CMDC 200900389 SM Miscellaneous Information
CMDC 200900389 SM Miscellaneous Information
CMDC 200900389 SM Miscellaneous Information
Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2009
cmdc_200900389_sm_miscellaneous_information.pdf
Supporting Information
Table of Contents
All reagents and solvents were used without further purification or drying. All reagents were
purchased from Sigma-Aldrich (Milan, Italy) unless otherwise specified. Commercial grade
anhydrous solvents were purchased from J. T. Baker (Deventer, Holland). Naphthalene-2-
carboxylic acids 9, 22, 23, 26, 34e-k, benzo[b]furan-2-carboxylic acid, 5-chloro-, 5-bromo- and 5-
methoxy-benzo[b]furan-2-carboxylic acid were commercially available. Reactions were performed
under an atmosphere of nitrogen, unless otherwise specified. Silica gel (Merck, Kieselgel 60) was
used for analytical thin-layer chromatography (TLC, F254 plates) and flash chromatography (230-
400 mesh). Melting points were measured in capillary tubes with a digital elecrothermal apparatus
Buchi B-540 and were uncorrected. 1H NMR spectra were acquired on a Varian 200 MHz and 600
MHz instruments and recorded in parts per million (ppm) δ values, relative to CHCl3 (δ 7.27),
CH3OH (δ 3.31) or DMSO (δ 2.50) as the internal standards. The data were processed using the
program MestReC 4.9.9.9. The LC–MS system was a Thermofinnigan LCQ mass spectrometer,
interfaced with an Agilent series 1100 liquid chromatograph, with binary pump, well-plate sampler,
column thermostat and diode-array UV detector. Either Electrospray (ESI) or Atmospheric Pressure
Chemical Ionization (APCI) were used as the ionization techniques. Ion polarity was positive,
unless otherwise specified. The samples were analyzed by MS and data-dependent tandem MS,
using an isolation width of 2 Th, an activation q of 0.25, and a relative normalized collision energy
of 30–35%. Chromatographic separation was achieved using a Luna® C8-2 column (Phenomenex, 3
µm, length of 7.5 cm, internal diameter of 4.6 mm). The mobile phases A and B were 0.1% TFA in
water and 0.1% TFA in acetonitrile, respectively. A gradient elution was performed from 5% to
95% B in 3 minutes, followed by a 2 minutes isocratic step at 95% B, at a flow rate of 1 mL/min.
Two UV signals, at wavelengths 220 and 270 nm, were also monitored. The HRMS system was a
1
Micromass Q-Tof micro mass spectrometer, equipped with Electrospray ion source with LockSpray
nebulizer, interfaced with an Agilent series 1200 liquid chromatograph, with binary pump, well-
plate sampler, column thermostat and variable wavelength UV detector. The mass spectrometer was
calibrated with 0.1% phosphoric acid in H2O/MeCN 1:1. This mixture was used also as internal
reference compound during ESI-MS accurate mass experiments and was introduced via the
LockSpray channel using an infusion pump. Chromatographic separation was achieved using a
Synergi Fusion column (Phenomenex, 2 µm, length of 2.0 cm, internal diameter of 2.0 mm). The
mobile phases A and B were 0.1% formic acid in water and 0.1% formic acid in acetonitrile,
respectively. A gradient elution was performed from 30% to 95% B in 0.1 minutes, at a flow rate of
0.2 mL/min. HPLC were recorded using the following methods. Method (A) parameters are as
follows: HP-1100 Agilent analytic HPLC system, Zorbax® SB-18 (Agilent), 100 Å, 50 x 4.6 mm,
H2O + 0.1% TFA / MeCN + 0.1% TFA, 95/5 → 5/95 in 6.5 min + 1 min isocratic, flow rate
3mL/min, λ = 220 nm. Method (B) parameters are as follows: Waters 2695 analytic HPLC system
Symmetry® C18 (Waters), 100 Å, 5 micron, 250 x 4.6 mm, H2O + 0.1% TFA / MeCN + 0.1% TFA,
85/15 → 5/95 in 20 min, flow rate 1 mL/min, λ = 220. The HPLC purities of tested compounds,
observed at 220 and 280 nm, were ≥95% and are reported after the retention time values.
