Organic Process Research & Development
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tert-Butyl (rel-1S,4R,6S)-7-oxo-2-azatricyclo[4.4.0.01,4]-
and extracted with CH2Cl2 (3 × 3 mL); the combined organic
layers were washed with brine (4 mL), dried (MgSO4) and
concentrated in vacuo. After purification by column chroma-
tography sulfonamide 11 (14 mg, 0.039 mmol, 71% over two
steps) was obtained as a colorless oil. IR (ATR) ν 2925, 1702,
decane-2-carboxylate (8, Analytical Sample Obtained in
1
Pure Form). IR (ATR) ν 2929, 1689, 1364, 1133 cm−1; H
NMR (400 MHz, CDCl3) δ 3.43 (dd, J = 8.9, 1.1 Hz, 1H), 3.37
(dt, J = 8.8, 1.1 Hz, 1H), 3.12 (dt, J = 3.1, 1.0 Hz, 1H), 2.48 (d,
J = 14.8 Hz, 1H), 2.42−2.33 (m, 2H), 2.32−2.09 (m, 4H), 1.94
(ddd, J = 8.0, 3.0, 0.7 Hz, 1H), 1.68 (dt, J = 13.4, 3.9 Hz, 1H),
1.48 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 209.86, 155.65,
79.62, 75.32, 61.30, 51.88, 40.73, 38.86, 37.24, 28.58, 27.08,
23.67; HRMS (ESI+) calcd for (C14H21NO3 + Na)+ 274.1419,
found 274.1416.
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1322, 1156 cm−1; H NMR (400 MHz, CDCl3) δ 7.77−7.63
(m, 2H), 7.36−7.24 (m, 2H), 3.44 (d, J = 8.4 Hz, 1H), 3.30 (d,
J = 8.3 Hz, 1H), 2.90 (d, J = 5.0 Hz, 1H), 2.74 (s, 1H), 2.61−
2.34 (m, 8H), 2.40 (s, 3H), 2.11−2.00 (m, 2H), 1.86 (d, J =
14.0 Hz, 1H), 1.74 (t, J = 6.8 Hz, 1H), 1.72−1.43 (m, 6H), 1.22
(t, J = 12.8 Hz, 1H), 0.60 (t, J = 7.9 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 143.20, 136.26, 129.73, 128.27, 74.66, 60.94,
55.62, 54.70, 53.54, 38.97, 35.26, 28.97, 27.94, 23.79, 21.65,
17.22; HRMS (ESI+) calcd for (C20H28N2O2S + H)+ 361.1950,
found 361.1954.
tert-Butyl (rel-3aR,4aS,8aS)-5-oxooctahydrobenzo-
[1,4]cyclobuta[1,2-b]pyrrole-1(2H)-carboxylate (9). A sol-
ution of enaminone 6b (4.16 g, 15.7 mmol) in acetonitrile (530
mL, 30 mM) was pumped through FEP tubing at a flow rate of
2.88 mL/min, corresponding to a 40 min irradiation time using
254 nm UV light. After concentrating the reaction mixture in
vacuo, cycloadduct 9 (3.95 g, 14.9 mmol, 95%) was obtained as
a colorless oil. Upon standing, even at low temperatures, the
compound slowly decomposes. Therefore, follow-up reactions
were carried out immediately after the photocycloaddition. IR
tert-Butyl (rel-3aR,4aR,8aS)-5-Phenyl-3,3a,4,4a,7,8-
hexahydrobenzo[1,4]cyclobuta[1,2-b]pyrrole-1(2H)-car-
boxylate (13). NaHMDS (643 μL of a 2 M solution in THF,
1.286 mmol) was added to a solution of compound 9 (310 mg,
1.168 mmol) in Et2O (3 mL) at −20 °C, and after 20 min
PhNTf2 (417 mg, 1.168 mmol). After warming to room
temperature, the mixture was stirred for 4 h. Then, the
temperature was lowered to −20 °C and NaHMDS (117 μL of
a 2 M solution in THF, 0.117 mmol) was added and after 20
min PhNTf2 (42 mg, 0.117 mmol). After 4 h, the same
additions were performed. The reaction mixture was stirred for
10 h at room temperature and then washed with saturated
aqueous NaHCO3 (2 × 4 mL) and water (4 mL). The
combined aqueous phase was reextracted with Et2O (2 × 10
mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo to obtain vinyl triflate 12 (slightly
contaminated with PhNHTf). The crude mixture was used for
the Suzuki coupling reaction. A mixture of vinyl triflate 12,
Pd(OAc)2 (38 mg, 0.17 mmol), PPh3 (133 mg, 0.507 mmol),
and 1.0 M aqueous sodium carbonate (2.34 mL) were dissolved
in 1,4-dioxane (6.5 mL). The mixture was stirred for 30 min at
room temperature. Then, phenylboronic acid (171 mg, 1.402
mmol) was added, and the mixture was stirred for 20 h. The
reaction was quenched with water (4 mL) and extracted with
EtOAc (3 × 5 mL). The combined organic fractions were
washed with brine (8 mL), dried (MgSO4), concentrated in
vacuo, and purified via silica column chromatography (EtOAc/
heptane 0 → 7%) to yield compound 13 (156 mg, 0.480 mmol,
41% over two steps) as a white solid. IR (ATR) ν 2977, 2928,
1688, 1363, 1170, 764, 694 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.34−7.17 (m, 5H), 6.1 (d, J = 5.9 Hz, 1H), 3.85−3.63 (m,
2H), 3.20−3.02 (m, 1H), 2.82−2.76 (m, 1H), 2.52−2.42 (m,
1H), 2.38−2.11 (m, 3H), 2.01−1.87 (m, 1H), 1.82 (ddd, J =
12.2, 9.1, 3.4 Hz, 1H), 1.78−1.63 (m, 1H), 1.40 (s, 9H), 1.40−
1.33 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 154.89. 140.70,
140.67. 128.34, 126.78, 125.31, 122.55, 79.35, 67.14, 47.85,
38.88, 38.28, 31.79, 28.67, 27.35, 25.59, 24.69; HRMS (ESI+)
calcd for (C21H27NO2 + Na)+ 348.1940, found 348.1942.
