D.M. Andrews et al. / Tetrahedron 65 (2009) 5805–5816
5815
precipitate was collected by filtration, washed with water (4310 mL)
4.7. 7-[4-(5-(3,5-Dimethylphenyl)-4-{2-[4-(2-oxo-2-
pyrrolidin-1-ylethyl)piperazin-1-yl]ethyl}-1H-pyrrol-3-yl)-
2,2-dimethylbutanoyl]-7-azabicyclo[2.2.1]heptane (30)
and dried to a constant weight in a vacuum oven at 40 ꢁC to afford 2-
[2-(3,5-dimethylphenyl)-3-(2-hydroxyethyl)-1H-thieno[3,4-b]pyr-
rol-4-yl]-2-methylpropanoic acid (0.40 g, 78%) as a pink solid,
which was used without further purification: LCMS (tR¼2.53 min,
To a stirred solution of 1 (0.30 g, 0.49 mmol) in EtOH (50 mL),
was added fresh RaneyÒ nickel (0.50 g) and the resulting suspen-
sion was stirred at room temperature for 3 days under nitrogen. The
catalyst was removed by filtration through a pad of Celite and the
filtrate was concentrated and purified by flash chromatography
eluting with DCM/7 N NH3 in MeOH (95:5) to afford 30 (0.102 g,
35%) as a pale yellow foam: LCMS (tR¼2.29 min, purity¼100%), ESIþ
purity¼88%), ESIþ m/z 358.22 (MþH)þ; 1H NMR (CDCl3)
d 1.70 (s,
6H), 2.36 (s, 6H), 3.12 (t, J¼5.5 Hz, 2H), 3.96 (t, J¼5.5 Hz, 2H), 6.89 (s,
1H), 6.91 (s, 1H), 7.11 (s, 2H), 8.92 (br s, 1H).
4.6.13. 2-[4-[2-(7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-
oxoethyl]-2-(3,5-dimethylphenyl)-1H-thieno[3,4-b]pyrrol-3-
yl]ethanol
m/z 588.36 (MþH)þ; 1H NMR (CDCl3)
d 1.29–1.40 (m, 6H), 1.49–1.42
To
a
stirred solution of 2-[2-(3,5-dimethylphenyl)-3-(2-
(m, 4H), 1.76–1.95 (m, 12H), 2.32 (s, 6H), 2.42–2.59 (m, 10H), 2.75–
2.79 (m, 2H), 3.11 (s, 2H), 3.46–3.50 (m, 4H), 4.66 (br s, 2H), 6.55 (s,
1H), 6.89 (s, 1H), 7.02 (s, 2H), 7.92 (s, 1H); 13C NMR (DMSO-d6)
hydroxyethyl)-1H-thieno[3,4-b]pyrrol-4-yl]-2-methylpropanoic
acid (0.400 g,1.12 mmol), 7-azanorborane$HCl (0.222 g, 1.68 mmol)
and DIPEA (0.434 g, 3.36 mmol) in DCM (10 mL) at 0 ꢁC, was added
solid TBTU (0.539 g, 1.68 mmol) over a period of 5 min. The
resulting dark brown suspension was allowed to warm to room
temperature and stirred for a further 1 h after which HPLC showed
no remaining starting material. The resulting suspension was di-
luted with DCM (50 mL) and washed with water (10 mL), a satu-
rated solution of citric acid (10 mL), a saturated solution of sodium
bicarbonate (10 mL) and water (10 mL). The organic extract was
dried (MgSO4), concentrated and purified by flash chromatography
on silica gel eluting with DCM/EtOAc (80:20) to afford 2-[4-[2-(7-
azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dime-
thylphenyl)-1H-thieno[3,4-b]pyrrol-3-yl]ethanol (0.240 g, 49%):
LCMS (tR¼3.86 min, purity¼100%), ESIþ m/z 437.23 (MþH)þ; 1H
d
20.8, 21.4, 24.0, 26.1, 26.5, 29.4, 41.6, 42.8, 45.7, 46.0, 53.1, 55.4,
59.6, 61.2, 115.2, 116.5, 123.4, 124.2, 127.3, 128.2, 134.1, 137.6, 167.7.
