170 Y. C¸ etinkaya et al.
J Enzyme Inhib Med Chem, 2014; 29(2): 168–174
1
3,50-(Azidomethylene)bis(1,2-dimethoxybenzene) (21)
(25) (2.02g, 92%) as a white solid. M.p. 221–223 ꢁC. H-NMR
(400 MHz, D2O) ꢀ 7.08–7.06 (m, 1H), 6.98–6.96 (m, 1H), 6.90–
6.82 (m, 4H), 5.66 (s, 1H), 4.64 (bs, OH of D2O and NH3), 3.69 (s,
3H, OCH3), 3.68 (s, 3H, OCH3), 3.65 (s, 6H, 2OCH3). 13C-NMR
(100 MHz, CDCl3) ꢀ 152.7 (C), 148.7 (C), 148.5 (C), 145.6 (C),
130.4 (C), 129.4 (C), 125.4 (CH), 120.5 (CH), 118.7 (CH), 114.1
(CH), 112.0 (CH), 110.9 (CH), 60.8 (CH–NH3Cl), 55.9 (OCH3),
55.8 (2OCH3), 53.6 (OCH3). Anal. Calcd for C17H22ClNO4: C
60.09, H 6.53 and N 4.12; Found: C 60.15, H 6.57 and N 4.09.
Compound 21 was synthesized according to the general procedure
given for 18. From 17 (1.22 g, 4.01 mmol), azide 21 (0.986 g,
75%) was obtained, after crystallized from CH2Cl2. Colorless
block crystals. M.p. 78–80 ꢁC. 1H-NMR (400 MHz, CDCl3) ꢀ 7.08
(t, 1H, J ¼ 8.1 Hz), 6.96 (d, 1H, J ¼ 7.7 Hz), 6.89–6.80 (m, 4H),
6.10 (s, 1H), 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3). 13C-NMR (100 MHz, CDCl3) ꢀ 152.8
(C), 149.2 (C), 148.8 (C), 146.6 (C), 133.9 (C), 132.5 (C), 124.4
(CH), 120.0 (CH), 119.7 (CH), 112.3 (CH), 111.1 (CH), 110.7
(CH), 62.6 (CHN3), 61.0 (OCH3), 56.12 (OCH3), 56.10 (OCH3),
56.0 (OCH3). IR (CH2Cl2, cmꢀ1) 3423, 2829, 2098, 1645, 1516,
General procedure for the synthesis of sulfonamides
26–28
1480, 1415, 1271, 1234, 1140, 1072, 1027 and 1001. Anal. Calcd N-(bis(3,4-dimethoxyphenyl)methyl)methanesulfonamide (26)
for C17H19N3O4: C 62.00, H 5.81 and N 12.76; Found: C 61.90, H
To a solution of bis(3,4-dimethoxyphenyl)methanamine hydro-
5.83 and N 12.77.
chloride (22) (0.197 g, 0.580 mmol) in MeOH (15 mL) was added
6 M NaOH (40 mL). The mixture was stirred at r.t. for 3 h. After
most of the MeOH was evaporated, H2O (20 mL) and CH2Cl2
(50 mL) were added to the residue. Organic phase was separated
General procedure for synthesis amine hydrochloride
salts 23–25
and H2O phase was extracted with CH2Cl2 (3 ꢂ 30 mL). Combined
(2,4-Dimethoxyphenyl)(3,4-dimethoxyphenyl)methanamine hydro-
chloride (23)
organic layers were dried over Na2SO4 and the solvent was
evaporated. After the residue was dissolved in CH2Cl2 (30 mL),
NEt3 (70 mg, 0.696 mmol) and MeSO2Cl (86 mg, 0.754 mmol)
were added to this solution at r.t. for 20 h. The solvent was
evaporated and to the residue were added H2O (20 mL) and EtOAc
(30 mL). The organic layer was separated and H2O layer was
extracted with EtOAc (2 ꢂ 30 mL). The combined organic layers
were dried over Na2SO4 and the solvent was evaporated. The
chromatography of the residue on silica gel (SiO2, 60 g) with ethyl
acetate/hexane (1:9) gave a yellowish solid N-(bis(3,4-dimethox-
yphenyl)methyl)methanesulfonamide (26) (0.202 g, 91%).
Solidified; m.p. 123–125 ꢁC. 1H-NMR (400 MHz, CDCl3)
ꢀ 6.83–6.78 (m, 6H), 5.60 (d, 1H, CH, J ¼ 8.1 Hz), 5.57 (d, 1H,
NH, J ¼ 8.1 Hz), 3.83 (s, 6H, 2OCH3), 3.80 (s, 6H, OCH3), 2.60 (s,
3H, CH3). 13C-NMR (100 MHz, CDCl3) ꢀ 149.5 (2C), 148.9 (2C),
133.5 (2C), 119.8 (2CH), 111.2 (2CH), 110,7 (2CH), 61.0 (CH-
NH), 56.2 (2OCH3), 56.1 (2OCH3), 42.0 (CH3). IR (CH2Cl2,
cmꢀ1) 3565, 3261, 2829, 2090, 1645, 1515, 1464, 1418, 1318,
1252, 1189, 1140, 1063, 1025, 1063, 1025 and 979. Anal. Calcd for
C18H23NO6S: C 56.68, H 6.08, N 3.67 and S 8.41; Found: C 56.73,
H 6.02, N 3.62 and S 8.40.
