406
F. Zhang et al. / European Journal of Medicinal Chemistry 55 (2012) 395e408
mixture was filtered through celite to remove Pd/C and concentrated
yellow oil. IR (KBr, cmꢂ1
1199,1122,1040.1H NMR (CD3CN)
2H), 2.74 (m, 2H), 2.62 (s, 3H), 2.51 (s, 3H), 2.38 (m, 2H),1.44 (m, 4 H),
1.28 (m, 12 H) 0.89 (m, 3H). 13C NMR (CD3CN)
155.9, 154.5, 149.8,
)
nmax: 2922, 2853, 2666, 2654, 1690, 1633,
7.53 (s,1H), 4.58 (m, 2H), 3.37 (m,
to remove MeOH to afford the product (10 mg, 66% yield) as a pale
d
yellow oil. 1H NMR (CD3CN)
d 4.57 (m, 2H), 2.75 (m, 2H), 2.72 (m, 2H),
2,58 (s, 3H), 2.40 (s, 3H), 2.35 (m, 4H),1.44 (m, 6H),1.28 (m, 26 H), 0.89
d
(m, 6H). (lit. [47]) HPLC: >95% pure (tR ¼ 12.80 min).
137.8, 122.3, 56.9, 48.5, 38.5, 31.4, 31.3, 29.0, 28.72, 28.67, 28.1, 27.9,
22.1, 20.2, 19.7, 16.1, 13.1. MS (ESI) m/z: 289.0 (Mþ).
4.1.32. 6-Dec-1-(E)-enyl-5,7-dimethyl-2,3-dihydro-1H-
indolizinium chloride (39)
4.1.34. 8-Dec-1-(E)-enyl-5,7-dimethyl-2,3-dihydro-1H-
Pd(OAc)2 (5 mg, 0.02 mmol), PPh3 (18 mg, 0.07 mmol), and 4
(138 mg, 0.38 mmol) were stirred in toluene (0.76 mL) and
aqueous Na2CO3 (0.38 mL, 2 M) under N2 for 0.5 h. To this solution
was added a solution of (E)-dec-1-enylboronic acid (105 mg,
0.57 mmol) in ethanol (0.38 mL). The solution was refluxed
overnight, then diluted with EtOAc, filtered and concentrated. The
residue was purified on silica gel (hexaneeEtOAc, 8:1) to afford
the product 6-(3-(4-methoxybenzyloxy)propyl)-3-((E)-dec-1-
enyl)-2,4-dimethylpyridine (116 mg, 72%) as a pale yellow oil. IR
indolizinium chloride (41)
Pd(OAc)2 (4 mg, 0.02 mmol), PPh3 (12 mg, 0.05 mmol), and 13
(91 mg, 0.25 mmol) were stirred in toluene (0.5 mL) and aqueous
Na2CO3 (0.25 mL, 2 M) under N2 for 0.5 h. To this solution was
added a solution of (E)-dec-1-enylboronic acid (69 mg, 0.38 mmol)
in ethanol (0.25 mL). The solution was refluxed overnight,
then diluted with EtOAc, filtered and concentrated; the residue
was purified on silica gel (hexaneeEtOAc, 4:1) to afford the
product
4,6-dimethylpyridine (91 mg, 86%) as a pale yellow oil. IR (KBr,
cmꢂ1
nmax: 2953, 2923, 2852, 1590, 1512, 1454, 1245, 1098, 1036,
969. 1H NMR (CDCl3)
7.25 (m, 2H), 6.86 (m, 2H), 6.80 (s, 1H), 6.29
2-(3-(4-methoxybenzyloxy)propyl)-3-((E)-dec-1-enyl)-
(KBr, cmꢂ1
(CDCl3)
)
nmax: 2923, 2852, 1511, 1245, 1099, 1035, 819. 1H NMR
7.26 (m, 2H), 6.87 (m, 2H), 6.79 (s, 1H), 6.26 (d,
d
)
J ¼ 16.1 Hz, 1H), 5.69 (dt, J ¼ 6.9, 16.1 Hz, 1H), 4.44 (s, 2H), 3.80 (s,
3H), 3.50 (t, J ¼ 6.5 Hz, 2H), 2.76 (t, J ¼ 6.9 Hz, 2H), 2.48 (s, 3H), 2.24
(s, 3H), 2.24 (m, 2H), 2.01 (m, 2H), 1.47 (m, 2H), 1.26e1.38 (m, 10H),
d
(d, J ¼ 16.1 Hz, 1H), 5.65 (dt, J ¼ 6.9, 16.1 Hz, 1H), 4.43 (s, 2H), 3.80 (s,
3H), 3.49 (t, J ¼ 6.7 Hz, 2H), 2.83 (m, 2H), 2.44 (s, 3H), 2.22 (s, 3H),
2.19 (m, 2H), 1.96 (m, 2H), 1.47 (m, 2H), 1.28e1.36 (m, 10H), 0.88 (t,
0.89 (t, J ¼ 6.6 Hz, 3H). 13C NMR (CDCl3)
