Croconamides: A new dual hydrogen bond donating motif for anion recognition and organocatalysis

Article abstract of DOI:10.1039/c7ob00441a

We introduce bis-aryl croconamides as a new member in the family of dual hydrogen bonding anion receptors. In this study a series of croconamides are synthesised, and the selectivity for anion binding is investigated (Cl^- > Br^- > I^- in CH₂Cl₂). The croconamides exhibit different structures in the crystal phase depending on the substituents on the aromatic rings, and furthermore, the crystal structure revealed the presence of tautomers. DFT calculations elucidated the complex structures formed upon addition of anion to the croconamides, confirming the order of association constants towards the halogen anions. The use of croconamides as organocatalysts in a proof-of-concept study is demonstrated in the formation of THP ethers. In addition to this, construction of a Hammet plot further elucidates the mechanism in action on formation of THP ethers.

Full text of DOI:10.1039/c7ob00441a

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2017, DOI: 10.1039/C7OB00441A.
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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00441A
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Croconamides: A new dual hydrogen bond donating motif for
anion recognition and organocatalysis
Anne Jeppesen,a Bjarne E. Nielsen,a Dennis Larsen,b Olivia M. Akselsen,a Theis I. Sølling,a Theis
Brock-Nannestada and Michael Pittelkowa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We introduce bis-aryl croconamides as a new member in the family of dual hydrogen bonding anion receptors. In this
study a series of croconamides are synthesised, and the selectivity for anionbinding is investigated (Cl->Br->I- in CH2Cl2).
The croconamides exhibit different structures in the crystal phase depending on the substituents on the aromatic rings,
and furthermore, the crystal structure revealed the presence of tautomers. DFT calculations elucidated the complex
structures formed upon addition of anion to the croconamides, confirming the order of association constants towards the
halogen anions. The use of croconamides as organocatalysts in a proof-of-concept study is demonstrated in the formation
of THP ethers. In addition to this, construction of a Hammet plot further elucidates the mechanism in action on formation
of THP ethers.
www.rsc.org/
potent anion recognition and organocatalysis properties
(Figure 1, c). Previous studies on similar croconamide
structures are scarce and do not consider the properties
investigated here.16-21 Here we present the first synthesis of a
series of bis-aryl croconamides and explore their abilities to
bind anions and, as proof-of-concept, to catalyse the
formation of THP ethers (Figure 1, d).
Introduction
Dual hydrogen bond donating motifs, such as those found in
(thio)ureas and squaramides (Figure 1), have been studied
intensively recently due to their ability to engage in strong
hydrogen bonds.1-4 The anion recognition capabilities have
been utilized in the design of anion transporters
(anionophores), anion sensors and in the development of
organocatalysts.5-7 A structurally simple organocatalyst that
has been widely adopted is the thiourea catalyst developed by
Schreiner (Figure 1, a),8 where the bis-trifluorophenyl groups
proved to be particularly important for catalytic activity.9
Another well-known dual hydrogen-bonding scaffold is that
based on squaramides (Figure 1, b).10 Squaramides and
thioureas have similar dual hydrogen bonding capabilities and
the acidic amide hydrogens (pKa = 8.37–12.48 vs 8.5-13.4 for
comparable squaramide and thiourea structures, respectively,
in DMSO) make them powerful anion receptors.11-13 Compared
to thioureas, these interactions are typically stronger for
squaramides, and squaramide-containing structures are also
popular organocatalysts.14-15
a) Thiourea
b) Squaramide
CF3
CF3
O
O
F3C
CF3
S
N
N
F3C
N
H
N
H
CF3
H
H
F3C
CF3
c) Croconamide (This work)
O
O
H2NAr, Zn(OTf)2
O
O
O
O
Toluene/DMF (19:1)
22 C, 4 h
Ar
Ar
N
O
O
N
(17-81 % yield)
H
H
X-
These observations led us to consider if the croconic acid
analogue to the squaramides, the croconamides could possess
Ar = 1a: 3,5-(CF3)2C6H3 1b: 4-(CF3)C6H4 1c: C6H5
1d: 4-(OCH3)C6H4 1e: 4-(n-Butyl)C6H4
d) Croconamide in organocatalysis
O
O
O
HO
Croconamide 1a-b
+
(10 mol %)
X
X
Benzoic acid (10 mol%)
DHP
10 eq.
p-subst. phenol
CH2Cl2, 36
C
THPx
50 mM
Figure
1 a) Example of thiourea, b) squaramide c) Preparation of N,N-bis-aryl
croconamides 1a-e, and d) The reaction catalysed by croconamides in this work.
