Total synthesis of (±)-quebrachamine via [3+2] cycloaddition and efficient chloroacetamide photocyclization

Article abstract of DOI:10.1002/ejoc.200801154

The total synthesis of (±)-quebrachamine has been completed in 13 linear steps and 17.8 % overall yield. The indole core was constructed via a formal [3+2] dipolar cycloaddition between a functionalized nitrile and donor-acceptor cyclopropane, and the syn

Full text of DOI:10.1002/ejoc.200801154

FULL PAPER
DOI: 10.1002/ejoc.200801154
Total Synthesis of (؎)-Quebrachamine via [3+2] Cycloaddition and Efficient
Chloroacetamide Photocyclization
Barbora Bajtos[a] and Brian L. Pagenkopf*[a]
Keywords: Total synthesis / Natural products / Alkaloids / Nitrogen heterocycles / Cycloaddition / Donor-acceptor cyclo-
propane / Photocyclization
The total synthesis of (Ϯ)-quebrachamine has been com- ring was secured by an efficient chloroacetamide photocycli-
pleted in 13 linear steps and 17.8% overall yield. The indole
core was constructed via a formal [3+2] dipolar cycloaddition
between a functionalized nitrile and donor-acceptor cyclo-
propane, and the synthetically challenging nine-membered
zation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
The utility of the dipolar methodology was recently illus-
trated by us with the total synthesis of (Ϯ)-goniomitine,
which featured a [3+2] annulation reaction between a func-
tionalized nitrile and DA cyclopropane to afford a substi-
tuted tetrahydroindole.[4] Building on these initial discover-
ies, we report here the total synthesis of (Ϯ)-quebrachamine
(1). This work further illustrates the value of indole 2 as a
synthetic precursor to several natural products, which was
first utilized by Takano and co-workers in the synthesis of
(–)-goniomitine.[5]
Quebrachamine (1), which was first isolated over a cen-
tury ago by Hesse from Aspidosperma quebracho tree bark,
is an intriguing tetracyclic indole alkaloid featuring a syn-
thetically challenging nine-membered ring.[6] This natural
product belongs to a large family of Aspidosperma alka-
loids possessing diverse biological activity,[7] including α-
adrenergic blocking behavior in urogenital tissue.[8] Attract-
ive pharmacological properties along with its complex
framework have inspired considerable and sustained syn-
thetic efforts, with the first reported total synthesis of queb-
rachamine in 1963 by Stork and Dolfini.[9] Interestingly, the
majority of previous syntheses feature a reductive ring-
opening of a 5–6 system to access the nine-membered ring,
presumably due to the notorious difficulty associated with
the formation of medium-sized rings.[10]
Introduction
Dipolar cycloadditions are widely utilized in the forma-
tion of functionalized heterocycles involving donor-ac-
ceptor (DA) cyclopropanes with nitriles,[1] indoles,[2] and
other reaction partners.[3] Part of our research efforts have
focused on developing efficient [3+2] annulation methodol-
ogy with nitriles to afford highly substituted pyrroles with
absolute regiochemical control. It was envisioned that this
powerful strategy could lead to indole 2, and subsequently
allow access to natural products such as quebrachamine (1),
goniomitine, aspidospermatine, and vinblastine (Scheme 1).
In light of these pioneering efforts, we envisioned a novel
approach to (Ϯ)-quebrachamine (1) that confronts forma-
tion of the nine-membered ring through an early retrosyn-
thetic disconnection that identified two strategic bonds
(Scheme 2). Either of these disconnections would allow for
a variety of Friedel–Crafts acylation or N-alkylation type
strategies to be explored, while greatly simplifying the syn-
thetic target to advanced key intermediate 2. Our previous
work on the (Ϯ)-goniomitine synthesis provided a route to
2, by oxidation and decarboxylation of the tetra-substituted
Scheme 1. Potential natural product targets from 2.
[a] Chemistry Department, The University of Western Ontario,
1151 Richmond Street, London, Ontario, Canada, N6A 3K7
Fax: +1-519-661-3022
E-mail: bpagenko@uwo.ca
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
1072
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1072–1077

Total Synthesis of (Ϯ)-Quebrachamine
pyrrole 3, which in turn is generated from the [3+2] cycload-
dition involving functionalized nitrile 4 and cyclopropane
5.
Scheme 2. Retrosynthetic strategy.
Scheme 4. Friedel–Crafts cyclization approach.
