Smiles Rearrangements in Ugi- and Passerini-Type Couplings
1
4
2
32.9, 132.5, 131.3, 130.2, 128.6, 125.1, 124.1, 70.8, 54.4, 52.6,
8.1, 33.5, 33.2, 25.9, 25.1, 22.9, 11.6; IR (thin film) 3338, 2932,
CI NH
419.1533; mp 143 °C.
2-(N-(4-Chlorobenzyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-
3 2 3
) m/z 420; HRMS calcd for C22H27Cl N O419.1531, found
-
1
853, 1717, 1674, 1449, 1086 cm ; MS (DI, CI NH
3
) m/z 444.
Anal. Calcd for C25
H, 7.13.
2 3
H31ClN O : C, 67.78; H, 7.05. Found: C, 67.59;
amino)-N-cyclohexylbutanamide (Table 4, entry 10): white solid;
1
yield (72 h at 90 °C in toluene) 44%; H NMR (CDCl
3
, 400 MHz)
δ 8.44 (d, 1H, J ) 2.5 Hz), 7.57 (dd, 1H, J ) 8.8, 2.5 Hz), 7.30
d, 2H, J ) 8.6 Hz), 7.15 (d, 2H, J ) 8.6 Hz), 6.42 (d, 1H, J ) 7.8
Hz), 6.36 (d, 1H, J ) 8.8 Hz), 5.19 (dd, 1H, J ) 8.8, 6.3 Hz), 4.80
2
-[(1-Cyclohexylcarbamoyl-3-methylbutyl)-(4-methoxybenzyl)-
(
amino]benzoic acid methyl ester (Table 3, entry 3): yellow oil;
yield (48 h at 60 °C in MeOH) 76%; H NMR (CDCl
δ 7.93 (br s, 1H), 7.63 (d, 1H, J ) 7.8 Hz), 7.31-7.27 (m, 1H),
1
3
, 400 MHz)
(d, 1H, J ) 17.6 Hz), 4.63 (d, 1H, J ) 17.6 Hz), 3.78-3.67 (m,
1
H), 2.16-2.04 (m, 1H), 1.93-1.84 (m, 1H), 1.75-1.50 (m, 6H),
.46-1.25 (m, 3H), 1.22-1.09 (m, 1H), 0.94 (t, 3H, J ) 7.8 Hz);
7
2
1
1
3
1
1
3
2
4
7
.15-7.05 (m, 3H), 7.03-6.97 (td, 1H, J ) 7.8, 1.7 Hz), 6.74 (dd,
H, J ) 7.8, 1.7 Hz), 4.27 (d, 1H, J ) 14.6 Hz), 4.01 (d, 1H, J )
4.6 Hz), 3.88 (s, 3H), 3.84-3.73 (m, 2H), 3.74 (s, 3H), 1.97-
.74 (m, 4H), 1.73-1.50 (m, 2H), 1.45-1.12 (m, 7H), 0.75 (d,
1
13
3
C NMR (CDCl , 100.6 MHz) δ 170.2, 160.4, 145.4, 136.7, 135.1,
133.3, 129.3, 128.1, 123.5, 116.4, 107.8, 60.4, 49.2, 48.3, 33.3,
13
33.1, 25.8, 24.9, 22.5, 11.5; IR (thin film) 3321, 2933, 2864, 1672,
3
H, J ) 6.6 Hz), 0.72 (d, 3H, J ) 6.6 Hz); C NMR (CDCl ,
-
1
1
529, 1318, 1135 cm ; MS (DI, CI NH
3
) m/z 453; HRMS calcd
00.6 MHz) δ 172.3, 168.8, 158.8, 149.2, 132.3, 131.2, 130.0,
29.6, 127.5, 124.3, 123.2, 113.9, 67.8, 55.5, 52.9, 52.6, 48.2, 38.2,
3.4, 33.2, 26.0, 25.9, 25.2, 25.1, 23.4, 22.4; IR (thin film) 3358,
for C23 O 453.1795, found 453.1797; mp 141 °C.
