2-(guanidiniocarbonyl)furans as a new class of potential anion hosts: Synthesis and first binding studies

Article abstract of DOI:10.1002/ejoc.200600324

The synthesis of a new class of potential anion hosts, the 2-(guanidiniocarbonyl)furans 5a-d, is presented in this study. The facile decomposition of furans under acidic conditions makes the synthesis of these compounds challenging. First binding studies showed that the (guanidiniocarbonyl)furans are much more acidic (pK_a ≈5.5) than the analogous pyrroles (pK_a ≈ 7) previously introduced by us for oxoanion binding in aqueous solvents. Hence, anion binding with the furan derivatives occurs only in acidic solutions below pH = 5. Therefore, carboxylates are not bound efficiently, whereas, for example, the less basic hydrogen sulfate is bound by 5b with an association constant of K = 600 M ^-1 in aqueous DMSO even in the presence of a large excess of buffer. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600324

FULL PAPER
DOI: 10.1002/ejoc.200600324
2-(Guanidiniocarbonyl)furans as a New Class of Potential Anion Hosts:
Synthesis and First Binding Studies
Carsten Schmuck*[a] and Uwe Machon[a]
Keywords: Furans / Guanidinium cations / Molecular recognition / Supramolecular chemistry
The synthesis of a new class of potential anion hosts, the 2-
(guanidiniocarbonyl)furans 5a–d, is presented in this study.
The facile decomposition of furans under acidic conditions
makes the synthesis of these compounds challenging. First
binding studies showed that the (guanidiniocarbonyl)furans
are much more acidic (pKa Ϸ 5.5) than the analogous pyrroles
(pKa Ϸ 7) previously introduced by us for oxoanion binding
in aqueous solvents. Hence, anion binding with the furan de-
rivatives occurs only in acidic solutions below pH = 5. There-
fore, carboxylates are not bound efficiently, whereas, for ex-
ample, the less basic hydrogen sulfate is bound by 5b with an
association constant of K = 600
the presence of a large excess of buffer.
M
–1 in aqueous DMSO even in
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
guanidinium compounds for anion binding, we decided to
synthesize 2-(guanidiniocarbonyl)furans 5 as potentially
new receptors for anion binding. So far there are only very
few furan-based synthetic receptors known in the litera-
ture.[9] We present here the synthesis of the 2-(guanidinio-
carbonyl)furans 5a–c and some first binding studies.
Introduction
The furan heterocycle 1 has a lower extent of aromaticity
and higher diene character than other heterocycles like pyr-
role (2) and thiophene (3). The chemical behaviour of fu-
rans is therefore quite different and often resembles more
that of an unsaturated than an aromatic compound. Never-
theless, furan compounds, which are ubiquitous and readily
available from the vegetable biomass,[1,2] are versatile build-
ing blocks for organic synthesis[3–7] and for medicinal chem-
istry. For example, ranitidine 4 is a very efficient histamine
receptor antagonist (type 2),[8] in which a furan is connected
to a cationic ammonium ion and a bidentate hydrogen-
bond donor (a urea analogue).
Results and Discussion
The design of 5 was based on our analogous pyrrole
compounds, a 2,5-disubstituted furan containing on one
side a positively charged guanidiniocarbonyl cation and on
the other side an ester or an amide that might be further
functionalized with an amino acid (Figure 1).
We were therefore interested in synthesizing cationic fu-
rans with similar hydrogen-bond donor functionalities.
With regard to our long-standing expertise with acylated
Figure 1. Target compounds 5a–5d.
Scheme 1 describes the synthesis of the 2-(guanidiniocar-
bonyl)furan 5a. The furan ester 7 was synthesized according
to literature methods.[10,11] Chloromethylation of commer-
cially available methyl furan-2-carboxylate (6) with para-
formaldehyde, zinc chloride and anhydrous hydrogen chlo-
[a] Institut für Organische Chemie, Universität Würzburg,
Am Hubland, 97074 Würzburg, Germany
Fax: +49-931-8884626
E-mail: schmuck@chemie.uni-wuerzburg.de
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C. Schmuck, U. Machon
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ride yielded 7. The chloro substituent was replaced accord- the monoacid 10 with ethylamine by using O-(6-chloro-1H-
ing to a literature procedure[12,13] to obtain 8 by heating 7 benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
with anhydrous sodium acetate in acetic acid containing phosphate (HCTU) as the coupling reagent gave the corre-
acetic anhydride. The selective hydrolysis of the acetic acid sponding amide 13 in a yield of 59%. However, for the actu-
ester group of 8 by reaction with NaOMe in methanol solu- ally isolated yield the specific work-up is very important.
tion gave the furfuryl alcohol 9.[13] For the subsequent oxi- Flash chromatography on silica gel provided very low yields
dation step, we first tested a literature procedure[14] reported mainly because of decomposition of the product on the col-
for a related 2,5-substituted furfuryl alcohol: a two-step oxi- umn. Even the use of triethylamine to deactivate the SiO2
dation with MnO2 in acetone with the corresponding alde- before chromatography could not prevent decomposition.
