Synthesis of Pyrrolidine and Indolizidine Alkaloids
FULL PAPER
(5 mL) and 1m HCl (0.2 mL). The mixture was pressurized with hydro-
gen (30 bar) and allowed to react at RT. When the reaction was complete
(generally after 4 d), the mixture was filtered through Celite with
CH2Cl2. A sat. NaHCO3 solution was added to the filtrate, and the aque-
ous layer was extracted (ꢄ5) with CH2Cl2. The combined organic layers
were dried over Na2SO4, and concentrated under reduced pressure. The
product was purified by flash chromatography on HMDS pre-treated
silica gel or basic alumina.
(21), 95 (15), 67 (16), 55 (19), 44 (57); HRMS (ESI): m/z calcd for
C12H22N: 180.1747; found: 180.1750.
Ethyl 3-(5-propylpyrrolidin-2-yl)propanoate (4 f): Following procedure C,
4 f was obtained from 3 f (255 mg, 1 mmol) as a colorless oil (210 mg,
99%, cis/trans 86:14); the diastereomers were not separated. cis/trans-3 f:
IR (neat): n˜ =2955, 2928, 2865, 1731, 1371, 1252, 1159 cmÀ1; HRMS
(ESI): m/z calcd for C12H24NO2: 214.1807, found: 214.1813. cis-3 f:
1H NMR (300 MHz, CDCl3): d=4.12 (q, J=7.1 Hz, 2H), 3.04–2.92 (m,
2H), 2.36 (td, J=7.4, 2.1 Hz, 2H), 1.98–1.67 (m, 4H), 1.56 (brs, 1H),
1.49–1.27 (m, 6H), 1.25 (t, J=7.2 Hz, 3H), 0.91 ppm (t, J=7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=173.45, 60.08, 58.96, 58.17, 38.92, 32.10,
Procedure E—stannous chloride/sodium triacetoxyborohydride-mediated
reductive amination: The azide
method.[14] Thiophenol (0.31 mL, 3.0 mmol), NEt3 (0.31 mL, 2.25 mmol),
and azide (0.5 mmol) were added to stannous chloride (142 mg,
3 was reduced by using Vilarrasaꢅs
1
3
31.70, 31.06, 30.91, 20.43, 14.11, 14.07 ppm. trans-3 f: H NMR (300 MHz,
0.5 mmol) in acetonitrile (5 mL) The reaction was stirred at RT for 3 h,
after which EtOAc and 1n NaOH solution were added. The phases were
separated and the aqueous layer was washed with EtOAc (ꢄ5). The com-
bined organic phases were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Acetic acid (2 mL)
and sodium triacetoxyborohydride (212 mg, 1 mmol) were added to the
crude amine. The reaction mixture was stirred at RT for 48 h, after which
CH2Cl2 and 1n NaOH were added. The phases were separated and the
aqueous layer was washed with CH2Cl2 (ꢄ5). The combined organic
phases were dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The product was purified by flash chromatography on
HMDS pre-treated silica gel.
CDCl3): d=4.12 (q, J=7.1 Hz, 2H), 3.19–3.07 (m, 2H), 2.36 (td, J=7.4,
2.1 Hz, 2H), 1.98–1.67 (m, 4H), 1.56 (brs, 1H), 1.49–1.27 (m, 6H), 1.25
(t, J=7.2 Hz, 3H), 0.91 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=173.45, 60.08, 57.80, 57.13, 39.05, 32.49, 32.05, 31.06, 30.91,
20.29, 14.11, 14.07 ppm.
2-Benzyl-5-propylpyrrolidine (4g): Following procedure C, 4g was ob-
tained from 3g (80 mg, 0.32 mmol) as a colorless oil (63 mg, 99%, cis/
trans 94:6); the diastereomers were not separated.cis/trans-4g: IR (neat):
n˜ =2955, 2927, 2870, 1496, 1453, 1403 cmÀ1; MS (EI, 70 eV): m/z (%): 157
(15), 112 (100), 91 (32), 69 (25), 57 (28); HRMS (ESI): m/z calcd for
C14H22N: 204.1747; found: 204.1750. cis-4g: 1H NMR (300 MHz, CDCl3):
d=7.33–7.11 (m, 5H), 3.23–3.16 (m, 1H), 3.07–2.90 (m, 1H), 2.84 (dd,
J=13.2, 6.8 Hz, 1H), 2.73 (dd, J=13.2, 6.8 Hz, 1H), 2.24 (brs, 1H), 1.94–
1.71 (m, 2H), 1.67–1.21 (m, 6H), 0.9 ppm (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=140.11, 128.94, 128.32, 126.01, 60.55, 58.92, 42.57,
38.90, 30.89, 30.64, 20.54, 14.22 ppm. trans-4g: 1H NMR (300 MHz,
CDCl3): d=7.33–7.11 (m, 5H), 3.51–3.41 (m, 1H), 3.07–2.90 (m, 1H),
2.84 (dd, J=13.2, 6.8 Hz, 1H), 2.73 (dd, J=13.2, 6.8 Hz, 1H), 2.24 (brs,
1H), 1.94–1.71 (m, 2H), 1.67–1.21 (m, 6H), 0.90 ppm (t, J=7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=140.11, 128.94, 128.32, 126.01, 59.27,
57.54, 42.57, 38.90, 31.83, 31.59, 20.33, 14.22 ppm.
