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D. Pez et al. / Bioorg. Med. Chem. 11 (2003) 4693–4711
1.35–1.65 (m, 6H, H300-H500), 0.95 (t, 3H, J=7.4 Hz,
H600). 13C NMR (CDCl3) d 191.5 (CHO), 154.4 (4),
150.1 (3), 136.8 (10), 130.8 (1), 129.1 (20,60), 128.5 (40),
127.5 (30,50), 126.8 (6) 113.3 (5), 111.2 (2), 71.2
(OCH2Ph), 69.5 (100), 32.0 (400), 29.4 (200), 26.1 (300), 23.0
(500), 14.6 (600). Found: C, 76.97; H, 7.79. calcd for
C20H24O3: C, 76.89; H, 7.74%.
(CDCl3) d 9.90 (s, 1H, CHO), 7.39 (dd, 1H, J=8.1 Hz,
1.9 Hz, H6), 7.34 (d, 1H, J=1.9 Hz, H2), 6.92 (d, 1H,
J=8.1 Hz, H5), 4.02 (t, 2H, J=6.7 Hz, H10), 4.01 (t,
2H, J=6.7 Hz, H100), 1.75–1.90 (m, 4H, H20+H200),
1.35–1.60 (m, 6H, H30-H50), 0.93 (t, 3H, J=6.6 Hz,
H300), 0.90 (t, 3H, J=6.6 Hz, H60). 13C NMR (CDCl3) d
191.5 (CHO), 155.1 (4), 149.8 (3), 130.3 (1), 127.1 (6),
112.1 (5), 111.2 (2), 69.5 (10+100), 32.2 (600), 32.0 (40),
29.8 (500), 29.7 (400), 29.5 (200), 29.4 (20), 26.4 (300), 26.1
(30), 23.1 (700), 23.0 (50), 14.6 (800), 14.5 (60). Found: C,
75.40; H, 10.28. calcd for C21H39O3: C, 75.41; H,
10.24%.
4-Hydroxy-3-hexyloxybenzaldehyde (18). 4-Benzyloxy-
3-hexyloxybenzaldehyde 17 (2.400 g, 7.69 mmol) was
dissolved in ethanol (40 mL), then palladium on actived
carbon 10% (400 mg, 0.38 mmol) was added. The reac-
tion was stirred under an atmosphere of hydrogen at
room temperature for 2 h. The mixture was filtered and
the solvent was removed to give as yellow oil 18 (1.472
g, 6.63 mmol, 86%). TLC Rf 0.18 (10% EtOAc/hexane).
IR (neat): n=3373 (OH), 2944 (Ar), 2729 (C¼O), 1682
(C¼O), 1269 (ArOR) cmÀ1. 1H NMR (CDCl3) d 9.90 (s,
1H, CHO), 7.32 (dd, 1H, J=8.5 Hz, 1.8 Hz, H6), 7.30
(d, 1H, J=1.8 Hz, H2), 6.92 (d, 1H, J=8.5 Hz, H5),
6.30 (br s, 1H, OH), 4.07 (t, 2H, J=6.7 Hz, H10), 1.80
(sext, 2H, J=6.6 Hz, H20), 1.35–1.60 (m, 6H, H30-H50),
0.90 (t, 3H, J=6.6 Hz, H60). 13C NMR (CDCl3) d 191.4
(CHO), 152.2 (4), 147.0 (3), 130.3 (1), 127.8 (6), 114.7
(5), 109.9 (2), 69.7 (10), 31.9 (40) 29.4 (20), 26.1 (30), 23.0
(50), 14.5 (60). LRMS (ESÀ mode): m/z=220.92
[(MÀH)+, 40%], 442.7 [(2 MÀH)+, 40%]. HRMS
(ES+ mode): calculated mass 240.1600 (M+NH4)+,
measured mass 240.1600 (M+NH4)+.
(E)-3-(3-Hexyloxy-4-propyloxyphenyl)-2-(ethoxymethyl)-
2-propenenitrile (20a). Following the general procedure
of condensation with ethoxypropionitrile using Dean–
Stark trap and starting from ethoxypropionitrile (750
mg, 7.58 mmol), 3-hexyloxy-4-propyloxybenzaldehyde
19a (523 mg, 3.79 mmol) and sodium ethoxide (515 mg,
7.58 mmol) in dry ethanol (100 mL), compound 20a was
isolated as a yellow oil (372 mg, 1.08 mmol, 28%). TLC
Rf 0.55 (40% EtOAc/hexane). IR (neat): n=2931, 2871,
2210, 1269, 1140 cmÀ1. 1H NMR (CDCl3) d 7.54 (d, 1H,
J=1.9 Hz, H20), 7.27 (dd, 1H, J=8.1 Hz, 1.9 Hz, H60),
7.11 (br s, 1H, H3), 6.98 (d, 1H, J=8.8, H50), 4.26 (s,
2H, CH2OEt), 4.10 (t, 2H, J=6.7 Hz, H100), 4.05 (t, 2H,
J=6.7 Hz, H1000), 3.64 (q, 2H, J=7.0 Hz, CH3CH2O),
1.75–1.90 (m, 4H, H200+H2000), 1.35–1.65 (m, 6H, H300-
500), 1.33 (t, 3H, J=7.0 Hz, CH3CH2O), 1.05 (t, 3H,
J=6.6 Hz, H3000), 0.93 (t, 3H, J=6.6 Hz, H600). 13C
NMR (CDCl3) ꢀ 151.7 (40), 149.3 (3), 145.3 (3), 126.3
(10), 124.2 (60), 119.0 (1), 113.2 (50), 113.0 (20), 105.4 (2),
72.5 (CH3CH2O), 70.8 (100), 69.6 (1000), 66.6 (EtOCH2),
31.4 (400), 29.5 (200), 26.1 (300), 29.7 (500), 23.0 (2000), 22.9
(500), 15.5 (CH3CH2O), 14.5 (600), 10.9 (3000). LRMS
(ES+ mode): m/z=368.2 [(M+Na)+, 70%], 713.1
[(2 M+Na)+, 100%]. HRMS (ES+ mode): calculated
mass 346.2382 (M+H)+, measured mass 346.2383
(M+H)+.