hyde as an intermediate. During the first step of this reac- Hence, for these furan systems the reversed phase flash col-
tion, we detected decomposition of the furan compound by umn chromatography with octadecyl-functionalized silica
TLC. So we decided to prepare 10 directly in a one-step gel (RP18) or the purification by extraction (with diethyl
oxidation of the hydroxymethyl group of 9 with potassium ether or ethyl acetate from the aqueous solution of the reac-
permanganate in acetone. The best yields obtained were tion mixture) lead to the best results. In this case PyBOP
about 66%. The moderate yield is most likely partly due to could not be used even though it gave better yields accord-
the decomposition of the product during the work up, ing to reaction monitoring by TLC. However, the coupling
which required precipitation of the free carboxylic acid product 13 could not be separated from the phosphane ox-
from an aqueous solution with HCl. Also, losses may have ide byproduct without significant losses. In general, product
occurred during the filtration of the large amounts of isolation and purification by using HCTU as the coupling
MnO2. Reaction of the carboxylic acid 10 with the mono- reagent was much easier even though the initial coupling
Boc-protected guanidine 11 by using (1H-benzotriazol- yields were significantly lower than those with PyBOP. To
1-yloxy)tripyrrolidinophosphonium hexafluorophosphate obtain the Boc-protected receptor 17 the methyl ester func-
(PyBOP) as the coupling reagent gave the protected com- tion of 13 was hydrolyzed with LiOH in methanol solution,
pound 12. Deprotection of 12 was achieved by using TFA and the carboxylic acid 15 was coupled with mono-Boc-
to provide the target compound 5a, which was easily pre- protected guanidine 11 after activation with HCTU. Depro-
cipitated and isolated as the corresponding picrate salt.
tection of 17 by using trifluoroacetic acid and precipitation
of the picrate from a methanol solution provided the N-
ethylcarbamoyl compound 5b. For the yields of this step,
the reaction conditions for the deprotection of the Boc-
group with TFA proved to be crucial. If the temperature
was too low (0 °C), the reaction time was too long for quan-
titative removal of the protecting group. Significant decom-
position led to low yields (34%). If the deprotection was
carried out at room temperature, the required reaction
times were much shorter, but also the decomposition of the
furan under these acidic conditions was much faster. Hence,
the isolated yield was only 12%. The best yields were ob-
tained by adding TFA at 0 °C and warming the mixture to
room temperature within 20 minutes before work-up. We
thus obtained an excellent yield of 86%.
The valine-substituted compound 5c was synthesized ac-
cordingly. Coupling of 10 with H-Val-NH2 using HCTU in
the presence of 4-methylmorpholine (NMM) yielded the es-
ter 14, which was hydrolyzed by using LiOH in MeOH to
obtain the acid 16. Coupling of 16 with mono-Boc-pro-
tected guanidine 11 to give 18 was achieved by using
PyBOP as the activating agent, the reaction with HCTU
failed in this case. However, extensive flash column
chromatography with octadecyl-functionalized RP18 silica
gel was needed to obtain 18 in pure form, which led to an
isolated yield of only 42%. After deprotection of 18 with
TFA, the picrate salt of compound 5c was isolated from
MeOH. The moderate isolated yield of 43% is most likely
to be a result of the high solubility of 5c in the methanol/
water mixture (Scheme 2).
Scheme 1. Synthesis of compound 5a.
The syntheses of compounds 5b and 5c were performed
For the lysine derivative 5d the same reaction route was
analogously to the pyridine compounds reported previously tested (Scheme 3). The coupling of the amino acid deriva-
by us[15] starting from the carboxylic acid 10. Coupling of tive 19 and acid 10 by using HCTU was successful as moni-
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A New Class of Potential Anion Hosts
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column chromatography. Unfortunately, the bis-cationic
compound 5d decomposed completely during purification.
1
We could only prove its formation in a H NMR spectrum
of the crude product before the purification attempts. So
far, we did not pursue the synthesis of 5d any further, as
any further investigations would also most likely be ham-
pered by the limited stability of this compound especially
in acidic aqueous solution. This instability would limit its
use as an anion sensor significantly, especially under acidic
conditions (vide infra).
Scheme 2. Synthesis of compounds 5b and 5c.
tored by TLC. However, compound 20 could not be iso-
lated from the reaction mixture by reversed phase
chromatography. Even after extensive chromatography, sig-
nificant amounts of impurities were still present. As the
yield of the crude product already dropped significantly as
a result of the purification attempts, we decided to first hy-
drolyse the crude product, hoping that purification of the
free acid 21 would be easier. The cleavage of the methyl
ester with LiOH provided the acid 21 in quantitative yields
according to TLC monitoring, but the acid 21 could not be
separated from the impurities either. Because of the diffi-
culties in isolating 21 in pure form, we tried a new route to
compound 5d. The idea was to replace the methyl ester by
a more hydrophobic benzyl ester so that the intermediate
could be purified more easily by reversed phase chromatog-
raphy. The benzyl ester 22 can be easily obtained by treating
the methyl ester of 10 with sodium benzylate in toluene.
Then the coupling with the amino acid 19 could be
achieved in a good yield of 71% under standard conditions
for coupling reactions with HCTU. This time, indeed, the
purification of the product by using RP18 chromatography
was without any problems. The benzyl ester group of 23
could easily be deprotected by palladium-catalyzed hydro-
genation to obtain the free acid 21 in a yield of 48%. This
reaction was carried out only once, and no further attempts
Scheme 3. Attempted synthesis of compound 5d.
After the successful synthesis of the three prototypes 5a–
to optimize the yield were made. The use of the benzyl ester c of this new class of cationic (guanidiniocarbonyl)furans,
instead of the methyl ester provided a better synthesis for we performed some first binding studies with the ethyl
compound 21. The following coupling reaction was carried amide derivative 5b as host and N-acetylated amino acid
out by using PyBOP under standard conditions, but again carboxylates as substrates.[17] Initially, the same conditions
the Boc-protected (guanidiniocarbonyl)furan Boc–5d could were tried as those used for the (guanidiniocarbonyl)pyr-
not be isolated, either by extraction from an aqueous solu- roles: bis-Tris buffer, pH = 6.2 in 40% water in DMSO.