Results and Discussion
Faced with an apparently unnavigable Friedel–Crafts
pathway, we retreated to an earlier position in 7, as a sub-
strate upon which to build the two carbon linker at the vac-
ant C3 position of the indole (Scheme 5). The effort began
by installation of a β-hydroxyethyl side-chain using ethylene
oxide under InIII catalysis conditions. Optimization experi-
ments for this reaction led us to 1 equiv. InBr3 and 4 equiv.
of KH, conditions that are likely generating KInH4 in situ
as the active Lewis acid in this process.[12] Aluminum and
gallium trihydrides are known to form stable N-, P-, and O-
donor complexes,[13] but the corresponding indium hydride
complexes have remained relatively unexplored.[14] This
novel method for indole β-hydroxyethyl alkylation at C3
provides an alternative strategy to methods employing
strong bases for indole deprotonation and oxoester interme-
diates where selective reduction can be difficult in the pres-
ence of other carbonyl substituents.[15]
The synthesis began with the preparation of nitrile 4,
which was completed in five steps from commercially avail-
able δ-valerolactam as described previously.[4] The cycload-
dition reaction between functionalized nitrile 4 and DA
cyclopropane 5 (Me3SiOTf, EtNO2, –30 °C) proceeded
smoothly to afford cycloadduct 3 in 74% yield (Scheme 3).
Oxidation of the tetra-substituted pyrrole 3 with catalytic
palladium on carbon in refluxing mesitylene provided the
indole core in an excellent 98% yield. In lieu of enforcing
an ungainly transformation on the ester group to convert it
into a precursor suitable for constructing the two-carbon
bridge of the nine-membered ring, it was deemed expend-
able and discarded by microwave-assisted decarboxylation
(NaOH, EtOH/H2O, 150 °C, 69%), thereby clearing the
field for exploring methods for ring closure.
Scheme 3. Synthesis of intermediate 7.
Our initial approach sought to enlist a Friedel–Crafts re-
action to form the nine-membered ring in the penultimate
step of the synthesis. The sequence began with deprotection
of tertiary lactam 7 (Na, NH3, THF) giving 2 in 93% yield
Scheme 5. Mitsunobu/N-alkylation cyclization approach.
After removal of the benzylic group, the secondary lac-
(Scheme 4). The cyclization precursor 9 was prepared by tam 10 was subjected to Mitsunobu reaction conditions.
Red-Al® reduction of lactam 2, N-alkylation of the re- Additionally, the halide derivatives 11 and 12 were treated
sulting amine 8 with ethyl bromoacetate, and saponifica- with a variety of bases with the expectation that a slow
tion. The key carboxylic acid 9 (as well as related acid chlo- intramolecular alkylation would ensue; however, both Mit-
rides and mixed anhydrides) was then subjected to a wide sunobu and SN2 strategies proved futile. We then moved
variety of established Friedel–Crafts acylation condi- away from anionic alkylation conditions in favor of a neu-
tions,[11] but the substrates were unresponsive to these ef- tral amine nucleophile prepared by reduction of the lactam,
forts, and decomposed when forcing conditions were ap- but after generation of the β-haloethyl side-chain the mate-
plied.
rial became too unstable for further investigation. In some
Eur. J. Org. Chem. 2009, 1072–1077
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B. Bajtos, B. L. Pagenkopf
FULL PAPER
cases it appears that the nucleophilicity of the indole was a nine-membered ring synthesis by a remarkably efficient
interfering with the desired cyclization, generating either photo-induced cyclization strategy. Studies are underway to
complex mixtures or the three-membered spirocycle 13. develop an asymmetric synthesis of nitrile 4.
Attempts to attenuate the indole nucleophilicity by install-
ing a TMS or Boc protecting group on several advanced
intermediates proved surprisingly elusive, perhaps due to
the steric hindrance from the side chain.