2-Propyl-1-azaspiroACHTUNGTRENNUNG[4.5]decane (4a): Following procedure C, 4a was ob-
tained from 3a (112 mg, 0.5 mmol) as a colorless oil (73 mg, 81%).
1H NMR (300 MHz, CDCl3): d=3.43–3.32 (m, 1H), 2.08–1.95 (m, 1H),
1.86–1.25 (m, 18H), 0.92 ppm (t, J=7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=64.57, 58.00, 37.34, 36.77, 36.66, 34.66, 30.20, 25.26, 23.68,
23.13, 20.33, 13.97 ppm; IR (neat): n˜ =2926, 2860, 2769 (br), 1592, 1450,
1428 cmÀ1
182.1905.
;
HRMS (ESI): m/z calcd for C12H24N: 182.1908; found:
2-Phenyl-1-azaspiroACHTUNGTRENNUNG[4.5]decane (4b): Following procedure E, 4b was ob-
tained from 3b (129 mg, 0.5 mmol) as a colorless oil (78 mg, 73%) after
purification by flash chromatography (pentane/Et2O 8:2). 1H NMR
(300 MHz, CDCl3): d=7.38 (d, J=7.1 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H),
7.21 (t, J=7.3 Hz, 1H), 4.28 (dd, J=8.1, 6.6 Hz, 1H), 2.20–2.12 (m, 1H),
1.81–1.33 ppm (m, 14H); 13C NMR (75 MHz, CDCl3): d=145.41, 128.20,
126.58, 126.53, 61.49, 61.28, 40.02, 38.97, 37.25, 34.63, 25.89, 24.11,
2-Butyl-5-propylpyrrolidinium 2,2,2-trifluoroacetate (4h): Following pro-
cedure C modified by addition of trifluoroacetic acid (0.1 mL) after filtra-
tion through Celite. After concentration under reduced pressure, 4h was
obtained from 3h (106 mg, 0.5 mmol) as colorless needles (138 mg, 98%,
cis/trans 9:1); the diastereomers were not separated. cis/trans 4h: M.p.
102.6–105.78C; 19F NMR (376 MHz, CFCl3 in CDCl3): d=À75.90 (s, 3F);
IR (neat): n˜ =3029 (br), 2962, 2933, 2875, 1666, 1467, 1428, 1199, 1173,
23.77 ppm; IR (neat): n˜ =2922, 2851, 1448, 748, 698 cmÀ1
; MS (EI,
70 eV): m/z (%): 215 (15) [M]+, 186 (11), 172 (100), 159 (32), 91 (21), 81
(12); HRMS (ESI): m/z calcd for C15H22N: 216.1752; found: 216.1749.
1134 cmÀ1
; HRMS (ESI): m/z calcd for C11H24N: 170.1908; found:
170.1914. cis-4h: 1H NMR (300 MHz, CDCl3): d=3.57–3.38 (m, 2H),
2.23–2.09 (m, 2H), 1.88–1.72 (m, 4H), 1.68–1.54 (m, 2H), 1.46–1.26 (m,
6H), 0.92 (t, J=7.3 Hz, 3H), 0.88 ppm (t, J=6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=159.29 (q, JCF =36.4 Hz), 109.45 (q, JCF =291.3 Hz),
60.33, 60.09, 34.28, 31.81, 28.76, 28.73, 28.54, 22.15, 19.82, 13.58,
1-AzaspiroACHTUNGTRENNUNG[4.5]decan-2-yl methyl acetate (4c): Following procedure C, 4c
was obtained from 3c (128 mg, 0.5 mmol) as a colorless oil (72 mg,
69%). 1H NMR (300 MHz, CDCl3): d=4.07 (dd, J=10.8, 4.8 Hz, 1H),
3.86 (dd, J=10.8, 7.2 Hz, 1H), 3.49–3.38 (m, 1H), 2.04 (s, 3H), 1.94–1.80
(m, 1H), 1.68 (brs, 1H), 1.63–1.30 ppm (m, 13H); 13C NMR (75 MHz,
CDCl3): d=171.06, 68.83, 61.68, 55.44, 39.89, 38.44, 35.70, 27.77, 25.79,
24.16, 23.79, 20.95 ppm; IR (neat): n˜ = 2925, 2853, 1739, 1449, 1367, 1227,
1034 cmÀ1; HRMS (ESI): m/z calcd for C12H22NO2: 212.1651; found:
212.1656.