tion or by flash column chromatography on RP18. As in However, no binding could be detected. Even though
the analogous reaction in the synthesis of the valine deriva- weaker binding was expected relative to that of the pyrrole
tive 5c, HCTU did not work. However, the formation of receptors because of a repulsive interaction between the fu-
Boc–5d could be proven by 1H NMR spectroscopy from the ran oxygen and the carboxylate substrate, the complete fail-
crude reaction mixture. Therefore, we deprotected the crude ure to see any binding was surprising. Even for (guanidinio-
product, hoping to obtain the pure compound 5d after flash carbonyl)pyridines, which also exhibit a repulsive dipole
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C. Schmuck, U. Machon
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interaction between the pyridine nitrogen and the carboxyl- DMSO (1:1) with 2 m acetate buffer. To a solution of the
ate anion, we could still detect binding affinities up to K = furan cation (c = 4×10–5 ) in this solvent were added ali-
500 –1 under these conditions.[15]
quots of a stock solution (c = 1 m) of the anion. The com-
We therefore investigated the protonation state of the plexation was monitored by the decrease in the UV ab-
(guanidiniocarbonyl)furans by potentiometric titrations of sorbance of the furan moiety of 5b at λ = 290 nm. The
5a and 5b (Figure 2). The titrations were carried out by resulting binding isotherm (Figure 3) was then analyzed by
starting with a 1 m aqueous solution of the compounds using a nonlinear curve-fitting procedure for a 1:1-bind-
adjusted to neutral pH with NaOH. Then 0.1  hydrochlo- ing.[17] To improve the accuracy of the fit, the molar ab-
ric acid was added stepwise, and the pH was recorded after sorbance coefficient of the furan was determined from a
each addition. A complete titration curve starting at basic Lambert–Beer dilution plot (ε = 4100 /cm). For dihydro-
pH could not be obtained, as the deprotonated compounds gen phosphate, no binding was observed, which means that
started to precipitate from solution at a pH Ͼ 7. From the the association constant is most likely smaller than 100 –1,
titration curves one can already see that the basicity of the the detection limit of the UV titration under these condi-
(guanidiniocarbonyl)furan is obviously lower than that of tions. However, hydrogen sulfate is bound efficiently by 5b
the pyrroles, which requires a lower pH for complete pro- with an association constant of K = 600 –1 even in the
tonation. We determined the pKa value of the (guanidinio- presence of the large excess of acetate and acetic acid in the
carbonyl)furans by using the Henderson–Hasselbach buffer.
equation: 1 m solutions of 5a or 5b were prepared and
0.5 equiv. NaOH (0.1 ) was added. The resulting pH value
of the solution provided the pKa values, which are 5.4 for
5a and 5.6 for 5b.
Figure 3. Binding isotherm at λ = 290 nm of 5b (4×10–5 ) for the
complexation of hydrogen sulfate in DMSO/water (1:1) at pH =
4.6. The dotted line represents the curve fitting for a 1:1 complex-
ation.
Whereas molecular recognition of carboxylates by these
new (guanidiniocarbonyl)furans is not possible because of
the mismatched pKa values of substrate and host, the less
basic anion, hydrogen sulfate, is bound by host 5b even un-
der polar conditions. The calculated structure (Macromodel
V. 8.0, MMFF force field, GB/SA solvation model)[18] for
the complex between the hydrogen sulfate and furan 5b is
shown in Figure 4. In comparison to the (guanidiniocar-
bonyl)pyrroles the binding mode is slightly different. The
oxoanion is shifted within the binding site so that only one
oxygen interacts with the guanidinium cation. In this way,
Figure 2. Potentiometric titration of a 1 m aqueous solution of
compound 5b with 0.1  hydrochloric acid.
The acidity of the guanidinium moiety is significantly in-
creased relative to the analogous pyrrole compounds, which
have pKa values between 7 and 8.[16] The furan heterocycle
is much less electron rich than a pyrrole. Hence, the furan
is a more electron withdrawing substituent, which further
reduces the electron density in the attached acylguanidin-
ium, thereby increasing its acidity. At pH = 6.2, the (guani-
diniocarbonyl)furans are not yet protonated. The deproton-
ated neutral form, however, is not expected to bind anions.
Binding studies have to be performed under more acidic
conditions at pH Ͻ 5 to ensure complete protonation.
However, this precludes carboxylates as substrates, as then
the carboxylate will also be protonated so that again no ion
pairing can occur. Only less basic anions, which are still
negatively charged at pH Ͻ 5, could serve as substrates.
Hence, we investigated the two singly charged anions hy-
drogen sulfate (tetrabutylammonium salt) and dihydrogen
phosphate (potassium salt) as potential substrates for 5b.
Figure 4. Energy-minimized structure for the complex between 5b
Binding studies were performed at pH = 4.6 in water/ and hydrogen sulfate.
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A New Class of Potential Anion Hosts
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3
3.90 (s, 3 H, OMe), 4.59 (s, 2 H, CH2), 6.48 (d, JHH = 3.4 Hz, 1
the repulsive interactions with the furan oxygen are mini-
mized. In the usual bidentate binding mode normally ob-
served for guanidinium cations, the lone pair of the second
oxygen directly points towards the furan oxygen. Therefore,
the guanidinium cation interacts with only one oxygen atom
of the anion in a bifurcated fashion. Furthermore, the OH
group of the hydrogen sulfate forms an H bond with the
CO of the amide group in position 5 of the receptor.
H, furan CH), 7.12 (d, JHH = 3.5 Hz, 1 H, furan CH) ppm. 13C
3
NMR (100 MHz, CDCl3, 27 °C, TMS): δ = 35.7, 51.0, 110.4, 117.8,
143.8, 153.1, 157.7 ppm. IR (KBr): ν = 3130, 2960, 1730, 1300,
˜
760 cm–1.