(rel-3aR,4aR,8aS)-5-Phenyl-1-tosyl-1,2,3,3a,4,4a,7,8-
octahydrobenzo[1,4]cyclobuta[1,2-b]pyrrole (14). A sol-
ution of Suzuki product 13 (27 mg, 0.083 mmol) was stirred at
room temperature in a TFA/CH2Cl2 mixture (1:1, 2 mL) for
15 min. The mixture was concentrated, dissolved in CH2Cl2 (1
mL), and at 0 °C treated with triethylamine (21 mg, 0.207
mmol) and p-toluenesulfonyl chloride (16 mg, 0.084 mmol).
After stirring for 2.5 h at room temperature, the reaction was
quenched with a saturated solution of NaHCO3 (1 mL),
extracted with CH2Cl2 (3 × 2 mL), the combined organic
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(ATR) ν 2947, 1686, 1364, 1161, 1115 cm−1; H NMR (500
MHz, CDCl3, −50 °C, mixture of rotamers) δ 3.69−3.46 (m,
2H), 2.88−2.67 (m, 2H), 2.56−2.32 (m, 2H), 2.27−2.12 (m,
2H), 2.08−1.91 (m, 2H), 1.90−1.74 (m, 1H), 1.73−1.51 (m,
2H), 1.41−1.37 (m, 1H), 1.42 (s, 9H); 13C NMR (126 MHz,
CDCl3, −50 °C) δ (major rotamer) 214.92, 154.16, 80.11,
68.94, 48.65, 47.39, 41.16, 40.39, 29.82, 28.50, 26.99, 25.72,
21.45; δ (minor rotamer) 215.61, 154.07, 79.61, 70.48, 47.61,
47.32, 40.82, 40.22, 28.75, 28.42, 26.61, 25.63, 22.00; HRMS
(ESI+) calcd for (C15H23NO3 + Na)+ 288.1576, found
288.1579.
(rel-3R,3aR,4R,7aS)-tert-Butyl 4-(pyrrolidin-1-yl)-
hexahydro-3,7a-methanoindole-1(2H)-carboxylate (10).
Acetic acid (24 mg, 0.40 mmol), pyrrolidine (28 mg, 0.40
mmol), NaBH(OAc)3 (152 mg, 0.72 mmol), and molecular
sieves (4 Å) were added to a solution of ketone 7 (100 mg, 0.40
mmol) in 1,2-dichloroethane (2 mL). The mixture was stirred
at room temperature for 48 h (additional pyrrolidine (28 mg,
0.40 mmol) was added after 24 h). The reaction was quenched
with water (2 mL) and extracted with CH2Cl2 (3 × 5 mL); the
combined organic layers were washed with brine (5 mL), dried
(MgSO4), and concentrated in vacuo. After purification by
column chromatography (EtOAc/heptane 4:1 → 1:0) com-
pound 10 (45 mg, 0.15 mmol, 37%) was obtained as a colorless
1
oil. IR (ATR) ν 1689, 1365, 1123 cm−1; H NMR (400 MHz,
CDCl3) δ 3.32 (d, J = 8.6 Hz, 1H), 3.28 (d, J = 8.6 Hz, 1H),
3.11 (dd, J = 6.7, 2.5 Hz, 1H), 2.83−2.78 (m, 1H), 2.72−2.38
(m, 5H), 2.26−2.17 (m, 1H), 2.11−1.96 (m, 1H), 1.88 (d, J =
14.1 Hz, 1H), 1.78 (dd, J = 8.0, 6.6 Hz, 1H), 1.76−1.65 (m,
4H), 1.65−1.54 (m, 1H), 1.49−1.42 (m, 1H), 1.45 (s, 9H),
1.26−1.13 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 156.26,
78.94, 72.16, 61.41, 56.01, 53.70, 53.59, 38.96, 38.73, 29.13,
28.78, 28.58, 23.84, 17.62; HRMS (ESI+) calcd for
(C18H30N2O2 + H)+ 307.2386, found 307.2389.
(rel-3R,3aR,4R,7aS)-4-(Pyrrolidin-1-yl)-1-tosyloctahy-
dro-3,7a-methanoindole (11). A solution of pyrrolidine 10
(17 mg, 0.055 mmol) was stirred at room temperature in a
TFA/CH2Cl2 mixture (1:1) for 20 min. The mixture was
concentrated, dissolved in CH2Cl2 (1 mL), and at 0 °C treated
with triethylamine (17 mg, 0.17 mmol) and p-toluenesulfonyl
chloride (11 mg, 0.055 mmol). After stirring for 2.5 h at room
temperature, the reaction was quenched with water (1.5 mL)
D
Org. Process Res. Dev. XXXX, XXX, XXX−XXX