Experimental Section
Ethyl 2-[2-(1-Benzyl-3-ethyl-2-oxopiperidin-3-yl)ethyl]-1H-indole-3-
carboxylate (6): Tetra-substituted pyrrole 3 (4.38 g, 10.0 mmol) was
added to a suspension of palladium on carbon (5% Pd/C, 665 mg)
in mesitylene (100 mL) and refluxed for 1 d. The palladium was
removed by filtration through a pad of silica gel and Celite. After
the solution was concentrated under reduced pressure, purification
by flash chromatography on silica gel using EtOAc/hexanes for elu-
tion, which provided the title compound as a white solid (98%,
4.24 g). Rf = 0.18 (33% EtOAc in hexanes); m.p. 134–136 °C (hex-
After extensive exploration of these classic alkylation and
acylation strategies, our successful route turned to a photo-
induced ring closure (Scheme 6). Chloroacetamide Witkop
photocyclizations[16] are important yet perhaps underuti-
lized synthetic processes that have been employed in the for-
mation of medium-sized lactams,[17] and in the synthesis of
Vinca and Strychnos alkaloids.[18] We were initially appre-
hensive about the potential efficiency of this process be-
cause while simple substrates, such as isotryptamine,[18d] cy-
clize in high yield, substrates with complexity comparable
to that of quebrachamine reportedly do so in low to modest
yields (15–55%).[18]
1
anes/EtOAc crystal). H NMR (400 MHz, CDCl3): δ = 9.69 (br. s,
1 H), 8.07 (d, J = 8.2 Hz, 1 H), 7.30–7.12 (m, 8 H), 4.69 (d, J =
14.6 Hz, 1 H), 4.54 (d, J = 14.6 Hz, 1 H), 4.39 (q, J = 7.0 Hz, 2
H), 3.62 (ddd, J = 6.4, 9.9, 14.0 Hz, 1 H), 3.29–3.19 (m, 2 H), 2.82
(ddd, J = 5.3, 9.9, 14.6 Hz, 1 H), 2.17 (ddd, J = 5.3, 9.9, 14.6 Hz,
1 H), 1.93–1.80 (m, 6 H), 1.66 (dq, J = 7.5, 15.0 Hz, 1 H), 1.45 (t, J
= 7.0 Hz, 3 H), 0.89 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 175.4, 166.1, 149.0, 137.1, 134.8, 128.6, 127.7, 127.3,
126.9, 122.1, 121.2, 111.0, 103.4, 59.3, 50.7, 47.9, 45.8, 37.4, 31.6,
28.8, 22.9, 19.5, 14.6, 8.5 ppm. HRMS: m/z 432.2419 (calcd. for
C27H32N2O3, 432.2413).
1-Benzyl-3-ethyl-3-[2-(1H-indol-2-yl)ethyl]piperidin-2-one (7): In-
dole 6 (4.32 g, 10.0 mmol) was dissolved in ethanol (85 mL) and a
solution of sodium hydroxide (4.00 g, 100 mmol) in water (85 mL)
was added. The mixture was heated to 150 °C in a microwave reac-
tor for 3 h (900 rpm stirring). The mixture was cooled and neutral-
ized with 1  HCl. The volatiles were removed under reduced pres-
sure and the residue was dissolved in 60 mL of EtOAc. The solu-
tion was extracted with EtOAc (3ϫ60 mL). The combined organic
layers were washed with brine, dried (MgSO4), filtered through Ce-
lite and concentrated under reduced pressure. Purification by flash
chromatography on silica gel using EtOAc/hexanes for elution pro-
vided the title compound as yellow solid (69%, 2.49 g). Rf = 0.27
(33% EtOAc in hexanes); m.p. 96–98 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.46 (br. s, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.32–7.22
(m, 6 H), 7.09 (app. t, J = 7.6 Hz, 1 H), 7.04 (app. t, J = 7.6 Hz, 1
H), 6.20 (s, 1 H), 4.66 (d, J = 14.6 Hz, 1 H), 4.53 (d, J = 14.6 Hz,
1 H), 3.22 (t, J = 5.3 Hz, 2 H), 2.86 (ddd, J = 5.8, 10.5, 15.2 Hz, 1
H), 2.66 (ddd, J = 4.7, 10.5, 15.2 Hz, 1 H), 2.19 (ddd, J = 4.1, 10.5,
13.5 Hz, 1 H), 1.88–1.77 (m, 6 H), 1.68 (dq, J = 7.5, 15.0 Hz, 1 H),
0.90 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.8, 140.0, 137.5, 136.0, 128.6, 127.9, 127.3, 120.8, 119.6, 119.3,
110.5, 99.1, 50.6, 47.7, 45.5, 37.8, 31.4, 29.1, 23.8, 19.6, 8.5 ppm.
HRMS: m/z 360.2203 (calcd. for C24H28N2O, 360.2202).
Scheme 6. Cyclization and completion.
Preparation of the photocyclization precursor began
with acylation of piperidine 8 with chloroacetyl chloride.
Upon irradiation of chloroacetylated amine 14 (254 nm,
Na2CO3, EtOH/H2O), we were delighted to find the desired
cyclization product 17 in an unprecedented 85% yield. The
photocyclization mechanism likely involves photo-exci-
tation and electron-transfer steps leading to an initial dirad-
ical species 15.[17] After chloride ionization, intramolecular
cyclization of 16 occurs at C3 of the indole, which is likely
the most favorable position for attack based on geometric
considerations and calculated spin density.[19] To complete
the synthesis, treatment of tetracyclic lactam 17 with
LiAlH4 secured (Ϯ)-quebrachamine (1) in 93% yield.