Methyl 5-(Acetoxymethyl)furan-2-carboxylate (8): To a solution of
methyl 5-(chloromethyl)furan-2-carboxylate (7, 5.50 g, 31.5 mmol)
in acetic acid (22 mL) and acetic anhydride (2.2 mL) was added
anhydrous sodium acetate (11.0 g, 134 mmol). The reaction mix-
ture was heated at 120 °C for 5.5 h, and after cooling, diethyl ether
(40 mL) was added. The suspension was neutralized with a satu-
rated sodium carbonate solution, and then the organic layer was
separated. The aqueous layer was extracted with diethyl ether
(5×30 mL). The combined organic phases were dried with magne-
sium sulfate, and the solvent was removed in vacuo. The residual
oil was distilled (70 °C/0.04 mbar) to obtain 8 (5.85 g, 93%) as a
Conclusions
We have shown here that cationic 2-(guanidiniocarbonyl)-
furans 5 can be synthesized even though special attention
has to be paid to the acid sensitivity of these compounds,
which requires carefully controlled reaction and work-up
conditions. The increased acidity of the (guanidiniocar-
bonyl)furans 5 relative to analogous pyrrole compounds 3.89 (s, 3 H, OMe), 5.07 (s, 2 H, CH2), 6.49 (d, JHH = 3.5 Hz, 1
makes them anion hosts that are selective for only weakly
basic oxoanions such as hydrogen sulfate, because low pH
values are required for the complete protonation of the gua-
nidinium moiety. This prevents the binding of more basic
anions such as carboxylates, which are normally bound
more effectively by anion hosts. However, one factor limit-
ing the use of these (guanidiniocarbonyl)furans for anion
sensing will most likely be their limited stability under these
acidic conditions.
1
colourless oil that crystallized after a few minutes: m.p. 39 °C. H
NMR (400 MHz, CDCl3, 27 °C, TMS): δ = 2.08 (s, 3 H, CH3),
3
H, furan CH), 7.12 (d, JHH = 3.4 Hz, 1 H, furan CH) ppm. 13C
NMR (100 MHz, CDCl3, 27 °C, TMS): δ = 20.0, 52.0, 57.6, 112.7,
3
118.7, 144.7, 153.5, 159.5, 170.8 ppm. IR (KBr): ν = 2951, 1737,
˜
1309, 1214 cm–1. EI-MS: m/z = 198.1 [M]+.
Methyl 5-(Hydroxymethyl)furan-2-carboxylate (9): To methyl 5-
(acetoxymethyl)furan-2-carboxylate (8, 5.50 g, 27.8 mmol) was
added a methanol solution of sodium methoxide (322 mg sodium
in 35 mL methanol). The mixture was stirred at room temperature
for 24 h. The yellow solution was passed over a cation exchange
resin, washed with methanol, and the solvent was removed in
vacuo. The residue was distilled (109 °C/0.33 mbar) to give 9
(3.86 g, 89%) as a colourless oil that crystallized after a few days:
m.p. 20 °C. 1H NMR (400 MHz, [D6]DMSO, 27 °C, TMS): δ =
Experimental Section
3
3.79 (s, 3 H, OMe), 4.45 (d, JHH = 5.8 Hz, 2 H, CH2), 5.48 (t,
General Remarks: Solvents were dried and distilled before use. The
starting materials and reagents were used as obtained from Aldrich
or Fluka. The amino acid derivative 19 was synthesized by starting
from Fmoc-Lys(Boc)-OH: the acid function was converted into the
acyl chloride and hydrolyzed with aqueous ammonia to obtain the
amide, finally the Fmoc group was cleaved with a piperidine solu-
tion. All experiments were run in oven-dried glassware. The com-
pounds were dried in high vacuum over phosphorus pentoxide at
room temperature overnight unless otherwise stated. The pH values
3JHH = 5.9 Hz, 1 H, OH), 6.49 (d, JHH = 3.5 Hz, 1 H, furan CH),
3
7.24 (d, 3JHH = 3.4 Hz, 1 H, furan CH) ppm. 13C NMR (100 MHz,
[D6]DMSO, 27 °C, TMS): δ = 51.7, 55.8, 109.2, 119.3, 142.8, 158.5,
160.3 ppm. IR (KBr): ν = 3402, 2953, 1719, 1524 cm–1. EI-MS: m/z
˜
= 156.1 [M]+.
5-(Methoxycarbonyl)furan-2-carboxylic Acid (10): Methyl 5-(hy-
droxymethyl)furan-2-carboxylate (9, 2.00 g, 12.8 mmol) was dis-
solved in acetone (200 mL) and cooled to 5 °C. Potassium perman-
ganate (4.10 g, 26.1 mmol) was then added, the ice bath was re-
moved, and the mixture was stirred for 40 min. Warming up and
weak boiling of the acetone were observed. The MnO2 was filtered
off and washed with methanol (20 mL). The solvent was removed
under reduced pressure, and the obtained yellow solid was dis-
solved in sodium hydroxide (0.1 , 20 mL). The solution was acidi-
fied with concentrated hydrochloric acid to pH = 4, and the desired
product was crystallized. The solid was collected, washed with
water and dried in vacuo to obtain the desired acid 10 (1.46 g,
1
were measured with a Knick pH meter 766 Calimatic at 25 °C. H
and 13C NMR spectra were recorded with a Bruker Avance 400
spectrometer. The chemical shifts are reported relative to the de-
uteriated solvents. The EI mass spectra were recorded with a Finni-
gan MAT 90 instrument, the ESI- and HR-mass spectra were re-
corded with a Finnigan MAT 900 S spectrometer. All UV spectra
were measured in 10-mm rectangular cells with a Jasco V530 spec-
trometer.