d 159.1, 158.2, 155.3, 137.1,
131.6, 130.8, 130.4, 129.2, 129.2, 125.4, 121.9, 113.8, 113.8, 72.5, 69.6,
55.3, 34.5, 33.4, 31.9, 30.0, 29.5, 29.4, 29.3, 29.2, 23.6, 22.7, 20.4,
14.1. MS (ESI) m/z: 424.7 (M þ H)þ.
J ¼ 6.7 Hz, 3H). 13C NMR (CDCl3)
d 159.0, 158.5, 154.9, 145.3, 137.1,
130.9, 130.0, 129.1, 129.1, 125.1, 122.4, 113.7, 113.7, 72.3, 70.0, 55.3,
33.4, 32.6, 31.9, 29.6, 29.5, 29.4, 29.3, 29.3, 24.0, 22.7, 20.4, 14.1. MS
(ESI) m/z: 424.7 (M þ H)þ.
To a solution of 6-(3-(4-methoxybenzyloxy)propyl)-3-((E)-dec-
1-enyl)-2,4-dimethylpyridine (205 mg, 0.48 mmol) in 8 mL of EtOH
was added 1 N HCl (4 mL). Then the mixture was refluxed for 3 h.
After cooling, the mixture was concentrated to remove EtOH. The
water layer was extracted with CH2Cl2 (3 ꢁ 20 mL) and the
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The residue was
purified on silica gel (DCMeMeOH, 30:1) to give 3-(5-(E)-dec-1-
enyl)-4,6-dimethylpyridine as 156 mg pale yellow oil in 95% yield
To a solution of 2-(3-(4-methoxybenzyloxy)propyl)-3-((E)-dec-
1-enyl)-4,6-dimethylpyridine (80 mg, 0.19 mmol) in 6 mL of EtOH
was added 1 N HCl (3 mL). Then the mixture was refluxed for 3 h.
After cooling, the mixture was concentrated to remove EtOH. The
water layer was extracted with CH2Cl2 (3 ꢁ 20 mL) and the
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The residue was
purified on silica gel (DCMeMeOH, 30:1) to give 3-(3-((E)-dec-1-
enyl)-4,6-dimethylpyridin-2-yl)propan-1-ol as 55 mg pale yellow
as the hydrochloride salt. IR (KBr, cmꢂ1
)
nmax: 3261, 2954, 2923,
6.84 (s,
2853, 1626, 1486, 1336, 1233, 1040, 977. 1H NMR (4CDCl3)
d
oil in 85% yield as the hydrochloride salt. IR (KBr, cmꢂ1
) nmax: 3262,
1H), 6.24 (d, J ¼ 16.2 Hz, 1H), 5.70 (dt, J ¼ 6.9, 16.2 Hz, 1H), 3.73 (t,
J ¼ 5.6 Hz, 2H), 2.89 (t, J ¼ 6.0 Hz, 2H), 2.47 (s, 3H), 2.25 (s, 3H), 2.24
(m, 2H), 1.94 (m, 2H), 1.24e1.51 (m, 12H), 0.89 (t, J ¼ 6.5 Hz, 2H). 13C
2954, 2923, 2853, 1593, 1455, 1246, 1036, 970. 1H NMR (CDCl3)
d
6.83 (s, 1H), 6.26 (d, J ¼ 16.1 Hz, 1H), 5.65 (dt, J ¼ 6.9, 16.1 Hz, 1H),
3.69 (t, J ¼ 5.6 Hz, 2H), 2.99 (m, 2H), 2.44 (s, 3H), 2.23 (m, 2H), 2.23
(s, 3H), 1.92 (m, 2H), 1.47 (m, 2H), 1,29e1.38 (m, 10H), 0.89 (t,
NMR (CDCl3)
d 157.5, 154.8, 146.0, 137.5, 130.7, 125.0, 122.4, 62.8,
35.7, 33.4, 31.9, 31.2, 29.4, 29.3, 29.3, 29.2, 23.2, 22.7, 20.4, 14.1. MS
(ESI) m/z: 304.3 (M þ H)þ. Methanesulfonyl chloride (105 mg,
0.92 mmol) was added to an ice-cooled solution of 3-(5-((E)-dec-1-
enyl)-4,6-dimethylpyridine (156 mg, 0.46 mmol) and triethylamine
(139 mg, 1.38 mmol) in 8 mL CH2Cl2. The resulting mixture was
allowed to warm to room temperature over 1 h. The mixture was
diluted with CH2Cl2 and washed with 1 N HCl twice, dried over
Na2SO4, filtered and concentrated. The residue was purified on
silica gel (DCMeMeOH, 10:1) to afford the product (78 mg, 53%) as
J ¼ 6.6 Hz, 2H). 13C NMR (CDCl3)
d 157.7, 154.2, 146.2, 137.6, 130.4,
124.8, 122.6, 62.8, 33.4, 33.3, 31.9, 30.6, 29.4, 29.3, 29.3, 29.2, 23.4,
22.7, 20.5, 14.1. MS (ESI) m/z: 304.3 (M þ H)þ.