3-Ethyl-3-[2-(1H-indol-2-yl)ethyl]piperidin-2-one (2): A solution of
lactam 7 (100 mg, 0.28 mmol) in THF (7.0 mL) and tert-butyl
alcohol (0.30 mL) was cooled to –78 °C and liquid ammonia
(5.0 mL) was added to the solution. Sodium metal (33 mg,
1.4 mmol) was cut into small portions, washed with dry hexanes
and added to the ammonia mixture. The reaction mixture was
stirred at –78 °C for 10 min and then solid NH4Cl (200 mg) was
added. The reaction was warmed to room temperature while the
ammonia evaporated completely. Water (10 mL) was added and the
heterogeneous mixture was separated. The aqueous layer was ex-
tracted with CH2Cl2 (3ϫ15 mL). The combined organic layers
were washed with brine, dried (MgSO4), filtered through Celite and
Conclusions
In summary, the total synthesis of (Ϯ)-quebrachamine
(1) has been accomplished in 13 steps and 17.8% overall
yield starting from commercially available δ-valerolactam.
This work highlights the utility of indole synthesis by the
formal [3+2] cycloaddition reaction between donor-ac-
ceptor cyclopropanes and nitriles. Additionally, it features concentrated under reduced pressure. Purification by flash
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Total Synthesis of (Ϯ)-Quebrachamine
chromatography on silica gel using EtOAc/hexanes for elution pro-
NaOH (0.25 mL, 0.5 mmol) was added slowly dropwise. After 8 h,
vided the title compound as white solid (93% yield, 70.0 mg). Rf =
the solution was neutralized with 1  HCl and concentrated under
0.12 (80% EtOAc in hexanes); m.p. 170–172 °C. 1H NMR reduced pressure. The residue was dissolved in EtOAc and water
(400 MHz, CDCl3): δ = 8.44 (br. s, 1 H), 7.49 (d, J = 7.6 Hz, 1 H),
7.27 (d, J = 8.2 Hz, 1 H), 7.08 (app. t, J = 7.6 Hz, 1 H), 7.03 (app.
t, J = 7.6 Hz, 1 H), 6.20 (s, 1 H), 5.91 (br. s, 1 H), 3.32–3.29 (m, 2
H), 2.86 (ddd, J = 5.8, 11.1, 15.2 Hz, 1 H), 2.68 (ddd, J = 4.1, 11.1,
14.6 Hz, 1 H), 2.13 (ddd, J = 4.7, 11.7, 14.0 Hz, 1 H), 1.86–1.75
(m, 6 H), 1.64 (dq, J = 7.5, 15.0 Hz, 1 H), 0.91 (t, J = 7.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.0, 139.9, 136.0,
128.6, 120.8, 119.6, 119.3, 110.5, 99.0, 45.0, 42.7, 37.7, 31.1, 29.0,
23.7, 19.6, 8.4 ppm. HRMS: m/z 270.1726 (calcd. for C17H22N2O,
270.1732).
(20 mL, 1:1) and the aqueous layer was extracted with EtOAc
(5ϫ10 mL). The combined organic layers were washed with brine,
dried (MgSO4), filtered through Celite and concentrated under re-
duced pressure. Purification by flash chromatography on silica gel
using EtOAc/hexanes for elution provided the title compound as
colourless oil (73% yield, 57.0 mg). Rf = 0.05 (10% MeOH in
1
EtOAc). H NMR (400 MHz, CDCl3): δ = 10.67 (br. s, 1 H), 7.45
(d, J = 7.2 Hz, 1 H), 7.33 (br. s, 1 H), 7.05–6.94 (m, 2 H), 6.12 (br.
s, 1 H), 3.80–2.62 (m, 1 H), 3.58–3.45 (m, 1 H), 3.42–2.13 (m, 2
H), 2.95–2.76 (m, 1 H), 2.54–2.41 (m, 1 H), 2.39–2.25 (m, 1 H),
2.18–1.82 (m, 2 H), 1.16–1.35 (m, 3 H), 1.34–1.16 (m, 3 H), 0.99–
0.83 (m, 2 H), 0.75 (br. s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 168.2, 139.9, 136.4, 128.4, 120.5, 119.4, 119.0, 111.0, 98.6, 59.5,
58.7, 53.9, 35.7, 31.6, 30.8, 29.6, 21.6, 18.9, 6.7 ppm. HRMS: m/z
314.1988 (calcd. for C19H26N2O2, 314.1994).
