1534 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 7
Regourd et al.
gradient of ethyl acetate:hexane (0:100-30:70) as eluent, the title
compound was obtained as a yellow film (71%); Rf 0.65 (50:50
ethyl acetate:hexane); δH (500 MHz, CDCl3) 11.08 (1H, bs), 7.12
(1H, s), 5.43 (1H, s), 3.90 (3H, s), 3.71 (3H, s), 3.07 (2H, t, J 6.5),
2.72 (2H, t, J 6.5), 2.60 (3H, s), 2.45 (3H, s); δC (125 MHz, CDCl3)
194.6, 173.6, 168.2, 162.0, 143.8, 133.7, 133.2, 126.0, 123.1, 118.7,
118.6 (q, J 321.1, CF3), 87.6, 58.9, 51.8, 37.4, 28.0, 16.0, 12.4; δF
(235 MHz, CDCl3) -73.83; m/z ESI+ 464.9 [(M + H)+, 15%)],
486.9 [(M + Na)+, 100%)].
(125 MHz, CDCl3) 194.5, 173.5, 166.8, 150.4, 148.8, 138.5, 128.8,
124.4, 123.4, 123.0, 122.0, 119.4, 112.6 (2C), 93.4, 59.0, 51.8, 37.6,
27.9, 15.7, 12.6; m/z EI+ 380.6 [(M - HCl)+, 6%] [found 381.1677
C21H23N3O4 expected 381.1688].
Methyl 6-[5-(4-Methoxy-1H,1′H-[2,2′]bipyrrolyl-5-ylmethyl-
ene)-2,4-dimethyl-5H-pyrrol-3-yl]-6-oxohexanoate Hydrochloric
Salt (54HCl). The procedure as for the synthesis of 11 and
purification using chromatography on silica and a gradient of ethyl
acetate:hexane (0:100-40:60) as eluent gave the brick-red free-
base 54 after addition of acetone to the concentrated chromatog-
raphy fractions and filtration (82%); mp ) 165 °C; Rf 0.48 (50:50
ethyl acetate:hexane); λmaxCHCl3 460 (ꢀ 35 340), 528 (ꢀ 21 631);
δH (500 MHz, CDCl3) 6.92 (1H, s), 6.77 (1H, s), 6.73 (1H, s),
6.22 (1H, s), 6.05 (1H, s), 3.98 (3H, s), 3.64 (3H, s), 2.68 (2H, t,
J 6.3), 2.40 (3H, s), 2.33 (2H, t, J 6.3), 2.21 (3H, s), 1.69-1.66
(4H, m); δC (125 MHz, CDCl3) 197.2, 174.0 (2C), 168.9, 160.7,
141.9, 129.5, 128.2, 126.3, 123.4, 123.1, 113.7, 112.0, 110.7, 95.9,
58.6, 51.5, 42.3, 34.0, 24.7, 23.6, 14.3, 12.3; m/z EI+ 409.2 (M+,
5%) [found 409.2007 C23H27N3O4 expected 409.2001]. Addition
of HCl in ether to the filtrate, followed by filtration, gave the title
compound as a crimson solid (15%, total yield 97%); mp ) 189
°C; λmaxCHCl3 529 (ꢀ 92 087), 499 (ꢀ 45 765); δH (500 MHz,
CDCl3) 13.01 (1H, bs), 12.72 (1H, s), 12.69 (1H, s), 7.31 (1H, s),
7.13 (1H, s), 7.02 (1H, s), 6.40 (1H, s), 6.12 (1H, s), 4.07 (3H, s),
3.67 (3H, s), 2.85 (3H, s), 2.77 (2H, t, J 6.6), 2.51 (3H, s), 2.37
(2H, t, J 6.6), 1.73-1.70 (4H, m); δC (125 MHz, CDCl3) 196.6,
173.9, 166.7, 150.4, 148.6, 138.5, 128.7, 125.0, 123.4, 122.9, 122.0,
119.3, 112.7, 112.6, 93.4, 59.0, 51.5, 42.6, 34.0, 24.6, 23.5, 15.6,
12.5; δN (50 MHz, CDCl3) -213.40, -218.67, -241.13; m/z EI+
409.0 [(M - HCl)+, 0.2%] [found 409.2008 C23H27N3O4 expected
409.2001].