Methyl 5-(Chloromethyl)furan-2-carboxylate (7): To a solution of
methyl furan-2-carboxylate (6, 10.7 mL, 100 mmol) in dichloro-
methane (50 mL) were added anhydrous zinc chloride (3.75 g,
27.5 mmol) and paraformaldehyde (4.29 g, 143 mmol). The mixture
was warmed to 35 °C, and anhydrous hydrogen chloride gas was
bubbled through it for 2.5 h. The mixture was poured into cold
water (250 mL), and the organic layer was separated. The aqueous
layer was extracted with dichloromethane (2×50 mL), and the col-
lected organic layers were washed with water (2×50 mL) and dried
with potassium carbonate. The solvent was removed under reduced
pressure, and the residual oil was distilled (72 °C/0.25 mbar) to ob-
1
66%) as a slightly yellow solid: m.p. 173 °C. H NMR (400 MHz,
3
[D6]DMSO, 27 °C, TMS): δ = 3.85 (s, 3 H, OMe), 7.32 (d, JHH
=
3
3.7 Hz, 1 H, furan CH), 7.39 (d, JHH = 3.6 Hz, 1 H, furan CH),
13.69 (br. s, 1 H, COOH) ppm. 13C NMR (100 MHz, [D6]DMSO,
27 °C, TMS): δ = 52.3, 118.5, 119.1, 147.1, 147.5, 158.0, 158.9 ppm.
IR (KBr): ν = 3130, 1737, 1688, 1294 cm –1. EI-MS: m/z = 170.1
˜
[M]+.
N1-(tert-Butoxycarbonyl)-N2-[5-(methoxycarbonyl)furan-2-ylcarbon-
yl]guanidine (12): To a stirred solution of 5-(methoxycarbonyl)fu-
ran-2-carboxylic acid (10, 100 mg, 0.59 mmol), PyBOP (307 mg,
0.59 mmol) and NMM (276 mg, 2.73 mmol) in DMF (4 mL) was
tain 7 (11.7 g, 67%) as a colourless oil that crystallized after a few
1
days: m.p. 30 °C. H NMR (400 MHz, CDCl3, 27 °C, TMS): δ = added Boc-protected guanidine (11, 94.5 mg, 0.59 mmol). The solu-
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C. Schmuck, U. Machon
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tion was stirred at room temperature for 1 d. Then it was cooled
in an ice bath, and water was added (6 mL). The precipitating white
solid was collected and dried to obtain product 12 (125 mg, 68%):
m.p. 152 °C. 1H NMR (400 MHz, [D6]DMSO, 27 °C, TMS): δ =
δ = 14.8, 27.7, 33.5, 69.3, 114.11, 116.74, 149.3, 157.1, 158.8,
162.6 ppm. IR (KBr): ν = 3395, 2974, 1752, 1685, 1573, 1531, 1420,
˜
1313 cm–1. ESI-MS: m/z = 347.3 [M+Na]+.
Methyl 5-{[(S)-1-Carbamoyl-2-methylpropyl]carbamoyl}furan-2-car-
boxylate (14): To a stirred solution of 5-(methoxycarbonyl)furan-
2-carboxylic acid (10, 300 mg, 1.76 mmol), HCTU (730 mg,
1.76 mmol) and NMM (535 mg, 5.29 mmol) in DMF (10 mL) was
added H-Val-NH2 (hydrochloride salt, 269 mg, 1.76 mmol). The re-
action mixture was stirred at room temperature for 1 d. After add-
ing water (30 mL) and stirring for 15 min, we extracted the mixture
with ethyl acetate (10×10 mL). The solvent of the combined or-
ganic layers was evaporated in vacuo to obtain a yellow solid. The
crude product was purified by flash column chromatography on
octadecyl-functionalized silica gel (methanol/water = 1:3) to give
14 (270 mg, 57 %) as a white solid: m.p. 135 °C. 1H NMR
3
1.45 (s, 9 H, CMe3), 3.83 (s, 3 H, OMe), 7.15 (d, JHH = 3.6 Hz, 1
3
H, furan CH), 7.34 (d, JHH = 3.6 Hz, 1 H, furan CH), 8.68 (br. s,
1 H, NH), 9.58 (br. s, 1 H, NH), 11.0 (br. s, 1 H, NH) ppm. 13C
NMR (100 MHz, [D6]DMSO, 27 °C, TMS): δ = 27.6, 52.1, 82.3,
116.3, 119.2, 144.6, 154.1, 158.2, 159.1, 163.4, 167.9 ppm. IR
(KBr): ν = 3358, 1723, 1644, 1244 cm–1. EI-MS: m/z = 311.1
˜
[M]+.
Methyl 5-(Ethylcarbamoyl)furan-2-carboxylate (13): To a solution
of 5-(methoxycarbonyl)furan-2-carboxylic acid (10, 300 mg,
1.76 mmol), HCTU (730 mg, 1.76 mmol) and NMM (535 mg,
5.29 mmol) in DMF (10 mL) was added ethylamine hydrochloride
(144 mg, 1.76 mmol). The reaction mixture was stirred overnight at
room temperature, and water (30 mL) was added. The mixture was
extracted with ethyl acetate (16×15 mL). The combined organic
layers were washed with brine (30 mL) and dried with magnesium
sulfate. The solvent was evaporated to give 13 (206 mg, 59%) as a
4
(400 MHz, [D6]DMSO, 27 °C, TMS): δ = 0.90 (dd, JHH = 6.7,
3JHH = 11.8 Hz, 6 H, valine CMe2) 2.08 (m, 1 H, valine CH), 3.86
3
3
(s, 3 H, OMe), 4.27 (dd, JHH = 7.5, JHH = 8.8 Hz, 1 H, valine
3
NCH), 7.15 (br. s, 1 H, NH), 7.40 (d, JHH = 3.7 Hz, 2 H, furan
CH), 7.56 (br. s, 1 H, NH), 8.18 (d, 3JHH = 8.8 Hz, 1 H, NH) ppm.
13C NMR (100 MHz, [D6]DMSO, 27 °C, TMS): δ = 18.4, 19.3,
1
slightly yellow solid: m.p. 72 °C. H NMR (400 MHz, [D6]DMSO,
27 °C, TMS): δ = 1.10 (t, 3JHH = 7.2 Hz, 3 H, ethyl CH3), 3.26 (m, 30.3, 52.2, 57.9, 114.9, 119.2, 144.5, 149.8, 156.8, 158.1, 172.4 ppm.
