672
steroids 7 3 ( 2 0 0 8 ) 669–675
Rf = 0.58 (CHCl3/EtOAc = 8/2); mp 159–163 ◦C (white crystalline
material).
(M = 423.55): C, 72.73; H, 7.85; N, 3.31; found: C, 72.80; H, 8.22;
N, 3.19. Rf = 0.74 (CHCl3/EtOAc = 8/2); mp 111–114 ◦C (off-white
solid).
3-Methoxy-17-[(N-methoxycarbonyl-methyl)carboxamido]-13˛-
estra-1,3,5(10),16-tetraene (4e): 1H NMR (CDCl3): 7.14 (d, 8.9 Hz,
1H, 2-H); 6.65 (dd, 8.9 Hz, 1.8 Hz, 1H, 1-H); 6.54 (br s, 1H, 4-H);
6.40 (br s, 1H, NH); 6.12 (br s, 1H, 16-H); 3.96 (m, 2H, NCH2);
3.70 (s, 3H, OCH3); 3.67 (s, 3H, OCH3); 2.78 (m, 2H, 6-H2); 2.65
(ddd, 1.7 Hz, 6.5 Hz, 15.5 Hz; 1H, 15-HaHb); 2.47 (d, 15.5 Hz,
1H); 1.10–2.32 (multiplets, 9H, skeleton protons); 1.21 (s, 3H,
18-H3); 13C NMR (CDCl3): 170.4; 166.9; 157.4; 146.3; 138.0; 134.7;
132.7; 126.9; 113.6; 111.6; 55.1; 52.1; 51.9; 49.3; 42.4; 41.3; 40.9;
35.6; 33.0; 30.6; 29.0; 28.2; 27.9. IR (KBr (cm−1)): 3314 (NH);
1747 (COO); 1661 (CON). MS (m/z/rel.int.): 383/100 (M+), 368/5,
295/14. Analysis calculated for C23H29O4N (M = 383.49): C,
72.04; H, 7.62; N, 3.65; found: C, 71.82; H, 7.70; N, 3.47. Rf = 0.49
(CHCl3/EtOAc = 9/1); mp 94–96 ◦C (pale yellow crystalline
material).
3-Methoxy-17-[N-(1ꢀ-methoxycarbonyl-ethyl)carboxamido]-
13˛-estra-1,3,5(10),16-tetraene (4f): 1H NMR (CDCl3): 7.20 (d,
8.9 Hz, 1H, 2-H); 6.67 (dd, 8.9 Hz, 1.8 Hz, 1H, 1-H); 6.60 (br s, 1H,
4-H); 6.20 (br s, 1H, NH); 6.17 (br s, 1H, 16-H); 4.61 (qi, 7.2 Hz,
1H, NHCH); 3.75 (s, 3H, OCH3); 3.70 (s, 3H, OCH3); 2.80 (m, 2H,
6-H2); 2.70 (ddd, 1.7 Hz, 6.5 Hz, 15.5 Hz; 1H, 15-HaHb); 2.50 (d,
15.5 Hz, 1H); 1.00–2.32 (multiplets, 9H, skeleton protons); 1.41
(d, 7.2 Hz, 3H, CHCH3); 1.23 (s, 3H, 18-H3); 13C NMR (CDCl3):
173.7; 166.2; 157.5; 146.6; 138.1; 134.3; 132.7; 126.9; 113.6; 111.7;
55.2; 52.4; 52.0; 49.4; 47.6; 42.4; 41.3; 35.6; 33.0; 30.6; 29.0;
28.3; 27.8; 18.5. IR (KBr (cm−1)): 3425 (NH); 1747 (COO); 1656
(CON). MS (m/z/rel.int.): 397/100 (M+), 366/5, 295/51. Analysis
calculated for C24H31O4N (M = 397.51): C, 72.52; H, 7.86; N, 3.52;
found: C, 72.37; H, 7.94; N, 3.39. Rf = 0.59 (CHCl3/EtOAc = 19/1);
mp 153–155 ◦C (off-white needle-like crystalline material).
