Formal Synthesis of Bioactive Indole Alkaloids Eburnamonine, Eburnaminol, and Vindeburnol

Article abstract of DOI:10.1055/s-0036-1588386

Starting from (±)-3-acetoxyglutarimide, diastereoselective formal synthesis of indole alkaloids (±)-eburnamonine, (±)-eburnaminol, and (±)-vindeburnol have been demonstrated via a common intermediate (±)-1-hydroxy-12-tosyl-2,3,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-4(1H)-one in very good overall yields. The acetoxy group from (±)-3-acetoxyglutarimide was first used to induce the diastereoselectivity and also as a latent source of ketone carbonyl group. The stereoselective eliminations, reductions, and intramolecular cyclizations were the involved key steps.

Full text of DOI:10.1055/s-0036-1588386

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
P. Mondal, N. P. Argade
Paper
Synthesis
Formal Synthesis of Bioactive Indole Alkaloids Eburnamonine,
Eburnaminol, and Vindeburnol
Pravat Mondal
H
H
1 step
N
5 steps
(28%)
N
N
O
Narshinha P. Argade*
N
H
N
N
(known)
Ts
HO
20
O
Division of Organic Chemistry, National Chemical
Laboratory (CSIR), Pune 411 008, India
np.argade@ncl.res.in
CO2Me
( )-alcohol
CO2Me
( )-eburnamonine
4+1 steps
(45%/62%)
6 steps
(51%)
H
H
3 steps
N
D
N
N
N
E
N
(known)
N
H
HO
HO
AcO
H
OH
( )-vindeburnol
(synthetic)
( )-eburnaminol
Received: 19.10.2016
Accepted after revision: 04.12.2016
Published online: 13.01.2017
interesting indole-based target compounds eburnamonine
(Scheme 1), eburnaminol (Scheme 2), and vindeburnol
(Scheme 3).
DOI: 10.1055/s-0036-1588386; Art ID: ss-2016-n0736-op
Abstract Starting from (±)-3-acetoxyglutarimide, diastereoselective
formal synthesis of indole alkaloids (±)-eburnamonine, (±)-eburnami-
nol, and (±)-vindeburnol have been demonstrated via a common inter-
mediate (±)-1-hydroxy-12-tosyl-2,3,6,7,12,12b-hexahydroindolo[2,3-
a]quinolizin-4(1H)-one in very good overall yields. The acetoxy group
from (±)-3-acetoxyglutarimide was first used to induce the diastereose-
lectivity and also as a latent source of ketone carbonyl group. The ste-
reoselective eliminations, reductions, and intramolecular cyclizations
were the involved key steps.
H
H
N
N
N
N
20
HO
(–)-eburnaminol
O
OH
(+)-eburnamonine
H
H
A
B
N
N
N
N
3
E
D
14
20
Key words hexahydroindoloquinolizinone, elimination, reduction, cy-
clizations, eburnamonine, eburnaminol, vindeburnol
O
HO
H
H
H
(–)-vindeburnol
(synthetic)
(+)-tacamonine
Indole alkaloids are an important class of compounds
with a broad range of biological activities, and some of
them are in clinical use. Hence they are the target com-
pounds of interest for a large number of synthetic organic
chemists (Figure 1).1 The (+)-eburnamonine from Hunteria
eburnean is a eumetabolic vasoregulator drug and prolyl
oligopeptidase inhibitor; IC50 = 8 μM.2a–d Eburnaminol from
Kopsia larutensis belong to the eburnan class of indole alka-
loids having an angular pentacyclic ring system with cis-ge-
ometry containing a quaternary carbon.2e Several elegant
diastereoselective and enantioselective total syntheses of
the above specified indole alkaloids have been reported in
