TABLE 3. Tandem Metalation/Cross-Coupling/Lactamization
entry
1
component I/II
reaction conditions
yield (%)
61
2a/3a
1. Pd(OAc)2 (5%), 7 (20%), Et3N (4.0 equiv), HB(pin) (3 equiv), dioxane, 80 °C, 30 min
2. H2O, 3a, Ba(OH)2‚8H2O (3 equiv), 80 °C, 4 h
(Suzuki)
2
3
4
5
6
7
8
9
2a/3a
Suzuki)
2a/3a
Suzuki)
2a/3a
Suzuki)
2a/3b
Suzuki)
2a/3b
Suzuki)
3a/2a
Suzuki)
1. Pd(OAc)2 (5%), 7 (20%), Et3N (1.5 equiv), HB(pin) (3 equiv), dioxane, 80 °C, 30 min
2. H2O, 3a, Ba(OH)2‚8H2O (3 equiv), 80 °C, 4 h
67
64
21
60
74
15
(
1. Pd(OAc)2 (5%), 7 (20%), Et3N (1.5 equiv), HB(pin) (3 equiv), dioxane, 80 °C, 30 min
2. H2O, 3a, CsF (3 equiv), 80 °C, 4 h
a
(
1. PdCl2 (5%), dppf (5%), KOAc, B2(pin)2 (3 equiv), dioxane, 80 °C, 3 h
2. H2O, 3a, Ba(OH)2‚8H2O (3 equiv), 80 °C, 18 h
(
1. Pd(OAc)2 (5%), 7 (20%), Et3N (1.5 equiv), HB(pin) (3 equiv), dioxane, 80 °C, 30 min
2. H2O, 3b, Ba(OH)2‚8H2O (3 equiv), 80 °C, 4 h
(
1. Pd(OAc)2 (5%), 7 (20%), Et3N (1.5 equiv), HB(pin) (3 equiv), dioxane, 80 °C, 30 min
2. H2O, 3b, CsF (3 equiv), 80 °C, 4 h
a
(
1. Pd(OAc)2 (5%), 7 (20%), Et3N (1.5 equiv), HB(pin) (3 equiv), dioxane, 80 °C, 60 min
2. H2O, 2a, Ba(OH)2‚8H2O (3 equiv), 80 °C, 4 h
(
b
3b/2a
Kumada)
3b/2b
Kumada)
3b/2b
Kumada)
1. i-PrMgCl (1.1 equiv), THF, -40 °C, 10 min
(
2. 2a, Pd2(dba)3‚CHCl3 (0.025 equiv), dppf (0.05 equiv), -40 or 0 °C for 7 h f 25 °C for 16 h
1. i-PrMgCl (1.1 equiv), THF, -40 °C, 10 min
(
2. 2b, Pd2(dba)3‚CHCl3 (0.025 equiv), dppf (0.05 equiv), -40 or 0 °C for 7 h f 25 °C for 16 h
1. i-PrMgCl (1.1 equiv), THF, -40 °C, 10 min
10
11
12
13
14
15
16
(
2. 2b, Pd(OAc)2 (5%), 7 (20%), -40 or 0 °C for 7 h f 25 °C for 16 h
1. 2a, Pd(PPh3)4 (7%), CuI (0.2 equiv), CsF (2 equiv), DMSO, 80 °C, 16 h
c
3a /2a
20
14
a
a
a
a
a
(
Stille)
c
3a /2a
Stille)
3b/2a
Stille)
3b/2a
Stille)
2a/3a
Stille)
3b/2a
Negishi)
1. 2a, Pd(PPh3)4 (5%), CuCl (5 equiv), LiCl (6 equiv), DMSO, rt, 24 h f 80 °C, 24 h
(
1. PdCl2(CH3CN)2 (5%), DMF, 80 °C, 7 days
2. 2a, CsF (3 equiv)
1. PdCl2(CH3CN)2 (5%), DMF, 80 °C, 7 days
2. 2a, P(Bu)3 (20%), CsF (3 equiv)
1. PdCl2(P(o-Tol)3)2 (5%), Bu3SnSnBu3 (1.2 equiv), DMSO, 80 °C, 16 h
2. 3a, CuCl (5 equiv), LiCl (6 equiv), DMSO, 80 °C, 20 h
1. i-PrMgCl, THF, -40 °C, 5 min
(
(
9d
(
(
2. ZnBr2, -40 f 25 °C, 2.5 h
3
. 3a, PdCl2(o-Tol)2 (10%), THF, 25 °C, 24 h, then more catalyst, 60 °C, 3 days
a
b
In cases with no base present, Ba(OH)2 was added after cross-coupling to ensure lactamization. 2a was deprotonated with i-PrMgCl prior to the
cross-coupling attempt. 6c was isolated by column chromatography prior to cross-coupling. d Homocoupling (31%) of 3a was observed.