6-Diethylamino-naphthalene-2-carboxylic acid methyl ester (7). Iodoethane (EtI, 1.7 mL, 21.00
mmol) and K2CO3 (0.92 g, 6.70 mmol) were added to a solution of methyl ester 3 (250 mg, 1.24
mmol) in acetonitrile (74 mL), then the reaction mixture was heated to reflux for 7 h. Further
iodoethane (0.8 mL, 10.50 mmol) was added and the mixture refluxed for 7 h. The procedure of
adding 0.8 mL of iodoethane and refluxing for 7 h was repeated for further six times. The solvent
was removed under reduced pressure and the residue was treated with ethyl acetate. The organic
phase was washed with a saturated aqueous (sat. aq.) NaHCO3 solution, dried over Na2SO4 and,
after removal of the solvent under reduced pressure, diethylamino derivative 7 (280 mg, 97%) was
obtained as a brown solid. HPLC: (B) 10.1 min, 92% purity; 1H NMR (200 MHz, CD3OD): δ =
8.36 (br s, 1H), 7.85–7.75 (m, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.19 (dd, J = 9.2, 2.6 Hz, 1H), 6.91–
6.88 (m, 1H), 3.91 (s, 3H), 3.53 (q, J = 7.0 Hz, 4H), 1.24 ppm (t, J = 7.0 Hz, 6H).
5-Bromo-naphthalene-2-carboxylic acid (10). Bromine (77 µL, 1.51 mmol) was added to a
boiling solution of carboxylic acid 9 (300 mg, 1.74 mmol) in AcOH (1.5 mL) and the mixture was
heated to reflux for 1.5 h. Then it was allowed to warm to room temperature and a solid
precipitated. The latter was filtered off, washed with AcOH and purified by crystallization (AcOH)
to give bromo derivative 8 (169 mg, 39%). 1H NMR (200 MHz, CD3OD): δ = 8.63 (br s, 1H), 8.31–
8.27 (m, 1H), 8.16 (dd, J = 8.9, 1.6 Hz, 1H), 8.06–8.02 (m, 1H), 7.97–7.92 (m, 1H), 7.5–7.42 ppm
(t, J = 7.9 Hz, 1H).
3
7-Methyl-naphthalene-2-carboxylic acid (12) and naphthalene-2,7-dicarboxylic acid (13). A
hot (80 °C) solution of KMnO4 (2.70 g, 17.40 mmol) in water (14 mL) was added to a solution of
naphthalene 11 (850 mg, 5.40 mmol) in pyridine (10 mL) pre-heated at 120°C. The mixture was
refluxed for 1.5 h, pyridine (6 mL) and a hot solution of KMnO4 (1.70 g, 10.76 mmol) in water (9
mL) were further added and the reaction mixture was refluxed for 1.5 h. The brown mixture was
allowed to cool to room temperature and filtered off. Water (15 mL) was added to the filtrated
solution and the precipitate was filtered off. The solution was treated with a 37% aq. HCl solution
to pH=1, the solid formed was filtered off and dried to give a mixture of compounds 12 and 13 (230
mg) in a 12/13 ratio of 3 : 1. HPLC: (B) 10.4 (13) and 14.49 (12) min; 1H NMR (200 MHz,
CD3OD): δ = 8.74 (br s, 2H, 13-H), 8.52 (br s, 1H, 12-H), 8.17 (dd, J = 8.5, 1.6 Hz, 2H, 13-H),
8.04–7.76 (m, 5H, 12-H), 7.47 (dd, J = 8.5, 1.6 Hz, 2H, 13-H), 2.53 ppm (s, 3H, 12-H); MS (12)
(APCI–): m/z calcd for C12H10O2: 186.1, found: 185.1 [M–H]–.
6-Methyl-naphthalene-2-carboxylic acid (15). Bromine (0.83 mL, 16.50 mmol) was added to an
aq. 5 M NaOH solution (10 mL) at 0°C. After 10 minutes, a solution of ketone 14 (1.00 g, 5.45
mmol) in 1,4-dioxane (5 mL) was added dropwise to the reaction mixture. After 2.5 h stirring,
water (2.5 mL) and Na2S2O5 (2.5 mL) were added then the mixture was treated with a 37% aq. HCl
solution to pH=3. The white precipitate was filtered off, washed with water and dried to yield
carboxylic acid 15 (1.45 g, quant.). 1H NMR (200 MHz, CD3OD): δ = 8.48 (br s, 1H), 7.99 (dd, J =
8.6, 1.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.67 (bs, 1H), 7.38 (dd, J = 8.4,
1.6 Hz, 1H), 2.52 ppm (s, 3H).
4
5-Methyl-naphthalene-2-carboxylic acid methyl ester (20). Nitromethane (1.5 mL, 28.00
mmoles) was added to a mixture of cesium carbonate (11.80 g, 36.20 mmoles) in DMSO (80 mL)
pre-heated at 50 °C under nitrogen. After 20 minutes at 50 °C, a solution of ester 19 (2.55 g, 9.60
mmoles) in DMSO (240 mL) was added dropwise over 3 h into the stirred pale yellow, warm
solution. The mixture was stirred at 50 °C for further 3 h and left overnight at room temperature.