3 3
H27ClF N
N-Cyclohexyl-2-[(4-methoxybenzyl)-(4-methylpyrimidin-2-yl)-
amino]butyramide (Table 5, entry 1): white solid; yield (15 h at
-
1
929, 2843, 1719, 1672, 1462, 1095 cm ; MS (DI, CI NH
68. Anal. Calcd for C28
1.85; H, 8.43.
Methyl 2-(N-(1-(cyclohexylcarbamoyl)propyl)-N-cyclopropyl-
amino)benzoate (Table 3, entry 4): white oil; yield (20 h at 60
3
) m/z
1
6
4
6
0 °C in MeOH with 1 equiv of MeONa) 38%; H NMR (CDCl
3
,
38 2 4
H N O : C, 72.07; H, 8.21. Found: C,
00 MHz) δ 8.23 (d, 1H, J ) 5.3 Hz), 7.28 (d, 2H, J ) 8.1 Hz),
.82 (d, 2H, J ) 8.1 Hz), 6.47 (d, 1H, J ) 5.3 Hz), 6.44 (br s, 1H,
NH), 5.02 (d, 1H, J ) 15.6 Hz), 4.72 (t,1H, J ) 7.3 Hz), 4.64 (d,
1
1H, J ) 15.6 Hz), 3.79 (s, 3H), 3.69-3.58 (m, 1H), 2.37 (s, 3H),
°
C in MeOH) 56%; H NMR (CDCl
J ) 7.8, 1.5 Hz), 7.40-7.34 (m, 2H), 7.17 (d, 1H, J ) 7.8 Hz),
.01 (t, 1H, J ) 7.8 Hz), 3.91 (s, 3H), 3.81 (dd, 1H, J ) 5.8, 3.8
Hz), 3.76-3.65 (m, 1H), 2.61-2.51 (m, 1H), 2.17-2.06 (m, 1H),
.96-1.81 (m, 1H), 1.74-1.53 (m, 4H), 1.40-1.08 (m, 6H), 0.95
t, 3H, J ) 7.3 Hz), 0.67-0.59 (m, 1H), 0.58-0.46 (m, 2H),
3
, 400 MHz) δ 7.64 (dd, 1H,
1
0
.89-1.70 (m, 2H), 1.64-1.44 (m, 2H), 1.38-1.18 (m, 4H), 1.17-
.93 (m, 4H), 0.85 (t, 3H, J ) 7.3 Hz); 13C NMR (CDCl
3
, 100.6
7
MHz) δ 171.2, 167.7, 162.3, 158.9, 157.6, 132.3, 129.5, 114.1,
10.5, 61.9, 55.6, 48.8, 47.9, 33.1, 32.9, 25.9, 24.9, 24.8, 22.3, 11.6;
IR (thin film) 3311, 2936, 2864, 1669, 1582, 1516, 1472, 1360,
1
1
(
0
1
3
2
-
1
1
3
275 cm ; MS (DI, CI NH
96.2525, found 396.2511; mp 87 °C.
-(N-(4-Chlorobenzyl)-N-(2,6-dimethylpyrimidin-4-yl)amino)-
N-cyclohexylbutanamide (Table 5, entry 2): colorless oil; yield
3 32 4 2
) m/z 396; HRMS calcd for C23H N O
.41-0.34 (m, 1H); 13C NMR (CDCl
3
, 100.6 MHz) δ 171.5, 169.4,
50.7, 132.5, 130.6, 125.9, 123.6, 122.1, 69.8, 52.6, 48.3, 33.3,
2
3.0, 32.9, 25.9, 25.3, 23.1, 11.9, 9.2, 8.5; IR (thin film) 3324,
936, 2858, 1719, 1665, 1534, 1490, 1453, 1087 cm-1; MS (DI,
1
(
3
72 h at 60 °C in MeOH) 78%; H NMR (CDCl , 400 MHz) δ
CI NH
58.2254.