3-Hexyloxy-4-propyloxybenzaldehyde (19a). Following
the general procedure of monoalkylation of hydroxyl-
benzaldehyde and starting from 4-hydroxy-3-hexyloxy
benzaldehyde 18 (609 mg, 2.74 mmol), 1-bromopropane
(674 mg, 5.48 mmol), anhydrous potassium carbonate
(1.134 g, 8.22 mmol) and a catalytic amount of potas-
sium iodide in acetonitrile (150 mL), compound 19a was
isolated as a white oil (539 mg, 2.04 mmol, 75%). TLC
Rf 0.27 (10% EtOAc/hexane). IR (neat): n=2947, 2826,
1682, 1270 cmÀ1 1H NMR (CDCl3) d 9.90 (s, 1H,
.
CHO), 7.39 (dd, 1H, J=8.1 Hz, 1.9 Hz, H6), 7.34 (d,
1H, J=1.9 Hz, H2), 6.92 (d, 1H, J=8.1 Hz, H5), 4.02
(t, 2H, J=6.7 Hz, H10), 4.01 (t, 2H, J=6.7 Hz, H100),
1.75–1.90 (m, 4H, H20+H200), 1.35–1.60 (m, 6H, H30-
H50), 1.05 (t, 3H, J=6.6 Hz, H300), 0.90 (t, 3H, J=6.6
Hz, H60). 13C NMR (CDCl3) d 191.5 (CHO), 160.4 (4),
155.1 (3), 130.3 (1), 127.1 (6), 112.1 (5), 111.3 (2), 70.9
(10), 69.7 (100), 32.0 (40) 29.4 (20), 26.1 (30), 23.0 (200), 22.8
(50), 14.5 (60), 10.8 (300). LRMS (ES+ mode): m/
z=265.2 [(M+H)+, 40%], 287.0 [(M+Na)+, 80%],
551.1 [(2 M+Na)+, 100%]. HRMS (ES+ mode): cal-
culated mass 265.1803 (M+H)+, measured mass
265.1807 (M+H)+.
(E)-3-(3-Hexyloxy-4-octyloxyphenyl)-2-(ethoxymethyl)-
2-propenenitrile (20b). Following the general procedure
of condensation with ethoxypropionitrile using Dean–
Stark trap and starting from ethoxypropionitrile (1.255
g, 12.68 mmol), 3-Hexyloxy-4-octyloxybenzaldehyde
19b (628 mg, 6.34 mmol) and sodium ethoxide (863 mg,
12.68 mmol) in dry ethanol (100 mL), compound 20b
was isolated as a yellow oil (279 mg, 0.67 mmol, 11%).
TLC Rf 0.45 (20% EtOAc/hexane). IR (film): n=2925,
1
2857, 2210, 1270, 1140 cmÀ1. H NMR (CDCl3) d 7.53
(d, 1H, J=1.9 Hz, H20), 7.20 (dd, 1H, J=8.1 Hz, 1.9
Hz, H60), 7.04 (br s, 1H, H3), 6.85 (d, 1H, J=8.8, H50),
4.20 (s, 2H, CH2OEt), 4.04 (t, 2H, J=6.7 Hz, H100), 4.01
(t, 2H, J=6.7 Hz, H1000), 3.57 (q, 2H, J=7.0 Hz,
CH3CH2O), 1.75–1.90 (m, 4H, H200+H2000), 1.35–1.65
(m, 16H, H300-500+H3000-7000), 1.33 (t, 3H, J=7.0 Hz,
CH3CH2O), 0.90 (t, 3H, J=6.6 Hz, H600), 0.87 (t, 3H,
J=6.6 Hz, H8000). 13C NMR (CDCl3) d 151.8 (40), 149.3
(30), 145.3 (3), 126.3 (10), 124.2 (60), 119.0 (1), 113.2 (50),
113.3 (20), 105.4 (2), 72.5 (CH3CH2O), 68.5 (100), 68.2
(1000), 66.6 (EtOCH2), 31.8 (6000), 31.6 (400), 29.3 (5000), 29.2
(2000+4000), 29.1 (200), 25.9 (300), 22.6 (7000), 22.5 (500), 15.5
(CH3CH2O), 14.0 (8000), 13.9 (600). LRMS (ES+ mode):
3-Hexyloxy-4-octyloxybenzaldehyde (19b). Following
the general procedure of monoalkylation of hydroxyl-
benzaldehyde and starting from 4-hydroxy-3-hexyloxy
benzaldehyde 18 (838 mg, 3.77 mmol), 1-iodooctane
(1.809 g, 7.54 mmol), anhydrous potassium carbonate
(1.563 g, 11.32 mmol) in 2-butanone (100 mL), com-
pound 19b was isolated as a white solid (925 mg, 2.77
mmol, 73%). TLC Rf 0.32 (10% EtOAc/hexane). IR
(neat): n=2924, 2853, 1686, 1275 cmÀ1 1H NM R
.