The reaction mixture was partitioned between tert-butyl methyl ether (TBME) and ice-water. The
aqueous phase was separated and extracted with TBME. The combined organic phases were washed
with water, brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the
crude product was purified by flash chromatography (cyclohexane/CHCl3 5 : 1) and compound 20
(0.95 g, 49%) was obtained as an oil. HPLC: (B) 6.5 min, 95% purity; 1H NMR (200 MHz, CDCl3):
δ = 8.59 (d, J = 1.6 Hz, 1H), 8.08 (dd, J = 8.8, 1.6 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.82–7.77 (m,
1H), 7.46–7.39 (m, 2H), 3.97 (s, 3H), 2.69 ppm (s, 3H).
5
(dd, J = 7.4, 0.8 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.45 (br t, J = 5.7 Hz,
1H), 7.20–7.12 (m, 5H), 4.47 (ddd, J = 10.5, 8.9, 4.2 Hz, 1H), 3.80–3.76 (m, 2H), 3.26–3.17 (m,
3H), 3.01–2.96 (m, 1H), 2.87–2.83 (m, 2H), 2.54–2.48 (m, 2H), 2.31 (dt, J = 13.3, 8.1 Hz, 1H),
1.99–1.94 (m, 1H), 1.92–1.85 (m, 2H), 1.81–1.76 (m, 1H), 1.72–1.38 (m, 12H), 1.26–1.20 (m, 1H),
1.05–0.91 ppm (m, 4H); MS (ESI): m/z: 703.4 [M+H]+; HRMS: m/z [M+H]+ calcd for
C38H48BrN4O4: 703.2859, found: 703.2845.
6
(m, 2H), 3.26–3.20 (m, 2H), 3.18 (dd, J = 14.0, 4.1 Hz, 1H), 3.00–2.95 (m, 1H), 2.90–2.83 (m, 2H),
2.62–2.57 (m, 2H), 2.29 (dt, J = 13.2, 7.9 Hz, 1H), 1.98–1.92 (m, 3H), 1.80–1.75 (m, 1H), 1.70–
1.44 (m, 12H), 1.31–1.23 (m, 1H), 1.06–0.95 ppm (m, 4H); MS (ESI): m/z: 655.2 [M+H]+; HRMS:
m/z [M+H]+ calcd for C39H51N4O5: 655.3859, found: 655.3853.
4-Chloro-2-methoxybenzoic acid methyl ester (31a). Compound 31a was obtained from methyl
ester 30a according to GP 2. 1H NMR (200 MHz, CDCl3): δ = 7.76 (d, J = 8.8 Hz, 1H), 7.01–6.94
(m, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
4-Bromo-2-methoxybenzoic acid methyl ester (31b). Compound 31b was obtained from methyl
ester 30b according to GP 2. 1H NMR (200 MHz, CDCl3): δ = 7.71 (d, J = 8.7 Hz, 1H), 7.18–7.12
(m, 2H), 3.90 (s, 3H), 3.89 (s, 3H).
4-Chloro-2-methoxybenzyl Alcohol (32a). Compound 32a was obtained from methyl ester 31a
according to GP 3. 1H NMR (200 MHz, CDCl3): δ = 7.21 (d, J = 8.0 Hz, 1H), 6.96–6.86 (m, 2H),
4.64 (s, 2H), 3.86 (s, 3H).
4-Bromo-2-methoxybenzyl Alcohol (32b). Compound 32b was obtained from methyl ester 31b
according to GP 3. 1H NMR (200 MHz, CDCl3): δ = 7.18–7.01 (m, 3H), 4.62 (s, 2H), 3.84 (s, 3H).
7
4-Bromo-2-methoxybenzaldehyde (33b). Compound 33b was obtained from benzyl alcohol 32b
according to GP 4. 1H NMR (200 MHz, CDCl3): δ = 10.40 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.22–
7.15 (m, 2H), 3.94 ppm (s, 3H).
4-Methyl-2-methoxybenzaldehyde (33c). Compound 33c was obtained from benzyl alcohol 32c
according to GP 4. 1H NMR (200 MHz, CDCl3): δ = 10.40 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 6.87–
6.78 (m, 2H), 3.92 (s, 3H), 2.41 ppm (s, 3H).