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Results and discussion
c
a
b
4.0 eq.
3.0 eq.
2.0 eq.
1.5 eq.
1.0 eq.
0.8 eq.
0.6 eq.
0.4 eq.
0.2 eq.
0.0 eq.
Synthesis
The bis-aryl croconamides were synthesised from dimethyl
croconate and the corresponding anilines (Figure 1, c).
Dimethyl croconate is readily available from croconic acid.22
We adapted the zinc triflate mediated reaction protocol
developed for squaramides from Taylor and co-workers, and
the procedure was successful with a range of electron rich and
electron deficient anilines.7 For the purpose of anion
recognition studies and organocatalysis we focused on the
trifluoromethyl substituted derivatives 1a and 1b, as these are
electron deficient and they are also suitably soluble in organic
solvents appropriate for the studies.
c
a
b
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
(ppm)
Anion recognition
Figure 2 Changes observed in the 1H-NMR (CD2Cl2) of 1a (1.0 × 10-3 M) upon increasing
The association properties of 1a and 1b towards various anions
were investigated in dichloromethane. The continuous
variation method (Job’s method) indicated a 1:1 binding
stoichiometry for all anions tested (see ESI). The association
constants for 1a towards anions as their tetrabutylammonium
(TBA) salts were determined by titration experiments using 1H-
NMR or UV/Vis spectroscopy (Table 1). It was convenient to
observe the changes in chemical shift for the aromatic CH-
protons (protons a and b, Figure 2), as these protons
experience a significant downfield shift upon addition of anion.
During the titration, the signal for the amide protons
broadened to such a degree as to make it impractical to
monitor these signals (Figure 2). Due to very strong binding
between 1a and chloride, this association constant could not
be accurately determined by a NMR titration and it was
therefore determined by a UV/Vis titration.23 From the
absorbance spectra (Figure 3) several isosbestic points are
evident indicating that only two species are present during the
experiment (1a and 1a∙Cl-), i.e. there is no evidence for
deprotonation of the croconamide. For the halides the binding
strength was in the order: Cl->Br->I- towards 1a. Chloride
the concentration of TBAI (0 – 4 × 10-3 M).
More anions were investigated towards 1a; nitrate and
hydrogensulphate, which both bind strongly to croconamide
1a with binding affinities of 2.3 × 104 m-1 and 2.5 × 103 m-1,
respectively. Titration with TBA acetate led to deprotonisation
rather than complexation with anion (see ESI). To enable a
comparison with the binding properties of thiourea- and
squaramide-based anion receptors, the binding constant
between 1b and Cl- was determined in anhydrous DMSO
(Table 1, entry 7). This binding constant is lower than for the
corresponding squaramide obtained in DMSO with 0.5 % water
(Ka = 458 m-1), but of the same order of magnitude as the
equivalent thiourea in DMSO (Ka = 41 m-1).24 To verify that it is
indeed 1:1 complexes formed, upon addition of anions to
croconamides 1a and 1b, we fitted the above titration data to
a 1:2 binding model (see ESI). The results from the 1:2 fits did
not give rise to true solutions, or the error on the fit was
greater than for the fit to a 1:1 binding model. This indicates
that the binding stoichiometry is in fact 1:1.
binding to 1b was in the same order of magnitude as for 1a
,
X-ray crystal structures
showing that the number of trifluoromethyl substituents does
not have a major effect in this case.
0.15
0.40
0.10
0.05
0.00
Table 1 Association constants for 1a and 1b determined by 1H-NMR or UV/Vis titration
experiments in CH2Cl2. Ka obtained by non-linear regression (see ESI).
0.35
0.30
0.25
Serie1
Serie2
Serie3
Serie4
Serie5
Serie6
1x10-5
2x10-5
3x10-5
0
Serie7
0.20
0.15
0.10
Serie8
Serie9
Guest conc. (M)
Serie10
Serie11
12
13
14
15
0.05
0.00
250
300
350
400
450
500
550
Wavelength (nm)
Figure 3 Absorbance spectra of 1a (1.0 × 10-5 M) in CH2Cl2 with increasing amounts of
TBACl (0 – 2.5 × 10-5 M) (Change of light source cause an artefact at 380 nm). Inset:
Changes in absorbance at 413 nm.
