C. Meyer, J. Cossy et al.
[IC3H4CO+], 165 (11) [ArCH2CH2+], 164 (100) [ArCH=CH2+], 151 (20),
149 (12), 121 (3), 108 (3), 107 (8), 106 (4), 105 (3), 103 (3), 91 (6), 79 (3),
78 (5), 77 (5), 68 (20), 65 (4); HRMS calcd for C14H18INO3Na [M+Na+]:
398.02236, found: 398.02217.
involving N-acyliminium ions and in particular those embed-
ded in bicyclic structures. The high diastereoselectivity ob-
served under kinetic and thermodynamic control in the
Pictet–Spengler cyclization involving the N-acyliminium ion
53, generated from enamide 35, is particularly noteworthy
because it allows a highly steroselective access to both epi-
mers 51 and 52 at the quaternary stereocenter by simply
tuning-up the reaction conditions.
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
(91.5 mg, 0.192 mmol, 9 mol%), Cs2CO3 (1.74 g, 5.33 mmol, 2.5 equiv),
and 2-iodocyclopropanecarboxamide 11 (800 mg, 2.13 mmol) followed by
toluene (15 mL). The resulting mixture was degassed under a positive
pressure of argon for 10 min. The vial was sealed (Teflon cap) and im-
mersed in a pre-heated oil bath at 1008C. A solution of phenylacetylene
(352 mL, 3.20 mmol, 1.5 equiv) in toluene (11 mL) was added in ten por-
tions at 10–12 min interval (by injection through the cap). After a total
duration of 11 h heating at 1008C, the reaction mixture was cooled to RT
and filtered through a pad of Celite (EtOAc). The filtrate was then con-
centrated under reduced pressure and the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc 20:80) to afford 12
Conclusion
We have demonstrated that the copper-free Sonogashira
coupling between readily available cis-2-iodocyclopropane-
carboxamides and terminal aryl-, heteroaryl-alkynes or
enynes followed by 5-exo-dig cyclization under basic condi-
tions, without isolation of the intermediate coupling product,
is a remarkably efficient strategy to access a variety of sub-
(661 mg, 89%) as
a
brown solid. M.p. 1028C; 1H NMR (400 MHz,
CDCl3): d=7.37–7.34 (m, 2H), 7.27–7.23 (m, 3H), 6.76 (d, J=7.9 Hz,
1H), 6.72 (dd, J=8.0 Hz and J=1.8 Hz, 1H), 6.71 (br s, 1H), 5.87 (brs,
1H, NH), 3.84 (s, 3H), 3.83 (s, 3H), 3.68–3.60 (m, 1H), 3.49–3.41 (m,
1H), 2.76 (t, J=6.9 Hz, 2H), 1.90 (ddd, apparent td, J=8.5 Hz and J=
6.6 Hz, 1H), 1.84 (ddd, apparent td, J=8.4 Hz and J=6.4 Hz, 1H), 1.45
(ddd, apparent td, J=6.2 Hz and J=4.8 Hz, 1H), 1.26 ppm (ddd, appa-
rent td, J=8.5 Hz and J=4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
168.9 (s), 148.9 (s), 147.5 (s), 131.7 (d, 2C), 131.6 (s), 128.2 (d, 2C), 127.9
(d), 123.2 (s), 120.6 (d), 112.0 (d), 111.3 (d), 87.7 (s), 80.2 (s), 55.9 (q),
55.8 (q), 41.1 (t), 35.5 (t), 23.4 (d), 13.7 (t), 8.7 ppm (d); IR (neat): n˜ =
stituted 4-methylene-3-azabicycloACTHUNTGRNEUNG[3.1.0]hexan-2-ones in high
yields. Protonation of these enamides provides access to N-
acyliminium ions that can be involved in Pictet–Spengler
cyclizations when an appropriately located and substituted
aromatic p-nucleophile is tethered to the nitrogen atom. A
variety of 3-azabicycloACHTUNTGRNEUNG[3.1.0]hexan-2-ones fused to tetrahy-
3259, 1635, 1567, 1516, 1245, 1235, 1144, 1028, 902, 803, 769, 699 cmꢁ1
.
droisoquinolines and bearing a quaternary stereocenter can
be easily and rapidly reached by this strategy. It is worth
mentioning that the access to similar 4-aryl- or 4-(hetero-
MS (70 eV): m/z (%): 349 (3) [M+], 165 (13) [ArCH2CH2+], 164 (100)
[ArCH=CH2+], 151 (17), 149 (11), 141 (13), 139 (5), 115 (23), 107 (9),
106 (5), 105 (5), 103 (6), 91 (11), 77 (11), 63 (5), 55 (7), 51 (4); HRMS
calcd for C22H23NO3Na [M+Na+]: 372.15701, found: 372.15651.
ACHTUNGTRENNUNGaryl)methylene-3-azabicycloCAHTUNGTRENN[UGN 3.1.0]hexan-2-ones from cyclo-
propyl imides would require the nucleophilic addition of
benzylic organometallic reagents whose preparation is not
always trivial, thereby highlighting the interest of this new
complementary strategy.