8
tert-Butyl 5-methylbenzo[b]furan-2-carboxylate (35f). Compound 35f was obtained from
aldehyde 34f according to GP 6. 1H NMR (200 MHz, CDCl3): δ = 7.58–7.24 (m, 4H), 1.63 ppm (s,
9H).
9
5-Trifluoromethoxybenzo[b]furan-2-carboxylic acid (36h). Compound 36h was obtained from
tert-butyl ester 35h according to GP 7. 1H NMR (200 MHz, [D6]DMSO): δ = 7.88–7.83 (m, 2H),
7.71 (s, 1H), 7.50 ppm (dd, J = 8.7, 2.3 Hz, 1H).
10
J = 13.9, 10.7 Hz, 1H), 2.71–2.69 (m, 1H), 2.63–2.61 (m, 1H), 2.24 (dt, J = 13.3, 8.0 Hz, 1H), 2.02–
1.99 (m, 2H), 1.92–1.86 (m, 1H), 1.81–1.76 (m, 1H), 1.73–1.46 (m, 20H), 1.42–1.36 (m, 2H), 1.11–
0.98 ppm (m, 4H); MS (ESI): m/z calcd for C40H54N4O5: 670.4, found: 671.6 [M+H]+.
11
2.96 (m, 1H), 2.91–2.84 (m, 1H), 2.82 (dd, J = 13.9, 10.6 Hz, 1H), 2.68–2.65 (m, 2H), 2.25 (dt, J =
13.3, 8.0 Hz, 1H), 2.01–1.98 (m, 2H), 1.95–1.90 (m, 1H), 1.80–1.75 (m, 1H), 1.71–1.43 (m, 12H),
1.36–1.29 (m, 1H), 1.10–1.00 ppm (m, 4H); MS (ESI): m/z: 649.5 [M+H]+; HRMS: m/z [M+H]+
calcd for C36H46ClN4O5: 649.3157, found: 649.3146.
12
3.01–2.96 (m, 1H), 2.91–2.87 (m, 1H), 2.82 (dd, J = 13.9, 10.6 Hz, 1H), 2.69–2.65 (m, 2H), 2.25
(dt, J = 13.4, 8.1 Hz, 1H), 2.01–1.98 (m, 2H), 1.95–1.88 (m, 1H), 1.80–1.75 (m, 1H), 1.72–1.43 (m,
12H), 1.37–1.30 (m, 1H), 1.09–0.99 ppm (m, 4H); MS (ESI): m/z: 649.3 [M+H]+; HRMS: m/z
[M+H]+ calcd for C36H46ClN4O5: 649.3157, found: 649.3151.
13
2.87 (m, 1H), 2.82 (dd, J = 13.9, 10.6 Hz, 1H), 2.70–2.64 (m, 2H), 2.25 (dt, J = 13.3, 8.0 Hz, 1H),
2.00–1.90 (m, 3H), 1.81–1.76 (m, 1H), 1.68–1.43 (m, 12H), 1.36–1.32 (m, 1H), 1.09–1.02 ppm (m,
4H); MS (ESI): m/z: 699.4 [M+H]+; HRMS: m/z [M+H]+ calcd for C37H46F3N4O6: 699.3369, found:
699.3361.
1
C-[1-(4-Methoxy-tetrahydropyran-4-ylmethyl)-piperidin-4-yl]-methylamine (50b). H NMR
(200 MHz, CDCl3): δ = 3.70–3.62 (m, 6H), 3.18 (s, 3H), 2.91–2.85 (m, 1H), 2.55–2.50 (m, 3H),
2.16–2.04 (m, 1H), 1.78–1.51 (m, 8H), 1.22–1.10 ppm (m, 2H); MS (ESI) m/z calcd for
C13H26N2O2: 242.2, found: 243.3 [M+H]+.
C-[1-(4-Methoxymethyl-tetrahydropyran-4-ylmethyl)-piperidin-4-yl]-methylamine (50c). MS
(ESI) m/z calcd for C14H28N2O2: 256.2, found: 257.3 [M+H]+.
1
C-[1-(4-Methyl-tetrahydropyran-4-ylmethyl)-piperidin-4-yl]-methylamine (50d). H NMR
(200 MHz, CDCl3): δ = 3.79–3.47 (m, 4H), 2.83–2.67 (m, 2H), 2.59–2.48 (m, 2H), 2.30–2.10 (m,
2H), 2.10 (s, 2H), 1.69–1.08 (m, 9H), 0.94 ppm (s, 3H); MS (ESI) m/z calcd for C13H26N2O: 226.2,
found: 227.2 [M+H]+.
