10 L. El Kaım, L. Grimaud and J. Oble, Angew. Chem., Int. Ed., 2005,
¨
44, 7961.
chromatography on silica gel (petroleum ether–ethyl acetate) to
give the desired adduct 1k as a yellow solid in 52% yield. Mp
149.7–151.1 1C. 1H NMR (CDCl3; 400 MHz) d 8.17 (d, 2H, J = 9.4
Hz), 7.43–7.41 (m, 3H), 7.35–7.32 (m, 2H), 6.77 (d, 2H, J = 9.4
Hz), 5.84 (br d, 1H, J = 8.3 Hz), 5.61 (ddt, 1H, J = 16.9, 10.4, 6.6
Hz), 5.41 (s, 1H, H4), 5.02 (d, 1H, J = 10.4 Hz), 4.97 (dd, 1H, J =
16.9, 1.5 Hz), 3.92–3.84 (m, 1H, H6), 3.46 (dt, 1H, J = 15.4, 6.1
Hz), 3.39 (dd, 1H, J = 16.9, 6.1 Hz), 2.39–2.31 (m, 1H), 2.01–1.84
(m, 3H), 1.71–1.52 (m, 2H), 1.42–1.28 (m, 2H), 1.17–1.00 (m, 3H).
13C NMR (CDCl3; 100.6 MHz) d 168.6, 153.4, 138.9, 135.0, 134.7,
129.8, 129.5, 129.3, 126.4, 117.8, 112.6, 68.4, 49.1, 48.6, 33.4, 33.2,
11 For a typical experimental procedure: Ugi–Smiles procedure for 1c:
To a 2 M solution of the benzaldehyde (1 mmol) in methanol was
added successively 1.0 equiv. of methoxyethylamine, 1.0 equiv. of
cyclohexyl isocyanide and 1.0 equiv. of para-nitrophenol under
inert atmosphere. The resulting mixture was stirred for 24 h at 60 1C.
It was then concentrated in vacuo and the crude product was
purified by flash chromatography on silica gel (petroleum
ether–ethyl acetate) to give the desired adduct 1c as a yellow solid
in an 87% yield. Mp 118.0–120.0 1C. 1H NMR (CDCl3; 400 MHz)
d 8.18 (d, 2H, J = 9.4 Hz), 7.74 (d, 1H, J = 8.0 Hz), 7.41–7.35 (m,
3H), 7.26–7.24 (m, 2H), 6.81 (d, 2H, J = 9.4 Hz), 5.37 (s, 1H),
3.95–3.86 (m, 1H), 3.79–3.73 (m, 1H), 3.44–3.42 (m, 3H), 3.36 (s,
3H), 1.98–1.86 (m, 2H), 1.71–1.63 (m, 3H), 1.42–1.32 (m, 2H),
1.15–1.03 (m, 3H). 13C NMR (CDCl3; 100.6 MHz) d 169.6, 153.4,
139.3, 134.9, 129.8, 129.3, 128.9, 126.1, 113.5, 70.7, 69.5, 59.2, 48.8,
47.6, 33.6, 33.5, 25.9, 25.3. IR (thin film) 2929, 1643, 1594, 1315,
32.5, 25.7, 25.0. IR (thin film) 3270, 2934, 1653, 1317, 1111 cmÀ1
.
HRMS calcd for C24H29N3O3 407.2209; found 407.2240. Cycliza-
tion procedure: To a 0.2 M solution of the Ugi–Smiles adduct (1
mmol) in DMF were added successively 2 equiv. of K2CO3, 10
mol% of PCy3 and 5 mol% of Pd(OAc)2. The resulting mixture
was stirred at 110 1C for 4 h under air before being concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel (petroleum ether–ethyl acetate) to give the tricyclic
compound 5k as a yellow solid in 55% yield. 1H NMR (CDCl3;
400 MHz) d 8.15 (d, 2H, J = 9.4 Hz), 7.61 (d, 1H, J = 8.0 Hz),
7.38–7.31 (m, 2H), 7.25 (t, 1H, J = 8.0 Hz), 6.78 (d, 2H, J = 9.4
Hz), 5.58 (br d, 1H, J = 8.3 Hz), 3.87–3.78 (m, 1H), 3.74–3.70 (m,
2H), 3.37 (qd, 1H, J = 7.5, 2.3 Hz), 3.22 (dd, 1H, J = 16.2, 7.5
Hz), 2.86 (dd, 1H, J = 16.2, 2.3 Hz), 2.39–2.31 (m, 1H), 1.95–0.98
(m, 11H). 13C NMR (CDCl3; 100.6 MHz) d 170.7, 151.1, 144.1,
141.5, 138.1, 130.1, 128.1, 126.8, 126.2, 113.1, 82.6, 53.7, 51.1, 48.9,
35.4, 33.3, 33.1, 29.8, 25.7, 25.0. IR (thin film) 2929, 2858, 1658,
1599, 1304 cmÀ1. HRMS calcd for C24H27N3O3 405.2052; found
405.2057.