General Procedure for Aminopyrimidine or Aminopyridine
Derivative Synthesis. To a 1 M solution of carbonyl compound
1 mmol) in methanol or toluene were added the amine (1.0 equiv),
the isocyanide (1.0 equiv), and the hydroxypyrimidine or hydroxy-
pyridine (1.0 equiv). The resulting mixture was stirred at 60 or 90
C under an inert atmosphere and concentrated in vacuo. The crude
3 30 2 3
) m/z 359; HRMS calcd for C21H N O 358.2257, found
7
5
1
2
1
.28 (d, 2H, J ) 8.3 Hz), 7.13 (d, 2H, J ) 8.3 Hz), 6.71 (br s, 1H),
3
.95 (s, 1H), 5.12 (br s,1H), 4.72 (d, 1H, J ) 17.9 Hz), 4.52 (d,
H, J ) 17.9 Hz), 3.75-3.65 (m, 1H), 2.56 (s, 3H), 2.26 (s, 3H),
.13-1.99 (m, 2H), 1.93-1.83 (m, 1H), 1.73-1.49 (m, 4H), 1.46-
(
13
.06 (m, 5H), 0.90 (t, 3H, J ) 7.3 Hz); C NMR (CDCl
3
, 100.6
MHz) δ 170.1, 166.6, 166.3, 163.2, 136.7, 133.2, 129.3, 128.0,
1
1
1
00.7, 59.8, 48.6, 48.1, 33.4, 33.1, 26.6, 25.9, 24.9, 24.8, 24.7, 22.3,
°
1.4; IR (thin film) 3338, 2940, 2856, 1680, 1596, 1489, 1355,
product was then purified by flash chromatography on silica gel to
give the desired adduct.
-1
3 31
282 cm ; MS (DI, CI NH ) m/z 415; HRMS calcd for C23H -
ClN
-(N-Allyl-N-(2,6-dimethylpyrimidin-4-yl)amino)-N-tert-bu-
tylbutanamide (Table 5, entry 3): colorless oil; yield (4 d at 60
4
O 414.2186, found 414.2179.
2-(N-(4-Chlorobenzyl)-N-(5-nitropyridin-2-yl)amino)-N-cyclo-
2
hexylbutanamide (Table 4, entry 4): yellow solid; yield (16 h at
1
6
0 °C in MeOH) 66%; H NMR (CDCl
J ) 2.7 Hz), 8.15 (dd, 1H, J ) 9.3, 2.7 Hz), 7.33-7.28 (m, 2H),
.14 (d, 2H, J ) 8.3 Hz), 6.33 (d, 1H, J ) 9.3 Hz), 6.22 (d, 1H,
3
, 400 MHz) δ 9.10 (d, 1H,
1
°
6
C in MeOH) 60%; H NMR (CDCl
3
, 400 MHz) δ 6.78 (s, 1H),
.14 (s, 1H), 5.79 (ddt, 1H, J ) 17.6, 10.3, 4.5 Hz), 5.19 (dd, 1H,
7
J ) 17.6, 1.7 Hz), 5.17 (dd, 1H, J ) 10.3, 1.7 Hz), 5.06 (br s, 1H),
J ) 7.8 Hz), 5.27 (t,1H, J ) 7.1 Hz), 4.87 (d, 1H, J ) 17.4 Hz),
4
2
1
.09 (dd, 1H, J ) 17.6, 4.5 Hz), 3.86 (dd, 1H, J ) 17.6, 4.5 Hz),
4
1
0
1
4
3
.75 (d, 1H, J ) 17.4 Hz), 3.78-3.67 (m, 1H), 2.17-2.06 (m,
.52 (s, 3H), 2.36 (s, 3H), 2.11-2.00 (m, 1H), 1.74-1.62 (m, 1H),
H), 1.95-1.86 (m, 1H), 1.77-1.54 (m, 4H), 1.46-1.09 (m, 6H),
13
3
.27 (s, 9H), 0.90 (t, 3H, J ) 7.3 Hz); C NMR (CDCl , 100.6
.95 (t, 3H, J ) 7.7 Hz); 13C NMR (CDCl
, 100.6 MHz) δ 169.4,
3
MHz) δ 170.6, 166.5, 165.7, 162.9, 133.9, 117.3, 170.8, 59.7, 51.2,
61.2, 146.0, 136.4, 135.7, 133.6, 133.5, 129.5, 128.0, 107.2, 61.0,
9.5, 48.5, 33.4, 33.1, 25.8, 25.0, 24.9, 22.7, 11.3; IR (thin film)
320, 2932, 2857, 1665, 1593, 1496, 1296, 1121 cm-1; MS (DI,
4
1
7.5, 29.1, 24.8 et 24.7, 21.8, 11.3; IR (thin film) 3365, 2946, 2859,
-1
670, 1506, 1285, 1126 cm ; MS (DI, CI NH
3
) m/z 305; HRMS
28 4
calcd for C17H N
O 304.2263, found 304.2260.
