remove Pd, 12 was then treated with t-BuONa and cyclized
to lactam 5 with heating in 50-75% yield.2 The modest yield
for the lactam cyclization was primarily a result of saponi-
fication of 12. Once saponified, the amino acid of 12 was
not observed to cyclize to 5 under any reaction conditions
examined. In an effort to minimize hydrolysis, the solvent
was switched from methanol to 2-propanol so that water
could be removed by azeotropic distillation prior to adding
the base for lactam cyclization. In practice, distilling off the
water with 2-propanol improved the yield (70-80%), but
the reaction became more sensitive to the level of water for
promoting saponification of 12.11 In general, we observed
that the more polar solvents slowed the competing rate of
ester hydrolysis (ethylene glycol had the slowest rate of
saponification, while n-butanol promoted more rapid hy-
drolysis). To convert lactam 5 to the desired benzazepine
(1), 5 was reduced with borane (generated in situ).2 Benz-
azepine 1 was decomplexed from the boron by heating with
methanol and HCl, and following aqueous workup, was
isolated as the tosylate salt in 81% yield.
Table 1. Additional Substrates Screened in the Tandem
Michael Addition/Pd-Catalyzed Cyclization
For an evaluation of substrate scope of the tandem Michael
addition and Pd-catalyzed cyclization, reactions were carried
out with readily available 2-halophenylacetonitrile derivatives
(Table 1). In general, the reactions were conducted in DME
at 60 °C.12 For the aryl chlorides, typically a loading of 10
mol % Pd was used. Comparable yields were realized for
(11) For more efficient azeoptropic removal of water, n-propanol could
be used.
(12) Representative procedure for Pd-catalyzed cyclization, entry 1 of
Table 1: A solution of tricyclohexylphosphine (204 mg, 0.720 mmol) in
ethylene glycol dimethyl ether (10 mL) under nitrogen was charged with
palladium (II) acetate (148 mg, 0.660 mmol). The reaction was stirred at
room temperature until the solution was homogeneous (approximately 25
min), cooled to 0 °C, and charged with t-BuONa (1.63 g, 16.6 mmol). After
10 min, a solution of 2-chlorophenylacetonitrile (1.00 g, 6.60 mmol) and
ethyl 3-trans-ethoxyacrylate (7) (953 µL, 6.60 mmol) in ethylene glycol
dimethyl ether (10 mL) was added dropwise over 5 min. Upon complete
addition, the reaction was warmed to room temperature and then heated to
60 °C for 22 h. The reaction was cooled to room temperature then diluted
with methyl tert-butyl ether (30 mL) and poured into aqueous potassium
dihydrogenphosphate (0.25 M, 40 mL), pH ) 7. The aqueous layer was
separated then saturated by addition of solid sodium chloride and extracted
with ethyl acetate (50 mL). The organic layer was separated and washed
with aqueous saturated sodium chloride (2 × 30 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo affording 3-(ethoxyhydroxy-
methylene)-3H-indene-1-carbonitrile, sodium salt (9), as a foamy orange
solid (1.06 g, 5.0 mmol, 75%): mp 150-152 °C; 1H NMR (400 MHz,
CD3CN) δ 8.04 (d, 1H, J ) 6.0 Hz), 7.58 (s, 1H), 7.43 (d, 1H, J ) 6.0
Hz), 6.98-6.91 (m, 2H), 4.25 (q, 2H, J ) 7.2 Hz), 1.35 (t, 3H, J ) 7.2
Hz); 13C NMR (100 MHz, CD3CN) δ 166.7, 135.5, 132.3, 131.3, 122.8,
120.5, 119.0, 118.4, 117.7, 103.3, 79.2, 58.2, 14.6; IR (ATR, neat) 2176,
1597, 1465, 1257, 1195, 1068, 1029, 754 cm-1. Data for entry 2, Table 1:
1H NMR (400 MHz, MeOH-d4) δ 7.64 (s, 1H), 7.46 (s, 1H), 6.99 (s, 1H),
4.56 (q, 2H, J ) 7.1), 3.86 (s, 6H), 1.38 (t, 3H, J ) 7.05); 13C NMR (100
MHz, MeOH-d4) δ 167.8, 145.0, 144.5, 130.2, 129.4, 126.4, 123.3, 112.5,
104.0, 102.6, 100.7, 79.0, 58.4, 55.6, 14.1; IR (ATR, neat) 3499, 2164,
1629, 1482, 1449, 1282, 1207, 1157, 1124, 1076, 845, 769 cm-1. Data for
zofulvene intermediate (13) in situ to facilitate isolation. This
was accomplished by adding ethylene glycol and sulfuric
acid (as a dehydrating agent) to the reaction mixture. As
product 13 formed, it precipitated from solution. After
prolonged stirring of the reaction mixture at room temper-
ature (12-48 h), 13 was isolated as a solid by filtration in
good yield (75-90%).10 Attempting to promote the formation
of 13 with heat led to inadvertent decarboxylation as a side
reaction. Because 13 had much greater crystallinity than 9,
it was preferable to isolate 13 to efficiently purge phosphines
and other inhibitors of the subsequent hydrogenation.