1104 cmÀ1
. HRMS calcd for C23H29N3O4 411.2158; found
411.2152. Oxidation procedure of 1c: To a 0.2 M solution of the
Ugi–Smiles adduct 1c (1 mmol) in freshly distilled DMF were
added 2 equiv. of K2CO3 and 5 mol% of Pd(OAc)2. The resulting
mixture was stirred at 110 1C for 3 h under air before being
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (petroleum ether–ethyl acetate) to
give the a-ketoamide 2c as white crystals in 69% yield and the
corresponding aniline 3 as a yellow solid in 80% yield. Spectro-
scopic data for 2c: mp 112.0–113.1 1C. 1H NMR (CDCl3; 400 MHz)
d 8.37 (d, 2H, J = 8.2 Hz), 7.66 (t, 1H, J = 7.4 Hz), 7.52 (t, 2H, J
= 7.4 Hz), 6.98 (br s, 1 H), 3.94–3.85 (m, 1H), 2.04–1.87 (m, 4H,
HCy), 1.49–1.38 (m, 2H), 1.34–1.23 (m, 4H). 13C NMR (CDCl3;
100.6 MHz) d 188.5, 161.2, 134.7, 133.8, 131.6, 128.8, 48.8, 33.1,
13 (a) D. Schroder, M. C. Holthausen and H. Schwarz, J. Phys.
¨
Chem. B, 2004, 108, 14407; (b) A. J. Clark, J. V. Geden, S. Thom
and P. Wilson, J. Org. Chem., 2007, 72, 5923.
25.8, 25.2. IR (thin film) 3279, 2933, 2360, 1652, 1647 cmÀ1
.
Spectroscopic data for 3: mp 87.2–88.7 1C. 1H NMR (CDCl3; 400
MHz) d 8.11 (d, 2H, J = 9.1 Hz), 6.57 (d, 2H, J = 9.1 Hz), 4.90 (br
s, 1H), 3.65 (t, 2H, J = 5.3 Hz), 3.42 (s, 3H), 3.40 (q, 2H, J = 5.3
Hz). 13C NMR (CDCl3; 100.6 MHz) d 153.6, 138.6, 126.8, 111.6,
70.6, 59.3, 43.2. IR (thin film) 3331, 2937, 1589, 1276 cmÀ1. HRMS
calcd for C9H12N2O3 196.0848; found 196.0839.
14 Further indication on the reaction mechanism was obtained by the
following experiment. When the a-arylamino amide 1j was treated
with Cu(OAc)2 instead of Pd(II), the amide 4j was isolated as the
major product, whereas it was obtained only as a trace under Pd
catalysis (see image below). These results with copper are consis-
tent with a radical mechanism involving the trapping of a peptidyl
radical with oxygen. The fragmentation of the resulting hydroper-
oxide could then lead to 4j.
12 For a typical experimental procedure: Staudinger–Ugi–Smiles pro-
cedure for 1k: A mixture of the homoallyl bromide (1 mmol) and
sodium azide (1 mmol) in DMSO (2 M) was stirred at 60 1C for
18 h under an inert atmosphere. Then were added, at room
temperature, methanol (to reach a concentration of 1 M), the
triphenylphosphine (1.2 mmol) and the aldehyde (1 mmol). The
resulting mixture was stirred at 60 1C. After 15 h, were added the
isocyanide (1 mmol) and nitrophenol (1 mmol). The resulting
mixture was stirred at 60 1C for 5 days. The reaction mixture
was diluted with ethyl acetate and washed with a saturated
aqueous NaHCO3 solution (3Â), dried over MgSO4 and concen-
trated in vacuo. The crude product was then purified by flash
.
ꢀc
This journal is The Royal Society of Chemistry 2008
1352 | Chem. Commun., 2008, 1350–1352