Ethyl 6-[5-(4-Methoxy-1H,1′H-[2,2′]bipyrrolyl-5-ylmethylene)-
2,4-dimethyl-5H-pyrrol-3-yl]-6-oxohexanoate Hydrochloric Salt
(55HCl). The procedure as for the synthesis of 11 and purification
using chromatography on silica and a gradient of ethyl acetate:
hexane (0:100-40:60) gave the title compound dark crimson solid
(54%); mp ) 146 °C; Rf (free base) 0.48 (50:50 ethyl acetate:
hexane); λmaxCHCl3 529 (ꢀ 110 605), 503 (ꢀ 54 168); δH (500 MHz,
CDCl3) 12.94 (1H, bs), 12.68 (2H, bs), 7.29 (1H, s), 7.02 (1H, s),
7.00 (1H, s), 6.39 (1H, s), 6.10 (1H, s), 4.13 (2H, q, J 7.1), 4.05
(3H, s), 2.83 (3H, s), 2.75 (2H, t, J 7.2), 2.49 (3H, s), 2.35 (2H, t,
J 6.7), 1.76-1.71 (4H, m), 1.26 (3H, t, J 7.1); δC (125 MHz, CDCl3)
196.6, 173.5, 166.7, 150.3, 148.6, 138.4, 128.6, 124.9, 123.3, 122.9,
122.0, 119.3, 112.6, 112.5, 93.5, 60.3, 59.2, 42.6, 34.2, 24.6, 23.5,
15.6, 14.2, 12.6; m/z EI+ 423.1 [(M - HCl)+, 3%)] [found 423.2156
C24H29N3O4 expected 423.2158].
Methyl 6-[5-(3-Methoxy-5-trifluoromethanesulfonyloxy-1H-
pyrrol-2-ylidenemethyl)-2,4-dimethyl-5H-pyrrol-3-yl]-6-oxohex-
anoate (49). Following the procedure as for the synthesis of 11,
the title compound was obtained as a yellow solid (81%); mp )
58 °C; Rf 0.71 (50:50 ethyl acetate:hexane); δH (500 MHz, CDCl3)
11.05 (1H, bs), 7.12 (1H, s), 5.43 (1H, s), 3.90 (3H, s), 3.67 (3H,
s), 2.75 (2H, t, J 6.7), 2.58 (3H, s), 2.43 (3H, s), 2.37 (2H, t, J
6.8), 1.73-1.70 (4H, m); δC (125 MHz, CDCl3) 196.7, 173.9, 168.1,
162.0, 143.5, 133.7, 133.0, 126.0, 123.5, 118.7, 118.6 (q, J 321.1,
CF3), 87.6, 58.9, 51.5, 42.3, 34.0, 24.6, 23.5, 15.9, 12.3; δF (235
MHz, CDCl3) -73.89; m/z ESI+ 515.0 [(M + Na)+, 100%)].
Ethyl 6-[5-(3-Methoxy-5-trifluoromethanesulfonyloxy-1H-
pyrrol-2-ylidenemethyl)-2,4-dimethyl-5H-pyrrol-3-yl]-6-oxohex-
anoate (50). Following the procedure as for the synthesis of 11
followed by purification using chromatography on silica and a
gradient of ethyl acetate:hexane (0:100-50:70) as eluent, the title
compound was obtained as a yellow film (83%); Rf 0.72 (50:50
ethyl acetate:hexane); δH (500 MHz, CDCl3) 11.06 (1H, bs), 7.13
(1H, s), 5.43 (1H, s), 4.12 (2H, q, J 7.1), 3.90 (3H, s), 2.75 (2H, t,
J 6.5), 2.58 (3H, s), 2.43 (3H, s), 2.35 (2H, t, J 6.8), 1.75-1.71
(4H, m), 1.25 (3H, t, J 7.1); δC (125 MHz, CDCl3) 196.8, 173.9,
173.5, 168.1, 162.0, 143.5, 133.7, 126.0, 123.6, 118.7, 118.4 (q, J
320.1, CF3), 87.6, 60.3, 58.9, 42.3, 34.2, 24.7, 23.5, 15.9, 14.2,
12.3; δF (235 MHz, CDCl3) -73.76; m/z ESI+ 504.9 [(M - H)+,
52%)].
Methyl 6-[5-(3-Methyl-4-ethyl-5-trifluoromethanesulfonyloxy-
1H-pyrrol-2-ylidenemethyl)-2,4-dimethyl-5H-pyrrol-3-yl]-6-oxo-
hexanoate (51). Following the procedure as for the synthesis of
11, the title compound was obtained as a yellow film (51%); Rf
0.84 (50:50 ethyl acetate:hexane); δH (500 MHz, CDCl3) 11.36 (1H,
bs), 6.96 (1H, s), 3.70 (3H, s), 2.78 (2H, t, J 6.7), 2.60 (3H, s),
2.47 (3H, s), 2.40 (2H, t, J 6.8), 2.40 (2H, q, J 7.6), 2.21 (3H, s),
1.75 (4H, m), 1.14 (3H, t, J 7.6); δC (125 MHz, CDCl3) 196.7,
174.0, 163.3, 143.4, 142.8, 141.3, 132.6, 126.6, 126.4, 123.4, 119.8
, 118.7 (q, J 321.2, CF3), 51.5, 42.3, 31.0, 24.7, 23.6, 16.6, 15.9,
13.7, 12.4, 9.9; δF (235 MHz, CDCl3) -73.60; m/z ESI+ 505.1
[(M + H)+, 10%], 527.0 [(M + Na)+, 98%)].