AHCTUNGTRENNUNG
A
E
A
from Na (118 mg, 5.13 mmol, 3.0 equiv) in absolute EtOH (12 mL)) was
added to a solution of alkynylcyclopropane 12 (590 mg, 1.69 mmol) in ab-
solute EtOH (10 mL) in an oven-dried vial. The vial was sealed (Teflon
cap) and heated under microwave irradiation (1508C) for 0.5 h. After
cooling to RT, the vial was opened and the resulting mixture was diluted
with CH2Cl2 and H2O and neutralized by addition of a 1m solution of hy-
drochloric acid. The layers were separated and the aqueous phase was
extracted twice with CH2Cl2. The combined organic extracts were washed
twice with H2O, dried over MgSO4, filtered and concentrated under re-
duced pressure. The residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc 50:50) to afford (Z)-13 (511 mg, 87%)
as a yellow solid. M.p. 1228C; 1H NMR (400 MHz, [D6]acetone): d=
7.43–7.38 (m, 2H), 7.33–7.29 (m, 3H), 6.70 (d, J=8.2 Hz, 1H), 6.24 (dd,
J=8.1 Hz and J=2.0 Hz, 1H), 6.16 (d, J=2.0 Hz, 1H), 5.93 (brs, 1H),
3.80–3.73 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 3.16 (ddd, J=13.8 Hz, J=
10.3 Hz and J=4.6 Hz, 1H), 2.51 (dddd, J=7.3 Hz, J=6.1 Hz, J=3.6 Hz
and J=0.5 Hz, 1H), 2.27 (ddd, J=13.0 Hz, J=10.4 Hz and J=4.6 Hz,
1H), 2.16 (ddd, J=8.6 Hz, J=5.6 Hz, J=3.3 Hz and J=0.5 Hz, 1H),
2.11–2.06 (m, 1H), 1.16 (ddd, J=8.4 Hz, J=7.4 Hz and J=4.1 Hz, 1H),
0.46 ppm (ddd, apparent q, J=3.5 Hz, 1H); 13C NMR (100 MHz,
[D6]acetone): d=175.8 (s), 149.8 (s), 148.6 (s), 140.2 (s), 137.2 (s), 131.1
(s), 130.2 (d, 2C), 128.5 (d, 2C), 127.1 (d), 121.2 (d), 112.8 (d), 112.4 (d),
102.9 (d), 55.9 (q), 55.8 (q), 42.1 (t), 33.4 (t), 19.4 (d), 18.9 (d), 15.2 ppm
(t); IR (neat): n˜ =1719, 1659, 1514, 1460, 1348, 1261, 1238, 1151, 1141,
1026, 978, 867, 813, 800, 750, 711, 609 cmꢁ1; MS (70 eV): m/z (%): 349
(12) [M+], 198 (5), 185 (21), 184 (15), 165 (13), 164 (100), 151 (19), 149
(11), 128 (11), 115 (17), 107 (11), 103 (14), 91 (19), 78 (11), 77 (18), 65
(11); HRMS calcd for C22H23NO3Na [M+Na+]: 372.15701, found:
372.15614.
Experimental Section
Representative examples are given below. Please see the Supporting
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
nyl)ethylamine (975 mL, 5.66 mmol, 1.2 equiv), ethyl [3-(dimethylamino)-
propyl]carbodiimide hydrochloride (EDCI) (1.36 g, 7.08 mmol, 1.5 equiv)
and 1-hydroxybenzotriazole (22.9 mg, 0.170 mmol, 3.6 mol%) were suc-
cessively added to a solution of cis-2-iodocyclopropanecarboxylic acid[57]
(1.00 g, 4.72 mmol) in CH2Cl2 (50 mL) at 08C. After 22 h stirring at RT,
the reaction mixture was diluted with H2O (50 mL), the layers were sepa-
rated and the aqueous phase was extracted with CH2Cl2. The combined
organic extracts were dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc 20:80) to afford 11 (1.68 g, 95%) as a
pale yellow solid. M.p. 968C; 1H NMR (400 MHz, CDCl3): d=6.83 (d,
J=8.2 Hz, 1H), 6.78 (dd, J=8.8 Hz and J=1.9 Hz, 1H), 6.77 (brs, 1H),
5.72 (brs, 1H, NH), 3.89 (s, 3H), 3.87 (s, 3H), 3.70–3.62 (m, 1H), 3.54–
3.45 (m, 1H), 2.85–2.77 (m, 2H), 2.72 (ddd, apparent td, J=8.0 Hz and
J=6.2 Hz, 1H), 1.59 (ddd, J=8.4 Hz, J=8.0 Hz and J=6.2 Hz, 1H), 1.46
(ddd, apparent q, J=6.2 Hz, 1H), 1.42 ppm (ddd, apparent td, J=8.6 Hz
and J=6.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=168.3 (s), 149.0 (s),
147.6 (s), 131.3 (s), 120.7 (d), 112.0 (d), 111.3 (d), 55.94 (q), 55.90 (q),
41.3 (t), 35.6 (t), 20.6 (d), 14.6 (t), ꢁ14.2 ppm (d); IR (neat): n˜ =3317,
1639, 1542, 1515, 1464, 1419, 1334, 1262, 1224, 1193, 1141, 1105, 1027,
962, 850, 811, 767, 627 cmꢁ1; MS (70 eV): m/z (%): 375 (3) [M+], 195 (3)
Preparation of enamide 13 from 11: Representative procedure (Table 1,
entry 2): An oven-dried resealable vial was successively charged with
[PdCl2ACTHNUGTRNE(UNG MeCN)2] (2.07 mg, 8.00 mmol, 3 mol%), X-Phos (11.4 mg,
16724
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16716 – 16727