3
2 H, ethyl CH2), 3.85 (s, 3 H, OMe), 7.20 (d, JHH = 3.7 Hz, 1 H,
IR (KBr): ν = 3365, 3227, 2966, 1724, 1638, 1297 cm–1. ESI-MS:
˜
3
furan CH), 7.37 (d, JHH = 3.5 Hz, 1 H, furan CH), 8.61 (br. t,
m/z = 291.3 [M+Na]+.
3JHH = 5.5 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO,
27 °C, TMS): δ = 14.6, 33.6, 52.1, 114.2, 119.2, 144.2, 150.6, 156.7,
5-{[(S)-1-Carbamoyl-2-methylpropyl]carbamoyl}furan-2-carboxylic
Acid (16): To a solution of the substituted methyl furan-2-carboxyl-
ate (14, 50 mg, 0.186 mmol) in methanol (7 mL) was added LiOH
(44.6 mg, 1.86 mmol). The reaction mixture was stirred at room
temperature for 75 min. The methanol was removed under reduced
pressure, and the residue was dissolved in water (5 mL). The solu-
158.1 ppm. IR (KBr): ν = 3296, 2965, 1724, 1653 cm–1. EI-MS: m/z
˜
= 197.1 [M]+.
5-(Ethylcarbamoyl)furan-2-carboxylic Acid (15): To a solution of
methyl 5-(ethylcarbamoyl)furan-2-carboxylate (13, 110 mg,
0.558 mmol) in methanol (5 mL) was added LiOH (133 mg, tion was acidified with 5% hydrochloric acid to pH = 3–4 and
5.58 mmol). The reaction mixture was stirred at room temperature
for 30 min. The methanol was removed under reduced pressure,
and the residue was dissolved in water (7 mL). The solution was
acidified with hydrochloric acid to pH = 3 at 0 °C and extracted
with ethyl acetate (6×10 mL). The collected organic layers were
dried with magnesium sulfate, and the solvents were evaporated to
dryness to give the desired product 15 (65 mg, 64%) as a slightly
yellow solid: m.p. 125 °C. 1H NMR (400 MHz, [D6]DMSO, 27 °C,
extracted with ethyl acetate (6×10 mL). The combined organic lay-
ers were dried with sodium sulfate, and the solvents evaporated to
dryness to give the desired product 16 (43 mg, 90%) as a white
solid: m.p. 192 °C. 1H NMR (400 MHz, [D6]DMSO, 27 °C, TMS):
4
3
δ = 0.90 (dd, JHH = 6.8, JHH = 12.1 Hz, 6 H, valine CMe2), 2.08
3
3
(m, 1 H, valine CH), 4.27 (dd, JHH = 7.4, JHH = 8.8 Hz, 1 H,
3
Valine NCH), 7.15 (br. s, 1 H, NH), 7.28 (d, JHH = 3.6 Hz, 1 H,
furan CH), 7.34 (d, JHH = 3.5 Hz, 1 H, furan CH), 7.56 (br. s, 1
3
3
3
TMS): δ = 1.10 (t, JHH = 7.2 Hz, 3 H, ethyl CH3), 3.26 (m, 2 H,
H, NH), 8.07 (d, JHH = 8.8 Hz, 1 H, NH), 13.50 (br. s, 1 H,
3
3
ethyl CH2), 7.17 (d, JHH = 3.7 Hz, 1 H, furan CH), 7.27 (d, JHH
COOH) ppm. 13C NMR (100 MHz, [D6]DMSO, 27 °C, TMS): δ =
= 3.6 Hz, 1 H, furan CH), 8.55 (t, 3JHH = 5.2 Hz, 1 H, NH), 13.47
18.3, 19.3, 30.3, 57.8, 114.9, 118.4, 149.4, 156.9, 159.0, 172.4 ppm.
(br. s, 1 H, COOH) ppm. 13C NMR (100 MHz, [D6]DMSO, 27 °C, IR (KBr): ν = 3365, 3268, 2952, 1738, 1654, 1255 cm–1. ESI-MS:
˜
TMS): δ = 14.7, 33.5, 114.1, 118.5, 145.5, 150.2, 156.9, 159.0 ppm.
m/z = 277.3 [M+Na]+.
IR (KBr): ν = 3421, 2966, 1717, 1641 cm–1. EI-MS: m/z = 183.0
˜
5-{[(S)-1-Carbamoyl-2-methylpropyl]carbamoyl}furan-2-carbonyl-
(tert-butoxycarbonyl)guanidine (18): A solution of the furan-2-car-
[M]+.
N1-(tert-Butoxycarbonyl)-N2-[5-(ethylcarbamoyl)furan-2-ylcarbon- boxylic acid (16, 100.0 mg, 0.393 mmol), Boc-protected guanidine
yl]guanidine (17): To a solution of 5-(ethylcarbamoyl)furan-2-car-
boxylic acid (15, 120 mg, 0.655 mmol), HCTU (271 mg,
0.655 mmol) and NMM (199 mg, 1.97 mmol) in DMF (4 mL) was
added a solution of Boc-protected guanidine (11, 104 mg,
0.655 mmol) in DMF (4 mL). The reaction mixture was stirred for
1 d at room temperature. After adding water (20 mL) and stirring
for 15 min, we extracted the mixture with ethyl acetate (5×20 mL).
The collected organic layers were washed with brine (20 mL) and
dried with sodium sulfate. The solvent was evaporated in vacuo to
obtain the desired product 17 (120 mg, 56%) as a slightly brown
(11, 93.9 mg, 0.590 mmol), PyBOP (205 mg, 0.393 mmol) and
NMM (0.129 mL) in DMF (10 mL) was stirred at room tempera-
ture for 24 h. After the addition of water (25 mL), the solution
was extracted with ethyl acetate (6×10 mL). The solvent of the
combined organic phases was removed in vacuo to obtain an oil.