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Single crystal X-ray structures of 1a and 1c (Figure 4) were
determined to confirm the chemical structures and to gain
insight to possible binding modes. In the crystalline state, 1a
shows intramolecular π-stacking of the two aromatic rings.
This forces the croconamide to adopt a conformation where
the amide hydrogens points in opposite directions, thereby
leaving no evidence of the dual hydrogen bond motive in the
crystal state. This is not the case for 1c, where the phenyls are
only slightly twisted in opposite directions allowing for
intermolecular hydrogen bonding between the center carbonyl
group and the amide hydrogens of the neighboring
croconamide molecule in the crystal lattice. In addition the
crystal structure for 1c indicated the presence of hydrogen
atoms on the carbonyl groups of the cyclopentene trione ring.
This could be due to tautomers present in the same crystal
structure (Figure 5). The bond distance of the central carbonyl
for 1a is 1.207 Å and 1.213 Å for croconic acid, whereas it is
elongated and measures 1.236 Å for 1c, suggesting a partial
single bond character.25 The mean bond length for a C-O bond
in carbonyls in cyclopentanones is 1.208 Å, and for the C-O
bond in enols it is 1.333 Å, revealing that the distance
measured for 1c is between the length of a C-O single bond
and a C-O double bond.26 The formal C-C double bond in the
five-membered ring is 1.401 Å for 1a, 1.382 Å for croconic acid,
and 1.440 Å for 1c. The mean bond distance for a C-C double
bond in cyclopentene is 1.323 Å, implying a partial single bond
Figure 4 Crystal structure indicating the presence of tautomers in the crystal phase of
1c.
hydrogen bond motif is indeed present for all croconamide
structures.
DFT-calculations
Previously, the dipole moment and hyperpolarisabilities have
been calculated for various croconamides.21 We wished to
perform DFT calculations, as these can give important insight
into the structure of supramolecular complexes. We calculated
the energy of complexation for 1c
, the corresponding
squaramide and thiourea with the halides chloride, bromide,
and iodide. Both the simple B3LYP/MidiX and the advanced
G4MP2 level was explored (Table 2 and ESI). The favorable
energy of complexation is in the order Cl->Br->I- and
squaramide>croconamide>thiourea. The calculations, thus, are
in accordance with the experimental data. The G4MP2-level
calculations (Table 2, entry 4), shows the same trend as the
lower level of calculations (B3LYP/MidiX). Structural
information can also be obtained from the calcuations, and a
twisting of the anilines with regards to the central five-
membered ring is observed (Figure 6). For complexation with
chloride and bromide one aniline was almost in plane with the
central aromatic ring (torsional angle ~ 6 - 9°) while the second
aniline was twisted out of the plane (torsional angle ~ 20°). For
iodide, the two anilines were twisted out of the plane in
opposite directions with a torsional angle ~ 19° for both
anilines. Complexation with iodide forces the conjugated
system of the croconamide out of planarity, which is highly
unfavorable. This is in agreement with the order of binding for
the halides, with the smaller chloride resulting in the strongest
character for the compounds, which is more expressed for 1c
.
The C-N bonds extending from the ring are 1.341 and 1.347 Å,
in 1a, compared to 1.330 Å for both C-N bonds in 1c. Although
not conclusive, this suggests a partly double bond character
for the C-N bonds in 1c
. From this we gather that
tautomerisation can occur and is evident in the crystal
structure. Despite extensive efforts, we have yet to obtain
crystal structures of anion conjugates of either of the
croconamides. It is important to stress that in solution we
observe symmetrical NMR spectra indicating the dual
Table 2 DFT calculated energies of complexation (gas phase, B3LYP/MidiX and G4MP2.
Figure 5 Single crystal X-ray structures of 1a (top) and 1c (bottom).
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Figure 6 Front and side views of the calculated complexation of 1c with bromide.
association.
