T. Kusukawa, R. Mura, M. Ooe et al.
Tetrahedron 77 (2021) 131770
added and extracted with CH2Cl2 (10 mL x 3). The combined
organic phase was dried (Na2SO4) and evaporated under reduced
pressure. The 1,8-di(40-aminophenyl)naphthalene (118 mg, 85%)
was isolated by column chromatography (SiO2, AcOEt).
was collected by filtration and washed with cold distilled water
(2 mL x 5) to give a colorless solid 1 (49 mg, 91%).
Colorless solid; mp 216.5e217.4 ꢂC; 1H NMR (500 MHz,
DMSO‑d6)
d
¼ 7.95 (d, J ¼ 7.5 Hz, 2H), 7.55 (t, J ¼ 6.8 Hz, 2H), 7.35 (d,
1H NMR (500 MHz, DMSO‑d6)
d
¼ 7.86 (d, J ¼ 8.2 Hz, 2H), 7.50 (t,
J ¼ 6.3 Hz, 2H), 6.76 (d, J ¼ 7.1 Hz, 2H), 6.38 (d, J ¼ 6.7 Hz, 2H); 13
C
J ¼ 7.6 Hz, 2H), 7.28 (d, J ¼ 7.1 Hz, 2H), 6.65 (d, J ¼ 8.4 Hz, 4H), 6.19
NMR (125 MHz, DMSO‑d6)
d
¼ 152.2 (Cq), 148.2 (Cq), 140.5 (Cq),
(d, J ¼ 8.4 Hz, 4H), 4.78 (s, 4H).
135.3 (Cq), 135.0 (Cq), 130.2 (CH), 130.0 (CH), 128.8 (Cq), 127.7 (CH),
125.2 (CH),121.5 (CH). HRMS (FAB, NBA) m/z ¼ 395.1985 (calculated
for [MþH]þ: 395.1984). Anal. Calcd. for C24H22N6ꢀ0.7H2O: C:70.81,
H:5.79, N:20.64. Found: C:70.84, H:5.44, N:20.41.
4.1.4. Synthesis of 1ꢀBoc4
1,8-Di(40-aminophenyl)naphthalene (102 mg, 0.33 mmol), 1,3-
bis(tert-butoxycarbonyl)-2-(trifluoro-methanesulfonyl)guanidine
(Goodman’s reagent, 315 mg, 0.81 mmol), and dry-Et3N (112
mL,
4.1.7. Synthesis of 5-methyl-1,3-benzenediacetic acid [10]
0.82 mmol) were mixed in 3 mL of dry CH2Cl2. The obtained
mixture was stirred for 1 day under an Ar atmosphere at room
temperature. During the course of the reaction, the amount of dry
CH2Cl2 (should not added a large amount of solvent) was main-
tained and the reaction was monitored by TLC (Rf ¼ 0.73 for 1ꢀBoc4,
Rf ¼ 0.37 for monoguanidineꢀBoc2, CHCl3 as the solvent). To obtain
the Boc-protected digauanidine 1ꢀBoc4, 1,3-bis(tert-butox-
ycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (Goodman’s re-
agent, 88 mg, 0.23 mmol) was additionally added to reaction
mixture, and stirred for a total of 6 days under an Ar atmosphere at
40e45 ꢂC. To the reaction mixture, CH2Cl2 (10 mL) and 5% NaHCO3
aq. (10 mL) were added, additionally extracted with CH2Cl2 (10 mL
x 2), and the combined CH2Cl2 layer was dried (Na2SO4), and
evaporated under reduced pressure. The target product 1ꢀBoc4
(50 mg, 84%) was obtained by column chromatography (SiO2,
toluene).
1,3-Bis(cyanomethyl)-5-methylbenzene (1.0 g, 5.9 mmol), EtOH
(13 mL), and a 2.7 M KOH aqueous solution (13 mL, 35 mmol) were
mixed and refluxed for 6 h. After cooling to room temperature,11 M
HCl aq. (4 mL) was added, then extracted with AcOEt (15 mL x 2).
The combined AcOEt layer was washed with brine (50 mL x 2),
dried (Na2SO4), then evaporated under reduced pressure to give the
target product 5-methyl-1,3-benzenediacetic acid (778 mg, 63%).
Colorless solid; mp 180.0e181.0 ꢂC; 1H NMR (500 MHz,
DMSO‑d6)
d
¼ 6.93 (s, 2H), 6.91 (s, 1H), 3.47 (s, 4H), 2.25 (s, 3H).
4.2. Jobs plot analysis (fluorescence spectroscopy)
The stock solutions of 1, dicarboxylic acids and diphosphonic
acids in DMSO were prepared in separate volumetric flasks. Several
sample solutions containing both the diguanidine 1 and carboxylic
acids (or diphosphonic acids) in different ratios (1/9 to 9/1) were
prepared and maintained at 0.2 mM. The fluorescence spectra of
the mixtures were recorded, and the intensities were analyzed by
the Job’s method.