Pd–C (100 mg) and 4-(azido(2,4-dimethoxyphenyl)methyl)-1,2-
dimethoxybenzene (19) (0.42 g, 1.28 mmol) in MeOH (40 mL)
and CHCl3 (6 mL) were placed in a 100 mL two-necked flask. A
balloon filled with H2 gas (3 L) was fitted to the flask. The
mixture was deoxygenated by flushing with H2 and then
hydrogenated at r.t. for one day. The catalyst was removed by
filtration. Recrystallization of the residue from MeOH–Et2O
yielded (2,4-dimethoxyphenyl)(3,4-dimethoxyphenyl)methana-
mine hydrochloride (23) (0.378 g, 87%) as a white solid. M.p.
230–232 ꢁC. 1H-NMR (400 MHz, D2O) ꢀ 6.93 (d, 1H, J ¼ 8.8 Hz),
6.88 (d, 1H, 8.1 Hz), 6.84–6.81 (m, 2H), 6.52 (s, 1H), 6.42 (qd,
1H, J ¼ 8.4), 5.51 (s, 1H), 4.64 (bs, OH of D2O and NH3), 3.68 (s,
6H, 2OCH3), 3.66 (s, 3H, OCH3), 3.64 (s, 3H, OCH3). 13C-NMR
(100 MHz, CDCl3) ꢀ 161.2 (C), 157.9 (C), 148.4 (C), 129.8 (CH),
129.2 (2C), 120.1 (CH), 117.2 (C), 111.9 (CH), 110.6 (CH), 105.4
(CH), 99.1 (CH), 55.8 (CH–NH3Cl), 55.75 (OCH3), 55.6
(2OCH3), 54.4 (OCH3). Anal. Calcd for C17H22ClNO4: C 60.09,
H 6.53 and N 4.12; Found: C 60.02, H 6.59 and N 4.13.
(4,5-Dimethoxy-2-methylphenyl) (3,4-dimethoxyphenyl) methana-
mine hydrochloride (24)
N-((4,5-dimethoxy-2-methylphenyl) (3,4-dimethoxyphenyl)methyl)
methane sulfonamide (27)
The general procedure was carried out with 1-(azido(3,4-
dimethoxyphenyl)methyl)-4,5-dimethoxy-2-methylbenzene (20)
(1.34 g, 3.90 mmol). Recrystallization of the residue from
MeOH–Et2O afforded (4,5-dimethoxy-2-methylphenyl)(3,4-
dimethoxyphenyl)methanamine hydrochloride (24) (1.28 g, 93%)
The general procedure for 26 was applied to (4,5-dimethoxy-2-
methylphenyl)(3,4-dimethoxyphenyl)methanamine hydrochloride
(24) (0.250 g, 0.707 mmol) to give yellowish solid 27 (0.260 g,
1
93%). M.p. 104–106 ꢁC. H-NMR (400 MHz, CDCl3) ꢀ 6.84 (bs,
1
as a white solid. M.p. 235–237 ꢁC. H-NMR (400 MHz, CDCl3)
1H), 6.83 (s, 1H), 6.78 (d, 1H, J ¼ 8.3 Hz), 6.75 (qd, 1H,
J ¼ 8.3 Hz), 6.68 (s, 1H), 5.83 (d, 1H, CH, J ¼ 7.2 Hz), 5.24 (d,
1H, NH, J ¼ 7.2), 3.86 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.81
(s, 6H, 2OCH3), 2.63 (s, 3H, CH3), 2.28 (s, 3H, CH3). 13C-NMR
(100 MHz, CDCl3) ꢀ 149.5 (C), 148.9 (C), 148.5 (C), 147.6 (C),
132.9 (C), 130.5 (C), 128.5 (C), 119.9 (CH), 114.2 (CH), 111.3
(CH), 111.0 (CH), 110.7 (CH), 57.7 (CH-NH), 56.4 (OCH3), 56.2
(OCH3), 56.11 (OCH3), 56.10 (OCH3), 42.2 (CH3), 19.1 (CH3).
IR (CH2Cl2, cmꢀ1) 3618, 3161, 2061, 1635, 1514, 1457, 1320,
1242, 1208, 1149, 1102, 1027 and 979. Anal. Calcd for
C19H25NO6S: C 57.70, H 6.37, N 3.54 and S 8.11; Found: C
57.75 H 6.32, N 3.51 and S 8.09.
ꢀ 6.93 (s, 1H), 6.87–6.77 (m, 4H), 5.61 (s, 1H), 4.64 (bs, OH of
D2O and NH3), 3.72 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.69 (s,
3H, OCH3), 3.66 (s, 3H, OCH3), 2.04 (s, 3H, CH3). 13C-NMR
(100 MHz, CDCl3) ꢀ 148.9 (C), 148.8 (C), 148.3 (C), 146.9 (C),
129.8 (C), 129.4 (C), 127.3 (C), 120.8 (CH), 115.0 (CH), 112.3
(CH), 111.4 (CH), 109.7 (CH), 56.4 (CH–NH3Cl), 56.1 (2OCH3),
56.0 (OCH3), 54.6 (OCH3), 18.0 (CH3). Anal. Calcd for
C18H24ClNO4: C 61.10, H 6.84 and N 3.96; Found: C 61.07, H
6.86 and N 3.94.
(2,3-Dimethoxyphenyl)(3,4-dimethoxyphenyl)methanamine
hydrochloride (25)
N-((2,3-dimethoxyphenyl)(3,4-dimethoxyphenyl)methyl)methane-
sulfonamide (28)
The general procedure was carried out with 3,50-(azidomethylene)
bis(1,2-dimethoxybenzene)
(21)
(2.14 g,
6.50 mmol).
Recrystallization of the residue from MeOH–Et2O yielded (2,3-
dimethoxyphenyl)(3,4-dimethoxyphenyl)methanamine hydrochloride
The general procedure described above was applied to 25 (0.300 g,