156.1 (36), 129.1 (100), 114.0 (25), 105.1 (23), 86.0 (47),
57.2 (41), 41.1 (21). MA: C8H14NO2Cl (191.658) calcd: C
) 50.14; H ) 7.36; N ) 7.31; found: C ) 50.25; H )
7.43; N ) 7.39.
the crude product was obtained as a brown oil, which became
a solid when stored in a freezer at -22 °C (9.17 g, 98 wt
%). TLC: Rf ) 0.76 (Hex/AcOEt ) 4:1). Mp: 55 °C. IR
(Nujol): ν ) 2978, 2925, 2854, 1716, 1594, 1484, 1470,
1449, 1386, 1366, 1346, 1257, 1219, 1189, 1166, 1093, 1048,
873, 804, 767, 484. 1H NMR (300 MHz, CDCl3): δ ) 7.94
(d, J ) 9.0, 1H), 6.92 (d, J ) 2.5, 1H), 6.84 (dd, J ) 2.6,
J ) 9.0, 1H), 6.31 (s, 1H), 4.06 (q, J ) 7.0, 2H), 3.61 (t, J
) 6.6, 2H), 3.16 (t, J ) 7.2, 2H), 2.17 (tt, J ) 6.6, J ) 7.2,
2H), 1.68 (s, 9H), 1.42 (t, J ) 7.0, 3H). 13C NMR (100 MHz,
CDCl3): δ ) 155.1, 150.4, 140.8, 131.3, 130.0, 116.4, 112.5,
107.9, 103.5, 83.8, 63.9, 44.3, 31.6, 28.3, 27.3, 15.0. MS
(m/z) ) 337.1 (26, M+), 281.1 (100), 237.2 (13), 218.1 (13),
208.1 (9), 175.1 (17), 146.1 (5), 57.1 (9). MA: C18H24ClNO3
(337.847) calcd: C ) 63.99; H ) 7.16; N ) 4.15; found:
C ) 64.13; H ) 7.24; N ) 4.07.
[2-(5-Chloro-2-oxo-pentyl)-4-ethoxy-phenyl]carbam-
ic Acid tert-Butyl Ester (16). A solution of 3.00 g of 14
(11.9 mmol) in 30 mL of THF was cooled to -40 °C under
argon atmosphere; 19.9 mL of s-BuLi (25.1 mmol, 2.1 equiv)
was slowly added so as to maintain a temperature below
-35 °C. The shiny, yellow mixture was stirred for 30 min
and cooled to -78 °C, and a solution of 2.75 g of 15 (14.3
mmol, 1.2 equiv) in 2.8 mL of THF was added dropwise.
The yellow color disappeared immediately after complete
addition, and the reaction was quenched after 5 min with 30
mL of saturated aqueous ammonium chloride. Ethyl acetate
(180 mL) was added, and the organic phase was washed
twice with 180 mL of saturated aqueous ammonium chloride
and once with 180 mL of saturated aqueous sodium chloride.
The organic phase was dried over 30 g of sodium sulfate
(30 min) and filtered. The solid was washed with 60 mL of
ethyl acetate. After evaporation of solvent on a rotary
evaporator (50 °C, 5 mbar), the crude product was obtained
as a slightly pink solid (4.35 g, 102 wt %). The crude product
(4.35 g) was dissolved in 12 mL of dichloromethane at 45
°C oil bath temperature. Ketone 16 was precipitated by
addition of 120 mL of hexane. To complete precipitation,
the mixture was put in a freezer at -22 °C overnight. Slightly
pink crystals were filtered from the cold mother liquid,
yielding product 16 (3.71, 87 wt %). TLC: Rf ) 0.22 (Hex/
AcOEt ) 4:1). IR (Nujol): ν ) 3353, 2925, 2854, 1706,
1690, 1522, 1464, 1446, 1369, 1247, 1234, 1165, 1120, 507.
1H NMR (300 MHz, CDCl3): δ ) 7.49 (d, J ) 2.8, 1H),
6.80 (dd, J ) 3.0, J ) 8.9, 1H), 6.70 (d, J ) 8.5, 1H), 4.00
(q, J ) 7.0, 2H), 3.68 (s, 2H), 3.54 (t, J ) 6.6, 2H), 2.74 (t,
J ) 7.0, 2H), 2.03 (tt, J ) 6.6, J ) 7.0, 2H), 1.50 (s, 9H),
1.39 (t, J ) 7.0, 3H). MS (m/z) ) 356.3 (23, M+), 300.3
(57), 256.2 (100). MA: C18H26ClNO4 (355.826) calcd: C
) 60.75; H ) 7.36; N ) 3.94; found: C ) 60.97; H )
7.29; N ) 4.12.