Colorless solid; mp > 300 ꢂC; 1H NMR (500 MHz, CDCl3)
d
¼ 11.62 (brs, 2H, NH), 9.97 (brs, 2H, NH), 7.94 (dd, J ¼ 8.3, 1.3 Hz,
2H), 7.54 (dd, J ¼ 8.1, 7.0 Hz, 2H), 7.40 (dd, J ¼ 7.0, 1.3 Hz, 2H), 7.17 (d,
J ¼ 8.5 Hz, 4H), 6.89 (d, J ¼ 8.5 Hz, 4H), 1.53 (s, 18H), 1.49 (s, 18H). 13
C
NMR (125 MHz, CDCl3);
d
¼ 163.7 (Cq), 153.6 (Cq), 153.1 (Cq), 151.4
4.3. DOSY measurements
(Cq), 140.0 (Cq), 139.8 (Cq), 135.4 (Cq), 134.3 (Cq), 130.7 (CH), 130.1
(CH), 129.5 (Cq), 128.5 (CH), 125.1 (CH), 122.0 (CH), 86.0 (Cq), 83.2
(Cq), 79.2 (Cq), 28.2 (CH3), 27.8 (CH3). HRMS (FAB, NBA) m/
z ¼ 795.4083 (calculated for [MþH]þ: 795.4081). Anal. Calcd. for
For the DOSY experiments with the free building blocks as well
as the complexes, the concentrations of 1, 2, 3a, 3b, 4c-4e, 5, 7a, 7c,
1ꢀ2, 1ꢀ3a, 1ꢀ3b, 1ꢀ4c-1ꢀ4e, 1ꢀ5, 1ꢀ7a and 1ꢀ7c were kept constant at
1.89 mM. The 1H DOSY experiments were carried out at 298 K using
a Bruker Avance III 500 MHz spectrometer equipped with a 5-mm
BBFO probe with a z-axis gradient coil. The data were acquired and
processed using the Bruker TopSpin 3.0 software. A series of
diffusion ordered spectra were collected of the samples using the
LEDbp pulse sequence [11]. The pulse-fields were incremented in
50 steps from 2% to 95% of the maximum gradient strength in a
linear ramp. The gradient length was selected between 2.0 and
3.0 ms with a diffusion time of 200 ms and an eddy current delay of
5 ms.
C
44H54N6O8ꢀH2O: C:65.01, H:6.94, N:10.34. Found: C:65.23, H:6.69,
N:10.36.
4.1.5. Synthesis of 1,8-di(40-guanidinophenyl)naphthalene
dihydrochloride 1ꢀ2HCl
To a suspension of 1ꢀBoc4 (30 mg, 37.9
mmol) in Et2O (15 mL) at
0 ꢂC was added 10 mL of 1 M HCl. The reaction mixture was stirred
at 0 ꢂC for 10 min, then at room temperature for 7 h. The reaction
(water layer) was monitored by 1H NMR (D2O) to confirm the dis-
appearence of the Boc group. To complete the deprotection, 5 mL of
11 M HCl was added to the reaction mixture and stirred at room
temperature for an additional 4 h. After the addition of distilled
water (20 mL x 2), the water phase was separated, then concen-
trated to provide the title compound (17 mg, 93%).
4.4. Fluorescence titrations
A solution of the diguanidine 1 was prepared (3e25
mM in
Colorless solid; mp 250.4 ꢂC (dec.); 1H NMR (500 MHz,
DMSO), and an aliquot (3 mL) was transferred to a 1 cm fluores-
cence tube. To this solution was dropwise added a stock solution of
the dicarboxylic acid or diphosphonic acid (0.3e25 mM in DMSO)
in small portions. The fluorescence spectra were recorded by
excitation at 313 nm. The association constants were calculated
using the program HYPSPEC [12] and are summarized in Table 3.
DMSO‑d6)
d
¼ 9.82 (brs, 2H, NH), 8.10 (dd, J ¼ 8.3, 1.2 Hz, 2H), 7.65
(dd, J ¼ 8.1, 7.1 Hz, 2H), 7.41 (dd, J ¼ 7.1, 1.3 Hz, 2H), 7.35 (brs, 8H,
NH), 6.97 (d, J ¼ 8.5 Hz, 4H), 6.82 (d, J ¼ 8.4 Hz, 4H). 13C NMR
(125 MHz, DMSO‑d6);
d
¼ 155.9 (Cq), 140.7 (Cq), 138.7 (Cq), 135.1
(Cq), 132.7 (Cq), 130.8 (CH), 130.6 (Cq), 129.0 (CH), 128.5 (Cq), 125.5
(CH), 123.2 (CH). Anal. Calcd. for C24H22N6ꢀ3.4HCl: C:55.60, H:4.94,
N:16.21. Found: C:55.35, H:5.05, N:16.61.
4.5. Computational methods
4.1.6. Synthesis of 1,8-di(40-guanidinophenyl)naphthalene 1
The ground-state geometries were fully optimized using the
density functional theory (DFT) with the B3LYP hybrid functional at
the basis set level of 6e31G*. The frequency calculations allowed
verification that these structures did not present imaginary fre-
quencies and we had global minima. All of the calculations were
To a stirred solution of 4 M NaOH (13 mL), an aqueous solution
of 1,8-di(40-amidinophenyl)-naphthalene dihydrochloride 1ꢀ2HCl
(64 mg, 0.14 mmol, 10 mL) was dropwise added at 0 ꢂC over 15 min,
and additionally stirred at 0 ꢂC for 40 min. The resulting precipitate
10