Methyl 10-[5-(3-Methoxy-5-trifluoromethanesulfonyloxy-1H-
pyrrol-2-ylidenemethyl)-2,4-dimethyl-5H-pyrrol-3-yl]-10-oxode-
canoate (52). Following the procedure as for the synthesis of 11
and purification using chromatography on silica and a gradient of
ethyl acetate:hexane (0:100-20:80) as eluent, the title compound
was obtained as a yellow film (70%); Rf 0.76 (50:50 ethyl acetate:
hexane); δH (500 MHz, CDCl3) 11.04 (1H, bs), 7.12 (1H, s), 5.43
(1H, s), 3.90 (3H, s), 3.66 (3H, s), 2.71 (2H, t, J 7.3), 2.58 (3H, s),
2.43 (3H, s), 2.30 (2H, t, J 7.5), 1.70-1.60 (4H, m), 1.35-1.30
(8H, m); δC (125 MHz, CDCl3) 197.5, 174.3, 168.1, 162.0, 143.5,
133.6, 133.2, 126.0, 123.7, 118.8, 118.7 (q, J 321.1, CF3), 87.5,
58.9, 51.4, 42.8, 34.1, 29.4 (2C), 29.2, 29.1, 24.9, 24.1, 15.9, 12.3;
δF (235 MHz, CDCl3) -73.64; m/z ESI+ 549.0 [(M + H)+, 20%)],
571.0 [(M + Na)+, 100%)].
Methyl 4-[5-(4-Methoxy-1H,1′H-[2,2′]bipyrrolyl-5-ylmethyl-
ene)-2,4-dimethyl-5H-pyrrol-3-yl]-4-oxobutanoate Hydrochloric
Salt (53HCl). Following the procedure as for the synthesis of 11
and purification using chromatography on silica and a gradient of
ethyl acetate:hexane (0:100-25:75) as eluent, the title compound
was obtained as a dark crimson solid (57%); mp ) 194 °C; Rf
(free base) 0.43 (50:50 ethyl acetate:hexane); λmaxCHCl3 529 (ꢀ
96 425), 501 (ꢀ 54 072); δH (500 MHz, CDCl3) 12.98 (1H, bs),
12.72 (1H, bs), 12.68 (1H, bs), 7.30 (1H, s), 7.11 (1H, s), 7.02
(1H, s), 6.40 (1H, s), 6.11 (1H, s), 4.05 (3H, s), 3.72 (3H, s), 3.07
(2H, t, J 6.4), 2.86 (3H, s), 2.72 (2H, t, J 6.4), 2.52 (3H, s); δC
Methyl 6-[5-(3-Ethyl-4-methyl-1H,1′H-[2,2′]bipyrrolyl-5-yl-
methylene)-2,4-dimethyl-5H-pyrrol-3-yl]-6-oxohexanoate Hy-
drochloric Salt (56HCl). The procedure as for the synthesis of 11
and purification using chromatography on silica and a gradient of
ethyl acetate:hexane (0:100-30:70) gave the title compound as a
dark purple solid (26%); mp ) 208 °C; Rf (free base) 0.70 (50:50
ethyl acetate:hexane); λmaxCHCl3 562 (ꢀ 104 039), 532 (ꢀ 55 377);
δH (500 MHz, CDCl3) 13.16 (1H, bs), 13.06 (1H, bs), 12.65 (1H,
bs), 7.36 (1H, s), 7.16 (1H, s), 7.05 (1H, s), 6.47 (1H, s), 3.71 (3H,
s), 2.87 (3H, s), 2.79-2.71 (4H, m), 2.52 (3H, s), 2.40 (2H, t, J
6.5), 2.35 (3H, s), 1.75 (4H, m), 1.23 (3H, t, J 7.4); δC (125 MHz,
CDCl3) 196.6, 173.9, 149.8, 148.5, 145.3, 139.7, 132.3, 130.2,
128.2, 125.4, 124.4, 121.5, 119.2, 115.3, 112.9, 51.6, 42.7, 34.0,
24.6, 23.5, 18.7, 15.6, 13.3, 12.7, 10.1; m/z ESI+ 422.3 [(M -
HCl)+, 100%)].
Methyl 10-[5-(4-Methoxy-1H,1′H-[2,2′]bipyrrolyl-5-ylmeth-
ylene)-2,4-dimethyl-5H-pyrrol-3-yl]-10-oxodecanoate Hydro-
chloric Salt (57HCl). The procedure as for the synthesis of 11
and purification using chromatography on silica and a gradient of
ethyl acetate:hexane (0:100-30:70) gave the title compound as a
dark crimson solid (29%); mp ) 167 °C; Rf (free base) 0.37 (50:
50 ethyl acetate:hexane); λmaxCHCl3 530 (ꢀ 108 531), 500 (ꢀ
55 742); δH (500 MHz, CDCl3) 13.01 (1H, bs), 12.73 (2H, bs),
7.34 (1H, s), 7.16 (1H, s), 7.05 (1H, s), 6.43 (1H, s), 6.14 (1H, s),
4.10 (3H, s), 3.70 (3H, s), 2.88 (3H, s), 2.76 (2H, t, J 7.3), 2.53