CI NH
30.1780; mp 119 °C.
-(N-(4-Chlorobenzyl)-N-(5-chloropyridin-2-yl)amino)-N-cy-
clohexylbutanamide (Table 4, entry 7): white solid; yield (72 h
3 4 3
) m/z 432; HRMS calcd for C22H27ClN O 430.1772, found
General Procedure for Phenol-Induced Passerini-3CR. To a
4
1
M solution of the aldehyde (1mmol) in methanol were added
2
successively 1.0 equiv of isocyanide and 1.0 equiv of phenol under
inert atmosphere. The resulting mixture was stirred until completion
(TLC). It was then concentrated in vacuo, and the crude product
was purified by flash chromatography on silica gel.
1
at 90 °C in toluene) 27%; H NMR (CDCl
3
, 400 MHz) δ 8.13 (d,
H, J ) 2.5 Hz), 7.33 (dd, 1H, J ) 8.8, 2.5 Hz), 7.28 (d, 2H, J )
.6 Hz), 7.16 (d, 2H, J ) 8.6 Hz), 6.49 (d, 1H, J ) 8.1 Hz), 6.26
1
8
(
2-(2-Nitrophenoxy)-N-cyclohexyl-4-methylpentanamide (Table
1
d, 1H, J ) 8.8 Hz), 5.05 (dd, 1H, J ) 8.6, 6.3 Hz), 4.73 (d, 1H,
J ) 17.7 Hz), 4.53 (d, 1H, J ) 17.7 Hz), 3.76-3.67 (m, 1H), 2.14-
.02 (m, 1H), 1.92-1.84 (m, 1H), 1.72-1.50 (m, 6H), 1.45-1.06
m, 4H), 0.92 (t, 3H, J ) 7.1 Hz); 13C NMR (CDCl
, 100.6 MHz)
δ 170.6, 157.2, 145.9, 137.8, 137.3, 133.1, 129.2, 128.1, 120.8,
09.3, 60.7, 49.5, 48.1, 33.3, 33.1, 25.9, 24.8, 22.5, 11.5; IR (thin
6, entry 1): yellow solid; yield 64%; H NMR (CDCl
3
, 400 MHz)
δ 7.87 (dd, 1H, J ) 8.4, 1.8 Hz), 7.55 (td, 1H, J ) 8.4, 1.8 Hz),
7.12-7.08 (m,2H), 6.97 (br s, 1H), 4.85 (dd, 1H, J ) 7.8, 3.9 Hz),
3.78-3.69 (m, 1H), 1.96-1.88 (m, 2H), 1.76-1.63 (m, 2H), 1.63-
1.52 (m, 2H), 1.40-1.11 (m, 7H), 0.97 (d, 3H, J ) 6.2 Hz), 0.93
2
(
3
1
(d, 3H, J ) 6.2 Hz); 13C NMR (CDCl
3
, 100.6 MHz) δ 169.9, 150.9,
-
1
film) 3311, 2937, 2854, 1665, 1477, 1496, 1273 cm ; MS (DI,
140.3, 135.0, 126.4, 121.8, 115.1, 78.9, 48.2, 41.8, 33.1, 25.8, 25.0,
J. Org. Chem, Vol. 72, No. 11, 2007 4179