the earlier and contemporary literature.3–6 (–)-Vindeburnol
is a potent central vasodilator, which also provides benefit
for severe depression.7a–e In continuation of our studies on
bioactive natural products based on cyclic anhydrides,8 we
herein report the application of well designed (±)-1-hydroxy-
12-tosyl-2,3,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-
4(1H)-one (2) from 3-acetoxyglutarimide (±)-1 to accom-
plish the concise diastereoselective synthesis of structurally
Figure 1 Bioactive indole alkaloids
Preparation of enantiomerically pure starting materials
(+)-2 and (–)-2 was not feasible due to the inherent acidity
of the methine proton in the corresponding ketone starting
material.9a,b The racemic synthesis of eburnan class of alka-
loid eburnamonine was intended from our common pre-
cursor (±)-2, which was obtained from 3-acetoxyglutarim-
ide (±)-19c,d using known procedures in five steps in 38%
overall yield.9a,b The common precursor (±)-2 on treatment
with magnesium and methanol in the presence of benzene
as a cosolvent (MeOH–C6H6, 1:1)10 underwent a smooth N-
detosylation and supplied a separable mixture of an in situ
cyclized and uncyclized products (±)-3 and (±)-4, respec-
tively, in 88% combined yield in 2 hours (3/4 = 1:9) (Scheme
1). As expected, the lactamization process of (±)-4 to (±)-3
with a cis-ring fusion was slow due to the 1,2-equatorial-
axial orientations of cyclizing groups (Figure 2). Hence it
was feasible to obtain the desired (±)-4 as the major prod-
uct even after arresting the reaction on complete consump-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
P. Mondal, N. P. Argade
Paper
Synthesis
O
H
5 steps (38%)
OAc
H
Mg, MeOH, benzene
H
N
N
O
N
O
N
O
N
N
(
(ref. 9a,b)
N
NH4Cl, 25 °C, 2 h
(88%, 3/4 = 1:9)
H
Ts
HO
O
HO
N
O
Ts
OH
CO2Me
CO2Me
( )-1
)-3
( )-2
(
)-4
H
N
(i) Lawesson's reagent
toluene, reflux, 1 h
(for 4) SOCl2, py, 0 to 25 °C
DBU, CH2Cl2, –60 °C, 1 h
N
O
N
S
O
N
H
N
H
N
30 min (89%)
(73%)
S
O
O
CO2Me
CO2Me
CO2Me
( )-5
( )-6
[( )-7]
O
1 step (known)3b
N
O
H
2 steps (known)6
H
N
(ii) Raney-Ni, THF, 25 °C, 6 h (55%)
N
N
H
N
N
O
HO
CO2Me
( )-8
( )-melohenine B (10)
( )-eburnamonine (9)
Scheme 1 Formal synthesis of (±)-eburnamonine and (±)-melohenine B
tion of starting material. The major product (±)-4 on treat-
ment with thionyl chloride and pyridine directly provided
the corresponding isolable cyclic sulfuramidite (±)-5 in 89%
yield.11 An increase in reaction time with a hope to directly
obtain the desired elimination product (±)-6 resulted in ex-
cessive decomposition of the formed sulfuramidite (±)-5.
The eliminative cleavage of sulfuramidite (±)-5 to the corre-
sponding α,β-unsaturated ester (±)-6 was both base and
temperature sensitive. In the presence of DBU, the com-
pound 5 was prone to transform back into the starting ma-
terial (±)-4 along with partial decomposition at and above
0 °C. Nonetheless, the compound (±)-5 on treatment with
DBU in dichloromethane at –60 °C stereoselectively formed
the thermodynamically more stable desired E-isomer (±)-6
in 73% yield with the release of sulfur dioxide as a leaving
group (Figure 3).