14
material after preparative HPLC (Symmetry C18, 300 Å, 300 mm × 19 mm, 7 µm, H2O + 0.1% TFA
/ MeCN + 0.1% TFA, gradient 30 to 60% MeCN in 60 min, flow rate 20 mL/min). HPLC: (A) 3.8
min, 99% purity; mp: 105–109 °C; 1H NMR (600 MHz, [D6]DMSO): δ = 8.86 (s, 1H), 8.25 (s, 1H),
7.90–7.86 (m, 2H), 7.80 (s, 1H), 7.59 (br t, J = 5.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.21–7.12 (m,
5H), 4.46–4.41 (m, 1H), 3.66–3.50 (m, 4H), 3.25–3.18 (m, 4H), 3.16 (s, 3H), 3.08–2.89 (m, 4H),
2.86 (dd, J = 14.1, 10.7 Hz, 1H), 2.45 (s, 3H), 2.26–2.19 (m, 1H), 1.93–1.89 (m, 1H), 1.79–1.45
ppm (m, 16H); MS (ESI): m/z: 675.4 [M+H]+; HRMS: m/z [M+H]+ calcd for C38H51N4O5S:
675.3580, found: 675.3560.
15
= 12.0, 6.3, 2.5 Hz, 2H), 3.20–3.16 (m, 1H), 3.00–2.90 (m, 2H), 2.85 (dd, J = 13.9, 10.7 Hz, 1H),
2.79–2.76 (m, 2H), 2.45 (s, 3H), 2.32–2.30 (m, 2H), 2.23 (dt, J = 13.4, 8.2 Hz, 1H), 1.93–1.76 (m,
5H), 1.71–1.30 (m, 9H), 1.12–1.04 ppm (m, 2H); MS (ESI): m/z calcd for C36H46N4O5S: 646.3,
found: 647.3 [M+H]+.
16
(m, 1H), 3.92–3.87 (m, 2H), 3.46–3.41 (m, 2H), 3.05–3.06 (m, 5H), 2.97–2.83 (m, 2H), 2.45 (s,
3H), 2.26–2.18 (m, 1H), 1.93–1.45 (m, 14H), 1.27–1.16 ppm (m, 2H); MS (ESI): m/z calcd for
C37H47N5O4S: 657.3, found: 658.4 [M+H]+.
17
1.21 ppm (s, 6H); MS (ESI): m/z: 673.3 [M+H]+; HRMS: m/z [M+H]+ calcd for C39H53N4O4S:
673.3788, found: 673.3807.
18
2. cLog D and cLog P Data Tables
Table A. cLog D6.4, cLog D7.4 and cLog P values are reported for compounds 1, 25a-j and 37a-o.
O H O
N
Ar N N O
H O H N
Entry Ar
cLog D6.4 cLog D7.4 cLog P
1
H3C S 2.28 3.15 4.82
25a
2.63 3.5 5.16
25b
3.17 4.04 5.70
CH3
25c
H3C
3.17 4.04 5.70
H3C
25d
3.17 4.04 5.70
25e
3.38 4.25 5.92
Br
25f
Br
3.38 4.25 5.92
Br
25g
3.38 4.25 5.92
25h
3.77 4.64 6.31
I
25i
H3CO
2.62 3.49 5.16
25j
3.41 4.41 6.14
Et2N
37a
O
2.47 3.34 5.01
37b
O 2.77 3.64 5.30
CH3
37c
O
3.02 3.89 5.55
H3C
H3C
37d
O
3.42 4.29 5.96
(H3C)3C
37f
O
4.29 5.16 6.83
F
37g
2.37 3.24 4.91
O
19
Entry Ar
cLog D6.4 cLog D7.4 cLog P
Cl
37h
3.17 4.04 5.71
O
37i Br
3.00 3.87 5.54
O
I
37j
O
3.39 4.26 5.93
37k
Cl O
3.06 3.93 5.60
37l
Br O
3.16 4.03 5.69
H3CO
37m
O
2.46 3.32 4.99
F3CO
37n
O
3.50 4.37 6.03
Et2N
37o
O
2.77 3.70 5.42
20
Table B. cLog D6.4, cLog D7.4 and cLog P values are reported for compounds 1, 41, 52a-d, 56a-c,
61a,b and 74a-c.
O H O
N
N N
S H O H N
H3C R
56b O
1.63 2.54 3.96
O
H2N
56c O
O
0.71 1.64 2.54
61a O 1.74 1.74 3.74
HN
61b O
C2H5N 4.12 4.12 6.12
74a O
2.53 3.37 5.17
H3C
74b O
H3 C
CH3
2.60 3.10 5.58
74c O 2.47 3.29 5.15
21