Analogous to the cyanohydrin route,2 9 or 13 was reduced
via Pd-catalyzed hydrogenolysis to 12. After filtration to
(10) A typical procedure for conducting the tandem Michael addition/
Pd cyclization/ketene acetal formation is as follows: A solution of
tricyclohexylphosphine (536 mg, 1.91 mmol) in THF (25 mL) was charged
with palladium (II) acetate (287 mg, 1.27 mmol) under nitrogen. After 15-
60 minutes the reaction mixture was cooled to 0 °C and charged with
t-BuONa (31.6 g, 319 mmol). After 5 min, a solution of 2-bromophenyl-
acetonitrile (10) (25.0 g, 128 mmol) and â-ethoxyacrylic acid ethyl ester
(7) (18.4 mL, 128 mmol) in THF (75 mL) was added dropwise over 15
min. The reaction was heated to 60 °C. After 2 h 30 min, the reaction
mixture was cooled to room temperature and charged with ethylene glycol
(200 mL) over 5 min and then charged with sulfuric acid (18.8 M, 36 mL)
added dropwise over 15 min. After 15 h the reaction was diluted with water
(90 mL) and a solid product was isolated by filtration. The solid was dried
under vacuum affording 13 (21.6 g, 102 mmol, 80%) as a light tan solid.
The crude material was slurried in 2-propanol (50 mL) for 2 h, filtered and
dried under vacuum affording 13 (20.8 g, 98.5 mmol, 77%) as a light tan
solid: 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.74 (d, 1H, J ) 7.9
Hz), 7.50 (d, 1H, J ) 7.1 Hz), 7.22 (m, 2H), 4.97 (t, 2H, J ) 7.8 Hz), 4.85
(t, 2H, J ) 7.8 Hz); 13C NMR (100 MHz, DMSO-d6) 167.4, 136.7, 135.7,
133.1, 124.7, 123.9, 121.1, 119.4, 118.1, 97.8, 92.7, 71.1, 69.9; mp 227-
229 °C dec.
1
entry 3, Table 1: mp 152-156 °C.; HNMR (400 MHz, CD3OD) δ 8.31
(s, 1H), 7.70 (s, 1H), 7.49 (d, 1H, J ) 7.9 Hz), 7.11 (d, 1H, J ) 7.9 Hz),
4.28 (q, 2H, J ) 7.1 Hz), 1.39 (t, 3H, J ) 7.1 Hz); 13C NMR (100 MHz,
CD3OD) δ 167.6, 137.4, 133.4, 131.0, 126.7 (q, J ) 201 Hz), 122.1, 120.5
(q, J ) 22.7 Hz), 117.3 (q, J ) 3.3 Hz), 117.1, 114.3 (q, J ) 2.5 Hz),
104.2, 79.6, 58.7, 14.0; IR (ATR, neat) 2986, 2943, 2180, 1606, 1465, 1326,
1284, 1197, 1156, 1105, 1076, 1027, 900, 853, 814, 778, 753, 708, 645
cm-1. Data for entry 4, Table 1: mp 250-260 °C; 1H NMR (400 MHz,
MeOH-d4) δ 7.63 (dd, 1H, J ) 2.5, 11.4 Hz), 7.60 (s, 1H), 7.32 (dd, 1H,
J ) 5.2, 8.5 Hz), 6.67 (dt, 1H, J ) 2.5, 7.1 Hz), 4.26 (q, 2H, J ) 7.1 Hz),
1.38 (t, 3H, J ) 7.1 Hz); 13C NMR (100 MHz, MeOH-d4) 168.1, 159.2,
132.65, 131.92, 122.92, 117.7, 112.5, 106.4, 105.2, 102.8, 79.8, 58.7, 14.1;
IR (ATR, neat) 2179, 1602, 1558, 1465, 1250, 1196, 1108, 1061, 1026,
775 cm-1. Data for entry 5, Table 1: 1H NMR (400 MHz, CD3CN) δ 7.81
Org. Lett., Vol. 6, No. 14, 2004
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