c
separated, and the aqueous layer was extracted with CH
2 2
Cl . The
combined organic phases were dried (Na SO ) and the solvents
2
4
evaporated. Column chromatography (EtOAc/heptane 1:4) of the
residue afforded the product as a light tan solid with spectroscopic
6,7
data in accordance with previous reports. Mp (MeOH): 207-
7
38
2
08 °C (lit. 216-218 °C, 207-209 °C ). Anal. Calcd for C16
NO : C, 73.00; H, 3.45; N, 5.34. Found: C, 72.65; H, 3.13; N,
.02.
Hippadine (1a) via Stille Coupling. A flask was charged with
9
H -
3
5
LiCl (36 mg, 0.85 mmol) and flame-dried under high vacuum. Upon
cooling, Pd(PPh ) (16.5 mg, 0.014 mmol) and CuCl (70 mg, 0.71
the tandem borylation/Suzuki/lactamization strategy, it was
possible to synthesize hippadine in two steps from commercially
available starting materials. Of the different cross-coupling
reactions, the Suzuki and Stille reactions were the only ones to
provide the desired product, with the Suzuki reaction being best
suited for the hippadine system. With an overall yield of 50%
from 6-bromopiperonal (via 3a), the route presented here is the
shortest and most efficient synthesis of hippadine reported to
date.
3
4
mmol) were added, and the mixture was degassed (×4) under high
vacuum. 7-Bromoindole (2a) (35 mg, 0.18 mmol) and the stannane
6c (66 mg, 0.14 mmol) were dissolved in DMSO (1.5 mL),
degassed, and added to the flask containing the salts. The resulting
mixture was degassed (×3) by the freeze-thaw process (-78 °C
f 20 °C, Ar). The reaction mixture was stirred overnight at 20 °C
and again overnight at 80 °C in order to complete the reaction.
Ba(OH)
2
2
‚8H O (131 mg, 0.415 mmol) was added, and after 2 h,
workup of the reaction and purification as described above afforded
the product (1a) as a solid (5 mg, 14%).
Experimental Section
Hippadine (1a) via Borylation and Suzuki-Miyaura Cou-
Acknowledgment. We gratefully thank The Lundbeck
Foundation, The Torkil Holm Foundation, The Danish Natural
Science Research Council, The Augustinus Foundation, and The
Ib Henriksen Foundation for the financial support which made
this work possible.
3 2
pling (one pot). Et N (0.09 mL, 0.6 mmol), Pd(OAc) (4.9 mg,
0
.022 mmol), and 2-(dicyclohexylphosphino)biphenyl (31 mg, 0.088
mmol) were successively added to a solution of 7-bromoindole (2a)
86 mg, 0.44 mmol) in dioxane (1.0 mL). The solution was heated
to 80 °C, and pinacolborane (0.19 mL, 1.3 mmol) was added
dropwise. After 30 min, H O (0.19 mL) was added dropwise
followed by a solution of methyl-6-bromopiperonate (3a) (114 mg,
.44 mmol) in dioxane (1.5 mL) and Ba(OH) O (417 mg, 1.32
(
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
2
0
2
‚8H
2
mmol). Stirring was continued at 80 °C until the reaction was
JO060729B
complete (monitored by GCMS). The reaction mixture was diluted
with CH
2
Cl
2
(50 mL) and H
2
O (20 mL). The solution was filtered,
Cl . The layers were
(
38) Ghosal, S.; Lochan, R.; Ashutosh, K.; Kumar, Y.; Srivastava, R. S.
and the dark precipitate was washed with CH
2
2
Phytochemistry 1982, 25, 1097.
5
810 J. Org. Chem., Vol. 71, No. 15, 2006