The yellow crude product was taken up in water (10 mL) and lyo-
philized and purified by flash column chromatography on octade-
cyl-functionalized silica gel (methanol/water = 1:3) to give 18
1
(66.3 mg, 42%) as a white solid: m.p. 76 °C. H NMR (400 MHz,
4
3
[D6]DMSO, 27 °C, TMS): δ = 0.90 (dd, JHH = 6.7, JHH
=
solid: m.p. 113 °C. 1H NMR (400 MHz, [D6]DMSO, 27 °C, TMS):
11.2 Hz, 6 H, valine CH3), 1.46 (s, 9 H, CMe3), 2.08 (m, 1 H, valine
3
3
δ = 1.11 (t, JHH = 7.2 Hz, 3 H, ethyl CH3), 1.47 (s, 9 H, CMe3), CH), 4.28 (dd, 3JHH = 7.5, JHH = 8.8 Hz, 1 H, valine NCH), 7.15
3
3.26 (m, 2 H, ethyl CH2), 7.13–7.14 (m, 2 H, furan CH), 8.50 (br. (br. s, 1 H, NH), 7.18 (d, JHH = 3.3 Hz, 1 H, furan CH), 7.30 (d,
s, 1 H, NH), 8.66 (br. s, 1 H, NH), 9.46 (br. s, 1 H, NH), 10.87 (br.
3JHH = 3.7 Hz, 1 H, furan CH), 7.58 (br. s, 1 H, NH), 8.02 (d,
3JHH = 7.0 Hz, 1 H, NH), 8.66 (br. s, 1 H, NH), 9.44 (br. s, 1 H,
s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO, 27 °C, TMS):
4390
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Eur. J. Org. Chem. 2006, 4385–4392

A New Class of Potential Anion Hosts
FULL PAPER
NH) ppm. 13C NMR (100 MHz, [D6]DMSO, 27 °C, TMS): δ = saturated solution of picric acid in water (8 mL) was added, and
18.4, 19.3, 27.7, 30.5, 57.7, 81.7, 115.1, 116.8, 148.6, 157.2, 158.9, the mixture was stirred for 1 h at room temperature (for compound
172.5, 173.2 ppm. IR (KBr): ν = 3384, 2979, 1737, 1638 cm–1. ESI- 5c the solution was stirred for 1 d). The picrate salt precipitated, it
˜
MS: m/z = 396.3 [MH]+.
was filtered, washed several times with cold water and dried to
obtain a yellow solid.
5-[(Benzyloxy)carbonyl]furan-2-carboxylic Acid (22): To a solution
of the methyl ester (10, 500 mg, 2.94 mmol) in toluene (70 mL) was
added dropwise a sodium benzylate solution (54.2 mg Na in 5 mL
benzylic alcohol). The mixture was heated at 110 °C for 12 h. After
cooling to room temperature, the mixture was extracted with water
(3×50 mL), and the combined aqueous layers were acidified with
concentrated hydrochloric acid to pH = 3. The precipitated solid
was collected, taken up in water (20 mL) and lyophilized to obtain
22 (318 mg, 45 %) as a white solid: m.p. 153 °C. 1H NMR
(400 MHz, [D6]DMSO, 27 °C, TMS): δ = 5.36 (s, 2 H, benzylic
1
5a: Yield 40.3 mg (57%); m.p. 187 °C. H NMR (400 MHz, [D6]-
3
DMSO, 27 °C, TMS): δ = 3.89 (s, 3 H, OMe), 7.53 (d, JHH
=
3
3.8 Hz, 1 H, furan CH), 7.58 (d, JHH = 3.3 Hz, 1 H, furan CH),
8.30 (br. s, 4 H, 2×guanidine NH2), 8.58 (s, 2 H, 2×picrate CH),
11.30 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO,
27 °C, TMS): δ = 52.6, 119.5, 119.6, 124.2, 125.2, 141.8, 146.3,
147.0, 154.6, 156.9, 157.7, 160.8 ppm. IR (KBr): ν = 3348, 3172,
˜
1747, 1717 cm–1. HRMS (ESI): calcd. for C8H10N3O4 [M]+
212.06658; found 212.06702.
3
CH2), 7.32 (d, JHH = 3.64 Hz, 1 H, furan CH), 7.36–7.47 (m, 6
1
5b: Yield 60.0 mg (86%); m.p. 244 °C. H NMR (400 MHz, [D6]-
H, furan CH, 5×benzene CH), 13.70 (br. s, 1 H, COOH) ppm. 13
C
3
DMSO, 27 °C, TMS): δ = 1.13 (t, JHH = 7.2 Hz, 3 H, ethyl CH3),
NMR (100 MHz, [D6]DMSO, 27 °C, TMS): δ = 66.5, 118.4, 119.4,
3
3.29 (m, 2 H, ethyl CH2), 7.33 (d, JHH = 3.8 Hz, 1 H, furan CH),
128.3, 128.4, 128.5, 135.5, 145.6, 147.5, 157.4, 158.7 ppm. IR
7.55 (d, 3JHH = 3.8 Hz, 1 H, furan CH), 8.30 (br. s, 4 H, 2×guani-
(KBr): ν = 3119, 3006, 1726, 1698, 1281 cm–1. EI-MS: m/z = 246.0
˜
3
dine NH2), 8.58 (s, 2 H, 2×picrate CH), 8.64 (t, JHH = 5.8 Hz, 1
[MH]+.