Organocatalysis
We sought to elucidate the ability of croconamides to act as
organocatalysts, and we chose the tetrahydropyranylation of
phenols as our model reaction (Table 3). Schreiner’s catalyst
has previously been used to catalyse this reaction.27-28 The
results are listed in Table 3, entry 1 - 3. The studied catalysts
1a catalyses the reaction with the highest rate, 3.74 × 10-5 m-1
s-1, 1b is slightly less efficient (1.06 × 10-5 m-1 s-1). This implies
that the number of trifluoromethyl groups does have an
impact on the croconamides’ ability to catalyse the reaction.
Schreiner’s catalyst works very well for this reaction when the
reaction is performed in neat DHP, but not under the dilute
conditions applied here, where we did not observe any
conversion.27 Structure 1a do, however, catalyse the reaction
with a higher rate than with Schreiner’s catalyst or with
benzoic acid alone (no catalyst present), which did not result in
product formation. To gain further insight to the reaction
catalysed by 1a, a series of p-substituted phenols were tested
in the tetrahydropyranylation reaction (Table 3, entry 4-8). The
Figure 7 Hammett plot for p-substituted phenols in tetrahydropyranylation with
catalyst 1a.
fits with the oxygen on the phenol taking part in a non-
covalent bond in the transition state, indicating that the
mechanism involves an organised complexation of the phenol
with DHP and the catalyst.
Acidity
The pKa values were determined for 1a and 1b in DMSO to
11.5 and 10.8 respectively (see ESI). We expected catalyst 1a
to possess more acidic croconamide protons than 1b, as 1a has
two CF3-groups per aryl group, and 1b only one. This would be
in agreement with 1a being the most effective catalyst, if the
croconamides enable the reaction via the dual hydrogen
bonding motif, as is the case for similar thio(urea) catalysts.24
The explanation for this unexpected result is that the more
electron deficient the aryl-substituent are, the more prone the
croconamide is to be present as the corresponding hydrate on
the central carbonyl group (Scheme 1). This phenomena is
conveniently observable in DMSO solution (the solvent used to
measure the pKa value) where water is often present, but less
so in CH2Cl2 solution (the solvent used for the catalysis
experiments). When leaving a sample of 1a in 0.5 vol. % water
in DMSO, the formation of the hydrate can be observed using
1H-NMR spectroscopy. After 48 hours the samples has reached
equilibrium, where half of 1a is present as the hydrate. In the
case of 1b, only 35 % existed as the hydrate after 48 hours.
The identities of the hydrates were confirmed with LC/MS
analysis. For the corresponding squaramide to 1a the pKa value
is 8.37 in DMSO,13 which means that the croconamide 1a is
less acidic than its squaramide analogue.
-
obtained rate constants and σp values were used to obtain a
Hammett plot with good linear correlation (Figure 7). The
negative slope (ρ = -0.27) indicates that electron donating
substituents on the aromatic ring of the phenol facilitate the
reaction, and a decrease in electron density on the phenol
occurs in the transition state. This could either be in the form
of build-up of positive charge or loss of negative charge. This
Table 3 Tetrahydropyranylation reaction. k2 obtained by non-linear regression (See ESI).
M
Conclusions
To conclude, we have introduced a new dual hydrogen bond
motif, the croconamides, and we have illustrated how this new
Scheme 1 Formation of croconamide hydrate.
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motif can be used for both anion recognition and 3,5-bis(trifluoromethyl)aniline (1.35 g, 0.9 ml, 5.9 mmol) was
organocatalysis. We are currently exploring further added. The flask was fitted with a stopper and the reaction
functionalisation of these structures and the preparation of was stirred at room temperature for four hours. The reaction
unsymmetrical croconamide structures with the aim of mixture was evaporated to dryness, redissolved in
enabling strong anion binding and further applications in ethylacetate and evaporated on Celite (25 g) for purification
catalysis.
using dry column vacuum chromatography. A column of 4 cm
in diameter charged with 4 cm silica gel, a gradient of 2.5 %
ethyl acetate in heptane was used. The gradient was held
constant from 10 % ethyl acetate in heptane, and all fractions
were 50 ml. Fraction 13 to 37 was evaporated, and the isolated
material was recrystallised from dichloromethane to yield 1a
Acknowledgements
We acknowledge financial support from the Lundbeck
Foundation for a Young Group Leader Fellowship (MP), the
Carlsberg Foundation for a PostDoc grant (DL), the Innovation
Fund Denmark and Department of Chemistry, University of
Copenhagen for a PhD scholarship (AJ).
as an orange solid (503 mg, 30 %), decompose above 250°
C. 1H
NMR (500 MHz, DMSO-d6) δ 10.72 (s, 2H), 7.39 (s, 2H), 7.19 –
7.16 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 186.54, 181.27,
142.42, 139.12,129.86 (q, J = 33.2 Hz), 122.77 (q, J = 273.0 Hz),
121.19, 116.12. 19F NMR (470 MHz, DMSO-d6) δ -60.52. LC-
HRMS: m/z = 563.0276 [M-H+] (Calculated 563.0271).
