h; details of computational studies and summa-
ries of the computed quantities and geometries; crystallographic
information files (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
3-(3-Methoxyphenylamino)-4-(4-bromophenylamino)cyclo-
but-3-ene-1,2-dione (4d). Synthesized on 0.4 mmol scale accord-
ing to general procedure C, the product was isolated as a white
solid (136 mg, 99% yield): IR (powder) 3147 (br), 1787 (m), 1667
3992 J. Org. Chem. Vol. 75, No. 12, 2010