2-[2-(3-Ethylpiperidin-3-yl)ethyl]-1H-indole (8): A solution of lac-
tam 2 (100 mg, 0.28 mmol) in THF (15 mL) was cooled to 0 °C and
Red-Al® (0.55 mL, 2.80 mmol of 65 wt% in toluene) was added
dropwise. The flask was fitted with a reflux condenser and the ice
bath removed. The solution was warmed to room temperature
slowly and was heated at reflux for 12 h. The mixture was cooled
to 0 °C and poured into a saturated solution of sodium potassium
tartrate (15 mL). After stirring for 1 h at room temperature, the
heterogeneous mixture was separated and the aqueous layer was
extracted with EtOAc (5ϫ15 mL). The combined organic layers
were washed with brine, dried (MgSO4), filtered through Celite and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel using a MeOH/EtOAc gradient sol-
vent system, which provided the title compound as an orange oil
(93% yield, 67.0 mg). Rf = 0.03 (10% MeOH in EtOAc). 1H NMR
(400 MHz, CDCl3): δ = 9.01 (br. s, 1 H), 7.51 (dd, J = 1.5, 7.0 Hz,
1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.09 (dt, J = 1.9, 7.6 Hz, 1 H), 7.04
(dt, J = 1.4, 7.3 Hz, 1 H), 6.23 (s, 1 H), 4.22 (br. s, 1 H), 2.96–2.90
(m, 1 H), 2.75–2.69 (m, 2 H), 2.67–2.62 (m, 2 H), 2.50 (d, J =
12.4 Hz, 1 H), 1.94 (ddd, J = 6.5, 10.2, 14.1 Hz, 1 H), 1.66 (ddd, J
= 6.7, 10.2, 14.1 Hz, 2 H), 1.55–1.25 (m, 6 H), 0.85 (t, J = 5.3 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.2, 136.0, 128.7,
120.7, 119.5, 119.3, 110.4, 98.9, 54.0, 46.5, 34.6, 33.8, 32.9, 28.2,
21.8, 21.4, 7.1 ppm. HRMS: m/z 256.1931 (calcd. for C17H24N2,
256.1939).
1-Benzyl-3-ethyl-3-{2-[3-(2-hydroxyethyl)-1H-indol-2-yl]ethyl}-
piperidin-2-one (19): Indole 7 (25.0 mg, 0.06 mmol) was dissolved
in 0.20 mL of methyl tert-butyl ether (MTBE) and cooled to
–25 °C. A solution of KH (9.6 mg, 0.24 mmol) in 0.50 mL of
MTBE was then added. InBr3 (21.0 mg, 0.06 mmol) and butylated
hydroxytoluene (1.00 mg, 0.005 mmol) were then added, followed
by ethylene oxide (45 µL, 0.9 mmol) as a solution in 0.30 mL of
MTBE. The flask was capped an the solution was held at 0 °C for
12 h. The solution was warmed to room temperature until the eth-
ylene oxide evaporated. The solution was poured into 10 mL of
water and the heterogeneous mixture was separated and the aque-
ous layer was extracted with EtOAc (5ϫ10 mL). The combined
organic layers were washed with brine, dried (MgSO4), filtered
through Celite and concentrated under reduced pressure. Purifica-
tion by flash chromatography on silica gel using EtOAc/hexanes
for elution provided the title compound as yellow oil (55% yield,
1
13.0 mg). Rf = 0.55 (100% EtOAc). H NMR (400 MHz, CDCl3):
δ = 8.59 (br. s, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.32–2.23 (m, 6 H),
7.11 (td, J = 7.5, 1.3 Hz, 1 H), 7.08 (td, J = 6.6, 1.2 Hz, 1 H), 4.68
(d, J = 14.0 Hz, 1 H), 4.55 (d, J = 14.0 Hz, 1 H), 3.83 (t, J =
6.4 Hz, 1 H), 3.29–3.21 (m, 2 H), 2.96 (td, J = 2.2, 6.4 Hz, 2 H),
2.92–2.85 (m, 1 H), 2.53 (ddd, J = 4.0, 10.0, 14.0 Hz, 1 H), 2.17
(ddd, J = 3.9, 10.0, 14.0 Hz, 1 H), 1.85–1.65 (m, 8 H), 0.89 (t, J =
7.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.1, 137.3,
135.5, 128.6, 127.9, 127.3, 121.1, 119.0, 117.9, 110.6, 106.5, 62.8,
50.7, 47.8, 45.8, 38.3, 31.6, 28.9, 27.7, 21.6, 19.5, 8.4 ppm. HRMS:
m/z 404.2474 (calcd. for C26H32N2O2, 404.2464).