1
13.51 ppm. trans-4h: H NMR (300 MHz, CDCl3): d=3.57–3.38 (m, 2H),
2.23–2.09 (m, 2H), 1.88–1.72 (m, 4H), 1.68–1.54 (m, 2H), 1.46–1.26 (m,
6H), 0.92 (t, J=7.3 Hz, 3H), 0.88 ppm (t, J=6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=159.29 (q, JCF =36.4 Hz), 109.45 (q, JCF =291.3 Hz),
59.75, 59.52, 34.56, 32.13, 30.66, 30.65, 28.41, 22.15, 19.71, 13.58,
13.51 ppm.
Methyl 3-(1-azaspiroACHTUNGTRENNUNG[4.5]decan-2-yl) propanoate (4d): Following proce-
3-Propyloctahydroindolizinium chloride (4i): Following procedure C, 4i
was obtained from 3i (246 mg, 1 mmol) as a white solid (197 mg, 97%).
M.p. 77.1–79.98C; 1H NMR (300 MHz, CDCl3): d=3.55 (t, J=6.4 Hz,
2H), 3.6–3.41 (m, 2H), 2.24–1.99 (m, 4H), 1.94–1.71 (m, 6H), 1.64–1.37
(m, 5H), 0.96 ppm (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
60.22, 60.00, 44.51, 34.23, 31.99, 31.40, 28.56, 28.50, 24.05, 20.15,
13.77 ppm; IR (neat): n˜ =3408 (br), 2960, 2934, 2868, 2763 (br), 2534,
1463, 1419 cmÀ1; MS (free amine, EI, 70 eV): m/z (%): 168 (4) [M+H]+,
160 (47), 124 (100), 112 (67); HRMS (ESI): m/z calcd for C11H23NCl:
204.1514; found: 204.1517.
dure C, 4d was obtained from 3d (95 mg, 0.36 mmol) as a yellow oil
(74 mg, 93%). 1H NMR (300 MHz, CDCl3): d=3.66 (s, 3H), 3.20–3.08
(m, 1H), 2.38 (t, J=6.9 Hz, 2H), 1.97–1.27 ppm (m, 17H); 13C NMR
(75 MHz, CDCl3): d=174.04, 61.42, 56.73, 51.38, 39.88, 38.51, 36.16,
32.08, 31.84, 31.34, 25.75, 24.06, 23.60 ppm; IR (neat): n˜ =2924, 2853,
1737, 1436, 1255, 1167 cmÀ1; HRMS (ESI): m/z calcd for C13H24NO2:
226.1802; found: 226.1804.
Hexahydro-1’H-spiro(cyclohexane-1,2’-cyclopenta[b]pyrrole) (4e): Fol-
lowing procedure C, 4e was obtained from 3e (111 mg, 0.5 mmol) as a
colorless oil (75 mg, 85%) after purification by flash chromatography on
HMDS pre-treated silica gel (pentane/Et2O 8:2). 1H NMR (300 MHz,
CDCl3): d=3.75–3.64 (m, 1H), 2.69–2.54 (m, 1H), 2.04 (dd, J=12.3,
8.9 Hz, 1H), 1.70–1.24 (m, 17H), 0.89 ppm (dd, J=12.3, 8.9 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=63.26, 61.66, 42.31, 39.11, 35.14, 34.45,
33.13, 30.90, 26.21, 24.34, 23.63, 23.40 ppm; IR (neat): n˜ =2927, 2855,
1448 cmÀ1; MS (EI, 70 eV): m/z (%): 179 (8), 150 (10), 136 (100), 123
(Æ)-Monomorine I (4j): Following procedure D, 4j was obtained from 3j
(25 mg, 0.1 mmol) as a colorless oil (16 mg, 82%) after purification by
flash chromatography on basic alumina (pentane/Et2O 9:1). 1H NMR
(300 MHz, CDCl3): d=2.52–2.40 (m, 1H), 2.26–2.14 (m, 1H), 2.12–1.98
(m, 1H), 1.90–1.58 (m, 6H), 1.57–1.16 (m, 10H), 1.12 (d, J=6.4 Hz, 3H),
0.88 ppm (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=67.16,
Chem. Eur. J. 2011, 17, 3207 – 3212
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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