Acknowledgements
The author would like to acknowledge the large-scale lab at
Reims, France and Mr. Stephen Hallam for carrying out the DSC
studies on the aminating agents.
Supplementary data
1H and 13C NMR spectra of compounds 1, 2, 3, 4 and 30 are
available free of charge. Supplementary data associated with this
NMR (CDCl3)
d 1.31 (m, 4H), 1.63 (s, 6H), 1.71 (m, 4H), 2.37 (s, 6H),
3.16 (t, J¼5.5 Hz, 2H), 4.00 (t, J¼5.5 Hz, 2H), 4.09 (br s,1H), 4.71 (br s,
1H), 6.68 (s, 1H), 6.90 (s, 1H), 7.14 (s, 2H), 8.97 (br s, 1H).
References and notes
4.6.14. 4-[2-(7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-
oxoethyl]-3-(2-bromoethyl)-2-(3,5-dimethylphenyl)-1H-thieno-
[3,4-b]pyrrole (29)
1. Furr, B. J. A.; Woodburn, J. R. J. Endocrinol. Invest. 1988, 11, 535–557.
2. Schally, A. V. Peptides 1999, 20, 1247–1262.
3. Debruyne, F. M. Rev. Urol. 2004, 6, 25–32.
To a stirred solution of 2-[4-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-
dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-thieno[3,4-b]pyr-
rol-3-yl]ethanol (0.240 g, 0.552 mmol) in MeCN (10 mL) at room
temperature, were added triphenylphosphine (0.190 g, 0.718 mmol)
and CBr4 (0.201 g, 0.61 mmol). The reaction mixture was heated at
60 ꢁC for 2 h after which HPLC showed no remaining starting ma-
terial. The reaction mixture was cooled to room temperature and
evaporated to dryness. The resulting solid was dissolved in DCM and
purified by flash chromatography (silica gel, DCM) to afford 29
(0.20 g, 73%) as a yellow foam: LCMS (tR¼3.91 min, purity¼99%), ESIþ
4. Huirine, J. A. F.; Lambalk, C. B. Lancet 2001, 358, 1793–1803; Persson, B. E.;
Jensen, J. K.; Olesen, T. K. 9th Int. Symp. GnRH 2008, Berlin; Boccon-Gibod, L.;
Klotz, L.; Schroeder, H.; Andreou, C.; Persson, B. E.; Cantor, P.; Jensen, J. K.; Kold
Olesen, T. Eur. Urol. Suppl. 2008, 7, Abstract 537.
5. (a) Regan, C. F.; Guo, Z.; Chen, Y.; Huang, C. Q.; Chen, M.; Jiang, W.; Rueter, J. K.;
Coon, T.; Chen, C.; Saunders, J.; Brown, M. S.; Betz, S. F.; Struthers, R. S.; Yang, C.;
Wen, J.; Madan, A.; Zhu, Y.-F. Bioorg. Med. Chem. Lett. 2008, 18, 4503–4507 (and
references cited therein); (b) Luthin, D. R.; Hong, Y.; Tompkins, E.; Anderes, K.
L.; Paderes, G.; Kraynov, E. A.; Castro, M. A.; Nared-Hood, K. D.; Castillo, R.;
Gregory, M.; Vazir, H.; May, J. M.; Anderson, M. B. Bioorg. Med. Chem. Lett. 2002,
12, 3635–3639; (c) Young, J. R.; Huang, S. X.; Walsh, T. F.; Wyvratt, M. J.; Yang,
Y. T.; Yudkovitz, J. B.; Cui, J.; Mount, G. R.; Ren, R. N.; Wu, T.-J.; Shen, X.; Lyons,
K. A.; Mao, A.-H.; Carlin, J. R.; Karanam, B. V.; Vincent, S. H.; Cheng, K.; Goulet,
M. T. Bioorg. Med. Chem. Lett. 2002, 12, 827–832 (and references cited therein);
Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.; Suzuki, N.; Furuya, S.; Fujino,
M. J. Med. Chem. 2003, 46, 113–124 (and references cited therein).
6. Arnould, J.-C.; Delouvrie, B.; Boutron, P.; Dossetter, A. G.; Foote, K. M.; Hamon,
A.; Hancox, U.; Harris, C. S.; Hutton, M.; Lamorlette, M.; Matusiak, Z. Bioorg.