Experimental
4,5-Bis((4-(trifluoromethyl)phenyl)amino)cyclopent-4-ene-
1,2,3-trione (1b)
General
All chemicals were purchased from commercial suppliers and
used as received unless otherwise stated. Dimethyl croconate
was synthesised according to the procedure by Williams,22 and
barium croconate for this synthesis was synthesised by
SunChemicals. For synthesis and kinetic studies HPLC grade
solvents were used, for kinetic studies these were dried using
molecular sieves (4 Å). For UV/Vis titrations spectroscopic
grade solvents were used, and dimethyl sulfoxide was dried by
standing over molecular sieves (4 Å) prior to use.
Dimethylcroconate (200 mg, 1.18 mmol) and Zn(OTf)2 (85 mg,
0.236 mmol) was suspended in toluene/DMF (19:1, 10 ml) and
4-(trifluoromethyl)aniline (400 mg, 2.5 mmol) was added. The
flask was fitted with a stopper and the reaction was stirred at
room temperature for four hours. The reaction mixture was
evaporated to dryness, redissolved in ethylacetate and
evaporated on Celite (20 g) for purification using dry column
vacuum chromatography. A column of 4 cm in diameter
charged with 4 cm silica gel, a gradient of 5 % ethyl acetate in
heptane was used. Fraction 10 to 13 were evaporated, and the
isolated material was recrystallised from chloroform to yield
A Bruker Ultrashield Plus 500 spectrometer with a Cryoprobe
was used to record NMR spectra of the synthesised
compounds. The spectrometer operated at 500 MHz for 1H
and 126 MHz for 13C. For 19F and titrations a Bruker Avance 3
spectrometer with a BBFO probe was used, operating at 470
MHz for 19F, 500 MHz for 1H and 126 MHz for 13C. The
spectrometers operated at 20 °C and all spectra were
1b as an orange solid( 85 mg, 17 %), decompose above 260°C.
1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 2H), 7.27 (d, J = 8.5
Hz, 4H), 6.84 (d, J = 8.5 Hz, 4H). 13C NMR (126 MHz, DMSO-d6)
δ 186.09, 180.93, 143.76, 141.14, 124.13 (q, J = 271.2), 124.88,
123.73 (q, J = 32.2), 121.77. 19F NMR (470 MHz, DMSO-d6) δ -
59.04. LC-HRMS: m/z = 427.0525 [M-H+] (Calculated 425.0523).
4,5-Bis(phenylamino)cyclopent-4-ene-1,2,3-trione (1c)
1
referenced to the internal solvent residue for H and 13C, and
to trifluoroacetic acid in a sealed tube for 19F. The 19F spectrum
for the Schreiner catalyst, however, was recorded on an
Oxford NMR 300 spectrometer, operating at 282 MHz.
MestReNova version 10.0.2 from MestreLab Research S.L. was
used to process the NMR data. Standard 1D and 2D NMR
Dimethylcroconate (200 mg, 1.18 mmol) and Zn(OTf)2 (85 mg,
0.236 mmol) was suspended in toluene/DMF (19:1, 10 ml) and
aniline (230 mg, 225 µl, 2.47 mmol) was added. The flask was
fitted with a stopper and the reaction was stirred at room
temperature for four hours. Hereafter, dicholoromethane (20
ml) was added and the precipitate was centrifuged down and
washed several times with ethyl acetate (7 × 40 ml) to yield 1c
1
techniques (COSY, 13C-APT, HSQC (for H and 13C), and HMBC
(for 1H and 13C)) was used to assign 1H and 13C resonances.