Ethyl {3-Ethyl-3-[2-(1H-indol-2-yl)ethyl]piperidin-1-yl}acetate (18):
Amine 8 (109 mg, 0.42 mmol) was dissolved in MeCN (30 mL) and
then diisopropylethylamine (96 µL, 0.55 mmol) was added slowly
dropwise followed by ethyl bromoacetate (62 µL, 0.55). After 14 h,
the solution was poured into 15 mL of 1  HCl. The heterogeneous
mixture was separated and the aqueous layer was extracted with
EtOAc (5ϫ10 mL). The combined organic layers were washed with
brine, dried (MgSO4), filtered through Celite and concentrated un-
der reduced pressure. Purification by flash chromatography on sil-
ica gel using EtOAc/hexanes for elution provided the title com-
pound as a colourless oil (82% yield, 119 mg). Rf = 0.67 (10%
3-Ethyl-3-{2-[3-(2-hydroxyethyl)-1H-indol-2-yl]ethyl}piperidin-2-one
(10): The title compound was prepared from indole 19 using the
same procedure as the deprotection of compound 7 and isolated as
1
a colourless oil (91% yield). Rf = 0.19 (5% MeoH in EtOAc). H
1
MeOH in EtOAc). H NMR (400 MHz, CDCl3): δ = 8.79 (br. s, 1
NMR (400 MHz, CDCl3): δ = 8.85 (br. s, 1 H), 7.50 (d, J = 7.4 Hz,
1 H), 7.26–7.24 (m, 1 H), 7.10–7.02 (m, 2 H), 6.10 (br. s, 1 H), 3.84
(t, J = 6.4 Hz, 2 H), 3.24–3.20 (m, 2 H), 2.99–2.94 (m, 2 H), 2.83
(ddd, J = 5.9, 12.0, 14.0 Hz, 1 H), 2.49 (ddd, J = 2.3, 12.0, 16.0 Hz,
1 H), 2.42 (br. s, 1 H), 2.10–2.02 (m, 1 H), 1.80–1.68 (m, 5 H),
1.65–1.54 (m, 2 H), 0.86 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 177.2, 137.2, 135.5, 128.3, 120.9, 118.8,
117.9, 110.6, 106.6, 62.6, 45.1, 42.6, 38.2, 31.4, 28.7, 27.8, 21.4,
19.6, 8.3 ppm. HRMS: m/z 314.1985 (calcd. for C19H26N2O2,
314.1994).
H), 7.53 (d, J = 7.5 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.11 (td,
J = 7.4, 1.5 Hz, 1 H), 7.07 (td, J = 7.3, 1.2 Hz, 1 H), 7.25 (d, J =
1.2 Hz, 1 H), 4.26 (d, J = 8.0 Hz, 1 H), 4.22 (d, J = 8.0 Hz, 1 H),
3.17 (q, J = 16.0 Hz, 2 H), 2.74–2.64 (m, 3 H), 2.51 (d, J = 11.0 Hz,
1 H), 2.31–2.27 (m, 1 H), 2.18–2.11 (m, 1 H), 1.99 (d, J = 11.0 Hz,
1 H), 1.81–1.71 (m, 1 H), 1.68–1.56 (m, 2 H), 1.52–1.43 (m, 2 H),
1.31 (t, J = 7.1 Hz, 3 H), 1.28–1.18 (m, 2 H), 0.90 (t, J = 7.5 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.2, 140.9, 136.1,
128.8, 120.5, 119.5, 119.2, 110.4, 98.8, 62.0, 60.5, 60.0, 54.8, 35.9,
33.6, 33.1, 29.0, 22.1, 21.7, 14.2, 7.2 ppm. HRMS: m/z 342.2358
(calcd. for C21H30N2O2, 342.2307).
3-{2-[3-(2-Chloroethyl)-1H-indol-2-yl]ethyl}-3-ethylpiperidin-2-one
(11): Alcohol 10 (30 mg, 0.09 mmol) was dissolved in CH2Cl2
(1.0 mL) and cooled to 0 °C. Methanesulfonyl chloride (10 µL,
{3-Ethyl-3-[2-(1H-indol-2-yl)ethyl]piperidin-1-yl}acetic Acid (9): Es-
ter 18 (85 mg, 0.25 mmol) was dissolved in EtOH (5.0 mL) and 2 
Eur. J. Org. Chem. 2009, 1072–1077
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Bajtos, B. L. Pagenkopf
FULL PAPER
0.13) and then Et3N (40 µL, 028 mmol) were added dropwise. After
3 h at room temperature, the solution was poured into a saturated
solution of NaHCO3 (10 mL). The heterogeneous mixture was sep-
arated and the aqueous layer was extracted with EtOAc
(5ϫ10 mL). The combined organic layers were washed with brine,
dried (MgSO4), filtered through Celite and concentrated under re-
duced pressure. Purification by flash chromatography on silica gel
using EtOAc/hexanes for elution provided the title compound as
yellow oil (52% yield, 48.0 mg). Rf = 0.41 (5% MeOH in EtOAc).