Med. Chem. Lett. 2007, 17, 6448–6454.
m/z 500.38 (MþH)þ; 1H NMR (CDCl3)
d 1.29 (m, 4H),1.63 (s, 6H),1.65
(m, 4H), 2.34 (s, 6H), 3.48 (t, J¼7.0 Hz, 2H), 3.63 (t, J¼7.0 Hz, 2H), 4.06
(br s, 1H), 4.72 (br s, 1H), 6.71 (s, 1H), 6.93 (s, 1H), 7.12 (s, 2H), 8.38
(br s, 1H).
7. (a) Blair, J. B.; Marona-Lewicka, D.; Kanthasamy, A. J. Med. Chem. 1999, 42, 1106–
1111; (b) Ontoria, J. M.; Martın Hernando, J. M.; Malancona, S.; Attenni, B.;
Stansfield, I.; Conte, I.; Ercolani, C.; Habermann, J.; Ponzi, S.; Di Filippo, M.;
Koch, U.; Rowley, M.; Narjes, F. Bioorg. Med. Chem. Lett. 2006, 16, 4026–4030.
8. (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241; (b) Fischer, E.; Hess, O. Ber. 1884,
17, 559.
9. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689–6690; (b) Larock, R.
C.; Zenner, J. M. J. Org. Chem. 1995, 60, 482–483; (c) Malacona, S; Martin Her-
nando, J. L.; Atteni, B; Ontoria, J. M.; Narjes, F Tetrahedron Lett. 2009, 50, 1625–
1628.
4.6.15. 4-[2-(7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-
oxoethyl]-2-(3,5-dimethylphenyl)-3-{2-[4-(2-oxo-2-pyrrolidin-1-
ylethyl)piperazin-1-yl]ethyl}-1H-thieno[3,4-b]pyrrole (4)
To a stirred solution of 29(0.150 g, 0.301 mmol) inDMF (2 mL)was
addedN-(2-(1-piperazino)-acetyl)-pyrrolidine(0.178 g, 0.904 mmol).
The reaction mixture was heated at 100 ꢁC for 2 h after which HPLC
showed no remaining starting material. The reaction mixture was
cooled to 5 ꢁC and triturated with water (30 mL). The resulting pre-
cipitate was collected by filtration, dissolved in DCM and purified by
chromatography on silica gel eluting with DCM/7 N NH3 in MeOH
(90:10) to afford 4 (0.068 g, 37%) as a beige foam: LCMS (tR¼2.53 min,
10. Garcia, F.; Gla`vez, C. Synthesis 1985, 143–156.
11. Binder, D.; Habison, G.; Noe, C. R. Synthesis 1977, 7, 487–489.
12. Tamura, Y.; Minamikawa, J.; Sumuto, K.; Fujii, S.; Ikeda, M. J. Org. Chem. 1973, 68,
1239–1241.
13. Colvin, E. W.; Kirby, G. W.; Wilson, A. C. Tetrahedron Lett. 1982, 23, 3835–3836.
14. DSC testing gave the following results: (a) O-(4-Nitrobenzoyl)-hydroxylamine;
purity¼100%), ESIþ m/z 616.35 (MþH)þ; 1H NMR (CDCl3)
d 1.29 (br s,
large exotherm from 78 ꢁC, which was complete at 200 ꢁ
C (heat of de-
4H), 1.64 (s, 6H), 1.70 (br s, 4H), 1.82–1.91 (m, 2H), 1.93–2.01 (m, 2H),
2.37 (s, 6H), 2.69 (br s, 8H), 2.70–2.78 (m, 2H), 3.06–3.13 (m, 2H), 3.21
(s, 2H), 3.46–3.54 (m, 4H), 4.13 (br s, 1H), 4.72 (br s, 1H), 6.75 (s, 1H),
6.88 (s, 1H), 7.14 (s, 2H), 10.63 (br s, 1H).
composition 821 J/g). Second large exotherm from 249 ꢁC, which was complete
at 393 ꢁC (heat of decomposition 1120 J/g); (b) O-(2,4-Dinitrophenyl)hydroxyl-
amine; sharp endotherm seen from 103 ꢁC which ran immediately into a large
exotherm from 112 ꢁC. The exotherm was complete at 176 ꢁ
C (heat of