UV/Vis measurements were performed using a Perkin Elmer
UV/Vis spectrometer Lamda 2. HPLC analysis was carried out
on a Dionex UltiMate 3000, which was coupled to an UltiMate
3000 diode array UV/Vis detector that measured absorbance
of light between 190 – 800 nm.
as a dark red solid (194 mg, 56 %), decompose above 240°
C. 1H
NMR (500 MHz, DMSO-d6) δ 10.07 (s, 2H), 7.01 (t, J = 7.8 Hz,
2H), 6.88 (t, J = 7.4 Hz, 2H), 6.75 (d, J = 7.6 Hz, 4H). 13C NMR
(126 MHz, DMSO-d6) δ 186.04, 180.20, 145.26, 137.51, 127.84,
124.07, 122.06. LC-HRMS: m/z = 291.0778 [M-H+] (Calculated
291.0775).
LC-MS analysis were obtained by coupling the above
mentioned HPLC apparatus with
system equipped with an ESI source.
a Bruker MicrOTOF-QII
4,5-bis((4-methoxyphenyl)amino)cyclopent-4-ene-1,2,3-
trione (1d)
Synthesis
Dimethylcroconate (200 mg, 1.18 mmol) and Zn(OTf)2 (85 mg,
0.236 mmol) was suspended in toluene/DMF (19:1, 10 ml) and
p-anisidine (304 mg, 2.47 mmol) was added. The flask was
fitted with a stopper and the reaction was stirred at room
temperature for four hours. The mixture was evaporated to
4,5-Bis((3,5-bis(trifluoromethyl)phenyl)amino)cyclopent-4-
ene-1,2,3-trione (1a)
Dimethylcroconate (500 mg, 2.94 mmol) and Zn(OTf)2 (214 mg,
0.587 mmol) was suspended in toluene/DMF (19:1, 10 ml) and
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6. R. B. P. Elmes, P. Turner and K. A. Jolliffe, Org. Lett., 2013,
15, 5638-5641.
7. A. Rostami, A. Colin, X. Y. Li, M. G. Chudzinski, A. J. Lough
and M. S. Taylor, J. Org. Chem., 2010, 75, 3983-3992.
dryness, and the resulting crude was dissolved in methanol (30
ml) to which was added diethyl ether (50 ml). The precipitate
was centrifuged down and washed several times with diethyl
ether (4 × 15 ml) to yield compound 1d (337 mg, 81 %) as a
dark red solid, decompose above 250°C. 1H NMR (500 MHz,
DMSO-d6) δ 9.94 (s, 2H), 6.69 (d, J = 8.9 Hz, 4H), 6.60 (d, J = 8.9
Hz, 4H), 3.67 (s, 6H). 13C NMR (126 MHz, DMSO-d6) δ 185.47,
179.99, 156.51, 145.72, 130.65, 123.80, 113.28, 55.32. LC-
HRMS: m/z = 351.0989 [M-H+] (Calculated 351.0986).
8. P. R. Schreiner and A. Wittkopp, Org. Lett., 2002,
220.
4, 217-
9. A. Wittkopp and P. R. Schreiner, Chem. Eur. J., 2003,
414.
9, 407-
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503–504, 28-32.
4,5-bis((4-butylphenyl)amino)cyclopent-4-ene-1,2,3-trione
(1e)
12. G. Jakab, C. Tancon, Z. Zhang, K. M. Lippert and P. R.
Schreiner, Org. Lett., 2012, 14, 1724-1727.
Dimethylcroconate (200 mg, 1.18 mmol) and Zn(OTf)2 (85 mg,
0.236 mmol) was suspended in toluene/DMF (19:1, 10 ml) and
4-butylaniline (0.37 ml, 2.5 mmol) was added. The flask was
fitted with a stopper and the reaction was stirred at room
temperature for four hours. The mixture was evaporated to
dryness, and the resulting crude dissolved in methanol (40 ml)
to which was added diethyl ether (50 ml). The precipitate was
centrifuged down and washed several times with diethyl ether
(4 × 15 ml) to yield 1e (220 mg, 46 %) as a dark solid, mp. 233 –
234 °C. 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 2H), 6.77 (d, J
= 8.3 Hz, 4H), 6.60 (d, J = 8.3 Hz, 4H), 2.39 (t, J = 7.6 Hz, 4H),
1.49 – 1.40 (m, 4H), 1.23 – 1.30 (m, 4H), 0.91 (t, J = 7.3 Hz, 6H).