H, NH), 11.18 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]-
DMSO, 27 °C, TMS): δ = 14.6, 33.6, 114.6, 119.7, 124.1, 125.1,
Benzyl Furan-2-carboxylate Derivative 23: To a solution of the ben-
zylic ester (22, 92.8 mg, 0.377 mmol), HCTU (157 mg, 0.377 mmol)
and NMM (1.14 mmol) in DMF (5 mL) was added H-Lys(Boc)-
NH2 chloride salt (19, 93.1 mg, 0.377 mmol), and the yellow solu-
tion was stirred at room temperature for 5 d. After the addition of
water (30 mL), the solution was extracted with ethyl acetate
(7×20 mL). The solvent of the combined organic phases was re-
moved in vacuo to obtain a yellow solid. The crude product was
purified by flash column chromatography on octadecyl-function-
alized silica gel (methanol/water = 1:3) to give 23 (128 mg, 71%)
as a white solid: m.p. 56 °C. 1H NMR (400 MHz, [D6]DMSO,
27 °C, TMS): δ = 1.18–1.39 (m, 13 H, CMe3, 2×lysine CH2), 1.70
(m, 2 H, lysine CH2), 2.87 (m, 2 H, lysine CH2), 4.34 (m, 1 H,
141.8, 145.1, 150.6, 154.6, 156.6, 157.0, 160.8 ppm. IR (KBr): ν =
˜
3356, 3158, 2952, 1726, 1568, 1266 cm–1. HRMS (ESI): calcd. for
C9H13N4O4 [M]+ 225.0987; found 225.098.
1
5c: Yield 28.5 mg (43%); m.p. 106 °C. H NMR (400 MHz, [D6]-
DMSO, 27 °C, TMS): δ = 0.91 (dd, 6 H, valine CMe2), 2.08 (m, 1
H, valine CH), 4.32 (dd, 1 H, valine NCH), 7.16 (br. s, 1 H, NH),
7.52 (d, 1 H, furan CH), 7.57 (d, 1 H, furan CH), 7.59 (br. s, 1 H,
NH), 8.28 (d, 1 H, NH), 8.33 (br. s, 4 H, 2×guanidine NH2), 8.58
(s, 2 H, 2×picrate CH), 11.30 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO, 27 °C, TMS): δ = 18.4, 19.3, 30.3, 58.0,
115.6, 119.7, 124.2, 125.2, 141.9, 145.4, 150.0, 154.6, 156.7, 157.1,
160.8, 172.3 ppm. IR (KBr): ν = 3370, 1724, 1345, 1268 cm–1.
˜
3
lysine NCH), 5.36 (s, 2 H, benzylic CH2), 6.73 (t, JHH = 4.9 Hz,
HRMS (ESI): calcd. for C12H18N5O4 [M]+ 296.1353; found
296.135.
1 H, NH), 7.06 (br. s, 1 H, NH), 7.34–7.47 (m, 8 H, 5× benzene
3
CH, 2×furan CH, NH), 8.42 (d, JHH = 8.1 Hz, 1 H, NH) ppm.
UV Titrations: All UV titrations were carried out by the addition
of aliquots (1×10–3 )of a solution of the substrate (tetrabutylam-
monium hydrogen sulfate or potassium dihydrogen phosphate) to
a solution of 5b (4×10–5 ) and recording the UV spectra after
each addition at 25 °C. The receptor and the substrate were dis-
solved in a solution (4×10–3 )of acetate buffer (pH = 4.6) in pure
water and then diluted with the same volume of DMSO. Dilution
was taken into account in analysis of the data in the 1:1 complex-
ation model by nonlinear regression. Each titration was performed
with 21 measurements.
13C NMR (100 MHz, [D6]DMSO, 27 °C, TMS): δ = 22.9, 28.2,
29.2, 31.4, 52.6, 66.3, 77.3, 114.8, 119.5, 128.2, 128.3, 128.5, 135.6,
144.3, 150.2, 155.5, 156.8, 157.5, 173.2 ppm. IR (KBr): ν = 3343,
˜
2931, 1715, 1685, 1287 cm– 1 . HRMS (ESI): calcd. for
C24H31N3NaO7 [M+Na]+ 496.20542; found 496.20664.
Furan-2-carboxylic Acid Derivative 21: A mixture of 23 (99.1 mg,
0.209 mmol) and Pd/C (10.2 mg) in methanol (5 mL) was hydroge-
nated at room temperature for 40 min. The mixture was filtered
through Celite to remove Pd/C, and the solvent was evaporated to
give 21 (38.5 mg, 48%) as a white solid: m.p. 105 °C. 1H NMR
(400 MHz, [D6]DMSO, 27 °C, TMS): δ = 1.19–1.36 (m, 13 H,
CMe3, 2×lysine CH2), 1.70 (m, 2 H, lysine CH2), 2.87 (m, 2 H,
lysine CH2), 4.34 (m, 1 H, lysine NCH), 6.73 (br. s, 1 H, NH), 7.07
Acknowledgments
3
Financial support by the Fonds der Chemischen Industrie and by
the Deutsche Forschungsgemeinschaft (SCHM 1501) is gratefully
acknowledged.
(br. s, 1 H, NH), 7.16 (d, JHH = 3.6 Hz, 1 H, furan CH), 7.24 (d,
3
3JHH = 3.6 Hz, 1 H, furan CH), 7.47 (s, 1 H, NH), 8.23 (d, JHH
= 8.2 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO, 27 °C,
TMS): δ = 22.9, 28.2, 29.2, 31.5, 52.4, 54.5, 77.3, 114.7, 148.9,
155.5, 157.5, 173.3 ppm. IR (KBr):
ν = 3352, 2938, 1685,
˜
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Eur. J. Org. Chem. 2006, 4385–4392
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4391

C. Schmuck, U. Machon
FULL PAPER
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Received: April 11, 2006
Published Online: August 1, 2006
4392
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Eur. J. Org. Chem. 2006, 4385–4392