Cascade Cyclization of Ynamides
COMMUNICATION
Acknowledgements
We thank the EPSRC (EP/E055273/1 and EP/H025839/1, E.A.A. and
C.D.C.) and Syngenta (R.L.G.) for generous financial support.
Keywords: cascade reactions · cross-coupling · electrocyclic
reactions · nitrogen heterocycles · ynamides
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Scheme 2. Selective oxidation of aminodienes. Reagents and conditions:
a) g-MnO2 (10 equiv), CH2Cl2, 2 h; b) g-MnO2 (10 equiv), acetone, 18 h;
c) Mg (5 equiv), MeOH, sonication, 1.5 h.
matic bicycles, thus providing a general and flexible route to
indoles, indolines, tetrahydroquinolines, and benzazepines.
Of particular note is the ability of this route to install a vari-
ety of functionalized sidechains on the carbocyclic ring in a
regiospecific manner in the course of the ring synthesis, thus
providing a unique alternative to classical and contemporary
methods. Ongoing work includes the extension of this meth-
odology towards the synthesis of other heterocycles and the
application of aminodienes in synthesis.
Experimental Section
Typical procedure for the cascade Suzuki cyclization—7-hexyl-5-phenyl-
1-tosyl-2,3,4,5-tetrahydro-1H-indole (8b): A degassed solution of yna-
mide 6a (50 mg, 0.12 mmol, 1.0 equiv) and boronic ester 9b (41 mg,
0.18 mmol, 1.5 equiv) in anhydrous DME (2 mL) was added to [Pd-
ACHTUNGTRENNUNG(PPh3)4] (6.9 mg, 0.006 mmol, 0.05 equiv) and Cs2CO3 (58 mg, 0.18 mmol,
1.5 equiv) under Ar. The reaction mixture was heated to reflux under Ar
until complete conversion, as analyzed by TLC (4 h), then it was cooled
to room temperature and concentrated. Column chromatography (petro-
leum ether/Et3N (1%) to petroleum ether/EtOAc (10:1)/Et3N (1%))
gave aminodiene 8b as a pale yellow oil (43 mg, 0.099 mmol, 83%). Rf =
0.38 (petroleum ether/EtOAc 10:1); IR (thin film): n˜ =2926, 2856, 1598,
1
1493, 1452, 1351, 1164, 1089, 1019 cmꢀ1; H NMR (500 MHz, CDCl3): d=
7.69 (2H, d, J=8.0 Hz; o-TsH), 7.39–7.30 (5H, m; PhH), 7.22 (2H, d, J=
8.0 Hz; m-TsH), 5.62 (1H, s; H6), 3.94–3.89 (1H, m H2), 3.71–3.65 (1H,
dt, J=13.5, 9.5 Hz; H2’), 3.64–3.57 (1H, m; H5), 2.77–2.70 (1H, m; H10),
2.50–2.40 (1H, m; H10’), 2.44 (3H, s; TsCH3), 2.36–2.27 (1H, m; H4),
2.24–2.16 (1H, m; H4’), 1.69–1.63 (2H, m; H3), 1.57–1.52 (1H, m; H11),
1.50–1.44 (1H, m; H11’), 1.41–1.27 (6H, m; H12–H14), 0.90 ppm (3H, t,
J=7.0 Hz; H15); 13C NMR (125 MHz, CDCl3): d=145.0, 143.8, 138.8,
135.3, 133.0, 131.9, 129.2, 128.5, 128.4, 127.5, 126.5, 125.4, 51.5, 41.1, 32.4,
32.1, 31.8, 30.4, 28.9, 28.8, 22.7, 21.6, 14.1 ppm; HRMS (ESI): m/z calcd
for C27H33NNaO2S: 458.2124 [M+Na]+; found: 458.2112. See the Sup-
porting Information for specific reaction details and product characteriza-
tion for other compounds, and for the preparation and characterization
of the ynamides.
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