13C NMR (126 MHz, DMSO-d6) δ 185.56, 180.42, 145.27,
138.27, 135.19, 127.60, 122.04, 34.26, 33.15, 21.63, 13.82. LC-
HRMS: m/z = 405.2171 [M-H+] (Calculated 405.2173).
13. X. Ni, X. Li, Z. Wang and J.-P. Cheng, Org. Lett., 2014, 16
1786-1789.
,
14. S. J. Edwards, H. Valkenier, N. Busschaert, P. A. Gale and A.
P. Davis, Angew. Chem. Int. Ed., 2015, 54, 4592-4596.
15. J. Liu, C. Chen, Z. Li, W. Wu, X. Zhi, Q. Zhang, H. Wu, X.
Wang, S. Cui and K. Guo, Polym. Chem., 2015, 6, 3754-
3757.
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1962, 657, 131-141.
17. S. Skujins and G. A. Webb, Tetrahedron, 1969, 25, 3947-
3954.
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1969, 25, 3935-3945.
19. J. Fabian and H. Junek, Monatsh. Chem., 1985, 116, 625-
632.
Bis(3,5-bis[trifluoromethyl]phenyl) Thiourea (Schreiner’s
catalyst)28
20. G. Seitz, J. Auch and W. Klein, Chemiker-Zeitung, 1987, 111
343-344.
21. J. O. Morley, J. Mol. Struct. Theochem, 1995, 357, 49-57.
,
3,5-Bis(trifluoromethyl)aniline (165 mg, 0.718 mmol, 1.2 eq.)
was
dissolved
in
CHCl3
(5.0
mL)
and
3,5-
22. R. F. X. Williams, Phosphorus, Sulfur Silicon Relat. Elem.,
1976, , 141-146.
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24. N. Busschaert, I. L. Kirby, S. Young, S. J. Coles, P. N. Horton,
M. E. Light and P. A. Gale, Angew. Chem. Int. Ed., 2012, 51,
4426-4430.
25. D. Braga, L. Maini and F. Grepioni, Chem. Eur. J., 2002, 8,
1804-1812.
26. F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G.
Orpen and R. Taylor, J. Chem. Soc. Perkin Trans. 2, 1987, 1-
19.
bis(trifluoromethyl)phenyl isothiocyanate (163 mg, 0.601
mmol, 1.0 eq.) was added. Acetonitrile (2.0 mL) was added and
the resulting clear solution was heated under reflux for 40
hours after which all of the solvent was removed under
reduced pressure. The white residue was recrystallized from
boiling chloroform (9 mL) to yield the title compound as white
2
needles (292 mg, 97 %.), mp. 174 – 175 °
C. 1H NMR (500 MHz,
DMSO-d6) δ = 10.64 (s, 2H), 8.20 (s, 4H), 7.87 (s, 2H). 13C NMR
(126 MHz, DMSO-d6) δ = 180.59, 141.15, 130.34 (q, J=32.7),
124.16, 123.16 (q, J=272.3), 117.79. 19F NMR (282 MHz, DMSO-
d6) δ = -59.77. Elemental analysis for C17H8F12N2S: Found
(calculated) 41.15 % C (40.81), 1.48 % H (1.61), 5.60 % N (5.60).
LC-HRMS: 501.0292 [M+H+] (Calculated 501.0289).
27. M. Kotke and P. R. Schreiner, Synthesis, 2007, 2007, 779-
790.
28. Y.-B. Huang and C. Cai, J. Chem. Res., 2009, 2009, 686-688
Notes and references
1. Z. Zhang and P. R. Schreiner, Chem. Soc. Rev., 2009, 38
1187-1198.
,
2. V. Amendola, L. Fabbrizzi and L. Mosca, Chem. Soc. Rev.,
2010, 39, 3889-3915.
3. J. Alemán, A. Parra, H. Jiang and K. A. Jørgensen, Chem. Eur.
J., 2011, 17, 6890-6899.
4. M. Tsakos and C. G. Kokotos, Tetrahedron, 2013, 69
10199-10222.
,
5. N. Busschaert, R. B. P. Elmes, D. D. Czech, X. Wu, I. L. Kirby,
E. M. Peck, K. D. Hendzel, S. K. Shaw, B. Chan, B. D. Smith,
K. A. Jolliffe and P. A. Gale, Chem. Sci., 2014, 5, 3617-3626.
6 | J. Name., 2012, 00, 1-3
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