Methanesulfonyl chloride (34 mg, 0.15 mmol) was added to an
ice-cooled solution of 3-(3-((E)-dec-1-enyl)-4,6-dimethylpyridin-
2-yl)propan-1-ol (51 mg, 0.15 mmol) and triethylamine (45 mg,
0.45 mmol) in 6 mL CH2Cl2. The resulting mixture was allowed to
warm to room temperature over 1 h. The mixture was diluted with
CH2Cl2 and washed with 1 N HCl twice, dried over Na2SO4, filtered
and concentrated. The residue was purified on silica gel
(DCMeMeOH, 10:1) to afford the product (39 mg, 82%) as a pale
a pale yellow oil. IR (KBr, cmꢂ1
)
nmax: 3385, 2956, 2923, 2853, 1626,
7.57 (s, 1H), 6.21 (d,
1486, 1336, 1233, 1040, 977. 1H NMR (CDCl3)
d
J ¼ 16.2 Hz, 1H), 5.86 (dt, J ¼ 6.9, 16.2 Hz, 1H), 5.00 (t, J ¼ 7.5 Hz, 2H),
3.58 (t, J ¼ 7.9 Hz, 2H), 2.82 (s, 3H), 2.58 (m, 2H), 2.46 (s, 3H), 2.29
(m, 2H), 1.49 (m, 2H), 1.29e1.37 (m, 10H), 0.89 (t, J ¼ 6.6 Hz, 3H). 13C
yellow oil. IR (KBr, cmꢂ1
1464, 1340, 1039, 978. 1H NMR (CDCl3)
)
nmax: 3445, 2956, 2923, 2853, 1626, 1490,
7.41 (s, 1H), 6.25 (d,
d
J ¼ 16.2 Hz, 1H), 6.05 (dt, J ¼ 6.8, 16.2 Hz, 1H), 5.05 (t, J ¼ 7.7 Hz, 2H),
3.51 (t, J ¼ 7.8 Hz, 2H), 2.87 (s, 3H), 2.57 (m, 2H), 2.47 (s, 3H), 2.28
(m, 2H), 1.49 (m, 2H), 1.24e1.37 (m, 10H), 0.89 (t, J ¼ 6.8 Hz, 3H). 13C
NMR (CDCl3)
d 155.9, 155.2, 149.8, 142.2, 136.2, 122.5, 121.6, 57.9,
33.2, 32.4, 31.8, 29.3, 29.1, 29.1, 28.7, 22.6, 21.7, 21.0, 18.7, 14.0. MS
(ESI) m/z: 286.2 (Mþ). HPLC: >97% pure (tR ¼ 7.29 min).
NMR (CDCl3) d 155.5, 155.0, 149.5, 142.1, 132.3, 127.9, 121.2, 57.3,
33.5, 33.0, 31.8, 29.3, 29.21, 29.17, 28.8, 22.6, 21.4, 20.7, 20.3, 14.1. MS
4.1.33. 6-Decyl-5,7-dimethyl-2,3-dihydro-1H-indolizinium chloride
(40)
(ESI) m/z: 286.2 (Mþ). HPLC: >99% pure (tR ¼ 6.75 min).
Hydrogenationwas conducted on 39 (25 mg, 0.08 mmol) and Pd/C
(2.5 mg, 10% by weight) in MeOH (2 mL) under 50 psi H2 for 6 h. The
mixture was filtered through celite to remove Pd/C and concentrated
to remove MeOH to afford the product (18 mg, 72% yield) as a pale
4.1.35. 8-Decyl-5,7-dimethyl-2,3-dihydro-1H-indolizinium chloride
(42)
Hydrogenation was conducted on 41 (29 mg, 0.09 mmol) and
Pd/C (3 mg, 10% by weight) in MeOH (3 mL) under 50 psi H2 for 6 h.