3-Methoxy-17-[N-(1ꢀ-methoxycarbonyl-2ꢀ-methyl-propyl)carbo-
xamido]-13˛-estra-1,3,5(10),16-tetraene (4g): 1H NMR (CDCl3):
7.18 (d, 8.9 Hz, 1H, 2-H); 6.65 (dd, 8.9 Hz, 1.8 Hz, 1H, 1-H);
6.56 (br s, 1H, 4-H); 6.20 (br d, 8.5 Hz, 1H, NH); 6.12 (br s, 1H,
16-H); 4.60 (m, 1H, NHCH); 3.70 (s, 3H, OCH3); 3.67 (s, 3H,
OCH3); 2.79 (m, 2H, 6-H2); 2.68 (ddd, 1.7 Hz, 6.5 Hz, 15.5 Hz;
1H, 15-HaHb); 2.49 (d, 15.5 Hz, 1H); 1.10–2.32 (multiplets, 10H,
skeleton protons + CH(CH3)2); 1.22 (s, 3H, 18-H3); 0.92 (d, 7.2 Hz,
3H, CH(CH3)); 0.86 (d, 7.2 Hz, 3H, CH(CH3)); 13C NMR (CDCl3):
172.6; 166.5; 157.5; 146.8; 138.0; 134.0; 132.6; 127.0; 113.6; 111.7;
56.6; 55.1; 52.0; 49.3; 42.5; 41.4; 35.6; 33.1; 31.4; 30.6; 29.1; 28.4;
27.9; 19.0; 17.9. IR (KBr (cm−1)): 3383 (NH); 1728 (COO); 1655
(CON). MS (m/z/rel.int.): 425/100 (M+), 366/14, 295/86. Analysis
calculated for C26H35O4N (M = 425.57): C, 73.38; H, 8.29; N, 3.29;
found: C, 73.18; H, 8.44; N, 3.15. Rf = 0.75 (CHCl3/EtOAc = 9/1);
mp 109–111 ◦C (yellow crystalline material).
3-Methoxy-17-[N,N-(1ꢀꢀ-benzyloxycarbonyl-1ꢀ,4ꢀ-butandiyl)-
carboxamido]-13˛-estra-1,3,5(10),16-tetraene (4i): 1H NMR
(CDCl3): 7.30–7.40 (m, 6H, Ph + NH); 7.21 (d, 8.9 Hz, 1H, 2-H);
6.71 (d, 8.9 Hz, 1H, 1-H); 6.61 (br s, 1H, 4-H); 5.99 (br s, 1H, 16-H);
5.26 and 5.10 (pair of doublets, 12 Hz, 2H, CH2Ph); 4.62 (t, 7Hz,
1H, NCH); 3.77 (s, 3H, OCH3); 3.60 (m, 2H, NCH2); 2.82 (m, 2H,
6-H2); 2.76 (ddd, 1.7 Hz, 6.5 Hz, 15.5 Hz; 1H, 15-HaHb); 0.96–2.38
(multiplets, 14H, skeleton protons + CH2CH2 (proline)); 1.33
(s, 3H, 18-H3); 13C NMR (CDCl3): 172.3; 167.2; 157.5; 145.4;
138.2; 136.0; 133.8; 132.5; 128.5; 128.1; 128.0; 127.1; 113.6; 111.7;
66.7; 58.5; 55.2; 51.7; 50.7; 49.4; 42.7; 41.5; 36.2; 33.3; 30.7; 29.2;
29.1; 28.9; 28.6; 25.6. IR (KBr (cm−1)): 1747 (COO); 1632 (CON).
MS (m/z/rel.int.): 499/11 (M+), 295/100. Analysis calculated
for C32H37O4N (M = 499.65): C, 76.92; H, 7.46; N, 2.80; found:
C, 76.78; H, 7.62; N, 2.67. Rf = 0.69 (CHCl3/EtOAc = 9/1); mp
87–90 ◦C (off-white solid material).