2-(3-Chloro-propyl)-5-ethoxy-indole-1-carboxylic Acid
tert-Butyl Ester (17). Two milliliters of acetyl chloride (28.3
mmol, 1.02 equiv) was added dropwise to a solution of 25
mL of methanol in 125 mL of TBME at 0 °C. A solution of
9.86 g of 16 (27.7 mmol) in 40 mL of THF was added all at
once to this mixture at 0 °C. The reaction was monitored by
HPLC. After 30 min at 0 °C (HPLC: < 0.5% area of 16),
the reaction was quenched by addition of 30 mL of saturated
aqueous sodium hydrogen carbonate and 350 mL of ethyl
acetate. The organic phase was washed with 350 mL of
saturated aqueous sodium hydrogen carbonate and subse-
quently with 350 mL of saturated aqueous sodium chloride,
was dried over 40 g of sodium sulfate (30 min), and filtered.
The solid was washed with 60 mL of ethyl acetate. After
evaporation of solvent on a rotary evaporator (50 °C, 5 mbar),
6-Ethoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene
(2). To a solution of 9.17 g of 17 (27.1 mmol) in 92 mL of
DMSO and 4.6 mL of water were added 5.60 g of sodium
hydroxide (135.7 mmol, 5.0 equiv) and 814 mg of sodium
iodide (5.4 mmol, 0.2 equiv). The vigorously stirred reaction
mixture was heated to 60 °C overnight under an argon
atmosphere. The reaction was monitored by HPLC. After
cooling to room temperature (HPLC: < 0.2% area of 17),
tricycle 2 was precipitated by addition of 365 mL of water
and filtered. The solid was dissolved in 250 mL of ethyl
acetate. The solution was washed with 250 mL of saturated
aqueous ammonium chloride and then with 250 mL of
saturated aqueous sodium chloride, was dried over 30 g of
sodium sulfate (30 min), and filtered. The solid was washed
with 50 mL of ethyl acetate. After evaporation of solvent
on a rotary evaporator (50 °C, 5 mbar), product 2 was
obtained as an off-white solid (5.12 g, 94 wt %).11 TLC: Rf
) 0.58 (Hex/AcOEt ) 4:1). Mp: 109 °C. IR (Nujol): ν )
2924, 2854, 1573, 1490, 1470, 1420, 1395, 1310, 1239, 1179,
1
1129, 1113, 1043, 848, 797, 767, 736, 502. H NMR (300
MHz, CDCl3): δ ) 7.13 (d, J ) 8.8, 1H), 7.06 (d, J ) 2.0,
1H), 6.80 (dd, J ) 2.0, J ) 8.8, 1H), 6.10 (s, 1H), 4.09 (q,
J ) 7.0, 2H), 4.02 (t, J ) 6.8, 2H), 3.00 (t, J ) 7.2, 2H),
2.60 (tt, J ) 6.8, J ) 7.2, 2H), 1.45 (t, J ) 7.0, 3H). 13C
NMR (100 MHz, CDCl3): δ ) 153.1, 145.2, 133.7, 128.2,
110.7, 109.9, 103.9, 92.0, 64.3, 43.8, 27.8, 24.5, 15.1. MS
(m/z) ) 201.1 (97, M+), 172.0 (100), 144.0 (54), 115.9 (12),
29.4 (18). MA: C13H15NO (201.269) calcd: C ) 77.58; H
) 7.51; N ) 6.96; found: C ) 77.48; H ) 7.57; N ) 6.99.
Acknowledgment
We thank Dr. Milan Soukup and Dr. Martin Karpf for
helpful discussions and Mr. Thomas Naber for skillful
experimental work. We also thank the members of the
analytical services of F. Hoffmann-La Roche Ltd., Basel,
for efficiently and persistently providing the physical data
of all compounds described.
(11) Evaporation to dryness was necessary at this stage of the development to
calculate the yield. On larger scale, however, this isolation procedure will
be replaced.
Received for review April 30, 2005.
OP050065S
512
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Vol. 9, No. 4, 2005 / Organic Process Research & Development