Due to the instability of this compound, 13C/1H NMR and HRMS
were not obtained. TLC analysis was the primary means of identifi-
cation and it was used immediately.
(5ϫ15 mL). The combined organic layers were washed with brine,
dried (MgSO4), filtered through Celite and concentrated under re-
duced pressure. Purification by flash chromatography on silica gel
using EtOAc/hexanes for elution provided the title compound as
1
colourless oil (96% yield, 51.0 mg). Rf = 0.57 (100% EtOAc). H
NMR (400 MHz, CDCl3): δ = 8.70 (br. s, 1 H), 7.49 (d, J = 7.8 Hz,
1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.08 (td, J = 1.2, 7.5 Hz, 1 H), 7.02
(td, J = 1.1, 7.4 Hz, 1 H), 6.18 (s, 1 H), 4.24 (d, J = 13.3 Hz, 1 H),
4.18 (d, J = 12.0 Hz, 1 H), 4.13 (d, J = 12.0 Hz, 1 H), 3.69 (ddd,
J = 3.7, 13.1 Hz, 1 H), 3.18 (ddd, J = 3.5, 10.2, 13.8 Hz, 1 H), 2.77
(dt, J = 3.1, 12.0 Hz, 1 H), 2.70–2.62 (m, 2 H), 1.69–1.58 (m, 5 H),
1.53–1.36 (m, 3 H), 0.92 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.9, 140.3, 136.1, 128.6, 120.6, 119.5,
119.1, 110.6, 98.8, 50.3, 47.7, 41.1, 37.1, 34.5, 32.9, 28.5, 22.6, 22.0,
7.1 ppm. HRMS: m/z 332.1647 (calcd. for C19H25ClN2O,
332.1655).
3-{2-[3-(2-Bromoethyl)-1H-indol-2-yl]ethyl}-3-ethylpiperidin-2-one
(12): CBr4 (68 mg, 0.2 mmol) and PPh3 (52.0 mg, 0.2 mmol) were
added to a solution of alcohol 10 (43 mg, 0.13 mmol) in CH2Cl2
(0.60 mL). After 3 h, the solution was concentrated under reduced
pressure. The residue was purification by flash chromatography on
silica gel using EtOAc/hexanes for elution. The semi-pure product
was triturated with cyclohexane to provide the title compound as
colourless oil (95 % yield, 48.0 mg). Rf = 0.29 (5 % MeOH in
EtOAc). Due to the instability of this compound, 13C/1H NMR
and HRMS were not obtained. TLC analysis was the primary me-
ans of identification and it was used immediately.
(؎)-Quebrachamine (1): Lactam 17 (9.0 mg, 0.03 mmol) in THF
(2.0 mL) was added to a cooled (0 °C) suspension of LiAlH4
(6.0 mg, 0.15 mmol) in THF (1.0 mL). The solution was warmed
to room temperature slowly and heated to refluxe for 3 h. The mix-
ture was cooled to 0 °C and poured into a saturated solution of
sodium potassium tartrate (15 mL). After 1 h at room temperature,
the heterogeneous mixture was separated and the aqueous layer
was extracted with EtOAc (5ϫ10 mL). The combined organic lay-
ers were washed with brine, dried (MgSO4), filtered through Celite
and concentrated under reduced pressure. Purification by flash
chromatography on silica gel using EtOAc/hexanes for elution pro-
vided the title compound as a white solid (93% yield, 8.0 mg). Rf
3-Ethyl-3-{3-[(E)-2-(1-methylcyclopropyl)phenylimino]propyl}-
piperidin-2-one (13): A solution of PPh3 (25.0 mg, 0.095 mmol) and
diisopropyl azodicarboxylate (19.0 mg, 0.09 mmol) in 2.0 mL of
THF was maintained at room temperature for 30 min and then
cooled to 0 °C. A solution of indole 10 (20 mg, 0.063 mmol) in
THF (0.75 mL) was added and stirred for 12 h at room tempera-
ture. The heterogeneous mixture was separated and the aqueous
layer was extracted with EtOAc (5ϫ10 mL). The combined organic
layers were washed with brine, dried (MgSO4), filtered through Ce-
lite and concentrated under reduced pressure. Purification by flash
chromatography on silica gel using EtOAc/hexanes for elution pro-
vided the title compound as yellow oil (50–56% yield). Rf = 0.18
1
= 0.39 (100% EtOAc). H NMR (400 MHz, CDCl3): δ = 7.69 (br.
s, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.26 (dd, J = 7.0, 1.5 Hz, 1 H),
7.08 (td, J = 7.0, 1.5 Hz, 1 H), 7.05 (td, J = 7.0, 1.5 Hz, 1 H), 3.24
(br. d, J = 11.7 Hz, 1 H), 2.92 (ddd, J = 4.4, 11.4, 16.0 Hz, 1 H),
2.83 (ddd, J = 2.9, 4.4, 15.0 Hz, 1 H), 2.75–2.64 (m, 2 H), 2.46–
2.44 (m, 1 H), 2.41 (ddd, J = 2.9, 4.4, 11.4 Hz, 1 H), 2.32 (td, J =
11.5, 4.4 Hz, 1 H), 2.23 (td, J = 11.3, 3.2 Hz, 1 H), 1.91 (dd, J =
7.0, 14.0 Hz, 1 H), 1.62–1.54 (m, 2 H), 1.49 (d, J = 11.7 Hz, 1 H),
1.32–1.27 (m, 2 H), 1.23–1.20 (m, 1 H), 1.17–1.08 (m, 2 H), 0.84
(t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.8,
134.7, 128.9, 120.1, 118.6, 117.3, 109.9, 108.7, 56.7, 55.0, 53.2, 37.1,
34.7, 33.4, 32.0, 22.6, 22.4, 21.9, 7.7 ppm. HRMS: m/z 282.2085
(calcd. for C19H26N2, 282.2096).
1
(5% MeOH in EtOAc). H NMR (400 MHz, CDCl3): δ = 7.65 (d,
J = 7.4 Hz, 1 H), 7.30 (t, J = 7.7 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1
H), 6.95 (d, J = 6.8 Hz, 1 H), 5.61 (br. s, 1 H), 3.29 (dt, J = 5.8,
1.9 Hz, 2 H), 2.48 (ddd, J = 5.9, 11.2, 15.1 Hz, 1 H), 2.25 (ddd, J
= 5.4, 11.0, 16.0 Hz, 1 H), 2.07–2.01 (m, 2 H), 1.97–1.93 (m, 1 H),
1.90–1.68 (m, 7 H), 1.63–1.54 (m, 2 H), 0.89 (t, J = 7.5 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 177.1, 137.0, 135.3, 127.8,
127.1, 119.1, 117.5, 110.7, 107.0, 45.3, 44.7, 42.7, 37.8, 31.2, 28.9,
28.2, 21.4, 19.5, 8.4 ppm.
Supporting Information (see also the footnote on the first page of
this article): All spectroscopic data and general experimental pro-
cedures.
The title compound can also be prepared by adding a solution of
indole 11 or 12 (0.05 mmol) in THF (8.0 mL) to a slurry of NaH
in 1.6 mL of THF. The solution was heated to reflux for 30 min,
cooled and then poured into 10 mL of water. The heterogeneous
mixture was separated and the aqueous layer was extracted with
EtOAc (5ϫ10 mL). The combined organic layers were washed with
brine, dried (MgSO4), filtered through Celite and concentrated un-
der reduced pressure. Purification by flash chromatography on sil-
ica gel using EtOAc/hexanes for elution provided the title com-
pound as yellow oil.
Acknowledgments
We thank Natural Sciences and Engineering Research Council of
Canada (NSERC), the donors of the American Chemical Society
Petroleum Research fund, and the University of Western Ontario
for financial assistance. We also thank Michael Johansen and other
members of the Kerr research group for helpful discussions as well
as Dr. Mark Workentin for providing a Rayonet Photochemical
Reactor.
2-Chloro-1-{3-ethyl-3-[2-(1H-indol-2-yl)ethyl]piperidin-1-yl}-
ethanone (14): A tin(IV) chloride solution (0.34 mL, 0.34 mmol, 1 
in CH2Cl2) was added slowly dropwise to a solution of amine 8
(40 mg, 0.16 mmol) in CH2Cl2 (8.0 mL) at 0 °C and stirred for
10 min. Chloroacetyl chloride (12 µL, 0.16 mmol) and 0.80 mL of
EtNO2 were then added. After 12 h at room temperature, the solu-
tion was poured into 15 mL of water and the heterogeneous mix-
ture was separated and the aqueous layer was extracted with EtOAc
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Published Online: January 1, 2009
Eur. J. Org. Chem. 2009, 1072–1077
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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