3-Methoxy-17-(methoxycarbonyl)-13˛-estra-1,3,5(10),16-
tetraene (4j): 1H NMR (CDCl3): 7.18 (d, 8.9 Hz, 1H, 2-H); 6.62–6.72
(m, 2H, 1-H + 4-H); 6.58 (br s, 1H, 16-H); 3.75 (s, 3H, OCH3);
3.70 (s, 3H, OCH3); 2.80 (m, 2H, 6-H2); 2.68 (ddd, 1.8 Hz, 6.4 Hz,
15.5 Hz; 1H, 15-HaHb); 1.10–2.32 (multiplets, 10H, skeleton pro-
tons); 1.20 (s, 3H, 18-H3); 13C NMR (CDCl3): 165.5; 157.4; 143.4;
142.0; 138.0; 132.9; 126.9; 113.5; 111.7; 55.2; 52.1; 51.0; 48.4;
42.3; 41.0; 35.7; 32.8; 30.6; 29.0; 28.0; 27.4. IR (KBr (cm−1)): 1615
(COO). MS (m/z/rel.int.): 326/55 (M+), 277/10, 207/16; 147/100.
Analysis calculated for C21H26O3 (M = 326.44): C, 77.27; H, 8.03;
found: C, 76.98; H, 8.26. Rf = 0.88 (CHCl3/EtOAc = 19/1); (pale
yellow highly viscous material).
3-Methoxy-17-(isopropyloxycarbonyl)-13˛-estra-1,3,5(10),16-
tetraene (4k): MS (m/z/rel.int.): 354/100 (M+), 295/21; 265/14;
207/13; 173/36.
3-Methoxy-17-(benzyloxycarbonyl)-13˛-estra-1,3,5(10),16-
tetraene (4l): MS (m/z/rel.int.): 402/100 (M+), 311/16; 267/19;
207/10; 173/31; 91/83.
3.
Results and discussion
The 17-iodo-16-ene derivative (3-methoxy-17-iodo-13␣-estra-
1,3,5(10),16-tetraene, 3), synthesized from the corresponding
3-methoxy-13␣-estra-1,3,5(10)-trien-17-one (1) according to a
modified method [20,21], was reacted with carbon monoxide
and various primary or secondary amines as N-nucleophiles
(tert-butylamine (a), aniline (b), pyperidine (c), morpholine (d),
methyl glycinate (e), methyl alaninate (f), methyl valinate (g),
methyl prolinate (h) or benzyl prolinate (i)) in DMF in the pres-
ence of palladium–phosphine ‘in situ’ catalysts (Scheme 1).
The corresponding 17-carboxamido-16-ene derivatives (4a–4i)
were synthesized in moderate to good yields depending on
the structure of the amine (Table 1). The in situ formation
of highly reactive, coordinatively unsaturated palladium(0)
complexes from palladium(II) acetate has been investigated
in details [22]. It has to be noted that the corresponding
enol triflate analogue, i.e. 3-methoxy-17-trifiloxy-13␣-estra-
1,3,5(10),16-tetraene could also be used as substrate. However,
it has been observed that the application of iodo-alkene func-
tionality as a substitute for enol triflate moiety in the steroidal
3-Methoxy-17-[N,N-(1ꢀꢀ-methoxycarbonyl-1ꢀ,4ꢀ-butandiyl)car-
boxamido]-13˛-estra-1,3,5(10),16-tetraene (4h): 1H NMR (CDCl3):
7.20 (d, 8.9 Hz, 1H, 2-H); 6.68 (d, 8.9 Hz, 1H, 1-H); 6.60 (br s,
1H, 4-H); 6.00 (br s, 1H, 16-H); 4.52 (t, 7Hz, 1H, NCH); 3.72 (s,
3H, OCH3); 3.68 (s, 3H, OCH3); 3.60 (m, 2H, NCH2); 2.82 (m, 2H,
6-H2); 2.74 (ddd, 1.7 Hz, 6.5 Hz, 15.5 Hz; 1H, 15-HaHb); 0.90–2.33
(multiplets, 14H, skeleton protons + CH2CH2 (proline)); 1.30 (s,
3H, 18-H3); 13C NMR (CDCl3): 173.1; 167.2; 157.5; 145.4; 138.3;
133.8; 132.5; 127.0; 113.6; 111.7; 58.4; 55.2; 52.1; 51.7; 50.6;
49.4; 42.7; 41.5; 36.2; 33.2; 30.7; 29.2; 29.1; 28.8; 28.5; 25.6. IR
(KBr (cm−1)): 1746 (COO); 1636 (CON). MS (m/z/rel.int.): 423/71
(M+), 408/31, 295/100. Analysis calculated for C26H33O4N