The 2 D NMR studies (see Supporting Information) indi-
cated that the vinylic proton has strong NOE interactions
with the proximal proton on indole nitrogen. The lactam
(±)-6 on reaction with the Lawesson reagent12 was trans-
formed into the expected intermediate thiolactam (±)-7 (by
TLC), which on an immediate column chromatographic fil-
tration followed by Raney nickel mediated desulfurization
reaction delivered the α,β-unsaturated ester (±)-8 in 55%
yield over two steps. Starting from the corresponding ethyl
ester, the one-step synthesis of (±)-eburnamonine (9) via
the stereoselective Michael addition of a cuprate from the
less hindered α-face in very good yield is known.3b The
two-step transformation of (±)-9 to (±)-melohenine B (10)
through an oxidative ring expansion is also known.6
The formal synthesis of yet another two interesting nat-
ural products (±)-ebumaminol (21) and (±)-larutensine (22)
was planned from the precursor (±)-2, but this time using
an intermediate 20, which does not contain a tetrahedral
stereogenic center (Scheme 2). The initially studied Horner–
Wadsworth–Emmons (HWE) reaction on ketone (±)-11 to
directly form the corresponding α,β-unsaturated ester was
not successful due to steric bulk of proximal N-tosyl moiety.
The above reaction instead delivered the corresponding rel-
atively more stable air-oxidized product (±)-12 in 62% yield
under refluxing conditions. The product (±)-12 was formed
under inert conditions and proved the higher propensity of
(±)-11 towards the facile air-oxidation process (Figure 4).
The tetrabutylammonium fluoride-induced detosylation of
compound 11 also resulted in product 12. In the above-
mentioned reactions, N-detosylation, introduction of an an-
gular hydroxyl group, and oxidative dehydrogenation reac-
tion to form the doubly conjugated C=C bond took place in
one-pot to provide (±)-12. The alternatively performed p-
O
R
H
N
O
N
slow cyclization
N
N
H
H
OH
O
OH
(
)-4: R = CH2CO2Me
(
)-3: cis-ring fusion
1,2-equatorial–axial orientation
Figure 2 Lactamization leading to cis-ring fusion
B
H
H
CO2Me
O
N
O
anti-elimination
N
N
H
N
H
NOE
( )-6
H
O
S
( )-5
CO2Me
O
Figure 3 Proposed mechanism for anti-elimination
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
P. Mondal, N. P. Argade
Paper
Synthesis
TSA-mediated dehydration of β-hydroxy ester (±)-2 also re-
sulted in the corresponding unexpected spiro β-lactone (±)-
13 in 85% yield. However, the thionyl chloride induced de-
hydration of tertiary alcohol (±)-2 exclusively provided the
thermodynamically more stable α,β-unsaturated ester (±)-
(E)-15 in 81% yield. An attempted naphthalene radical in-
duced N-detosylation of product (±)-(E)-15 caused the
deprotection, but with a ring expansion via the cleavage of
more reactive internal carbon–nitrogen single bond to form
a 10-membered macrolactam (±)-14 in 56% yield.13 Treat-
ment of compound (±)-15 with magnesium and methanol
in the presence of benzene as a cosolvent (MeOH–C6H6, 1:1)
or on treatment with sodium amalgam in methanol deliv-
ered the planned N-detosylation product. However, it was
accompanied with a nonstereoselective reduction of α,β-
unsaturated C–C double bond resulting in ~1:1 mixture of
oxidative dehydrogenation] delivered the known product
20 in 89% yield via formation of the corresponding iminium
intermediate followed by an instantaneous intramolecular
prototropic shift. We were unable to purify compound 20
by silica gel column chromatography for stability issues.
Lounasmaa and Karvinen have reported only the selected
1
signals of IR, H NMR, and mass spectra for compound 20.
The obtained spectral data of as such isolated compound 20
were in complete agreement with the assigned structure
and the reported data.4a Starting from compound 20, a
three-step stereoselective synthesis of (±)-eburnaminol
(21) through enamine alkylation followed by a reductive in-
tramolecular cyclization and the one-step transformation
of (±)-20 to (±)-larutensine (22) via an intramolecular dehy-
drative cyclization are known.4a
1
the corresponding diastereomers of 16 (by H NMR analy-
N
O
N
O
sis). Finally, the catalytic hydrogenation of the C=C bond in
the α,β-unsaturated ester (±)-(E)-15 using H2/PtO2 was ste-
reoselective and exclusively formed the product (±)-16 in
98% yield. Plausibly three dimensional features of com-
pound (±)-(E)-15 dictate the site for adsorption of π-lobes
on platinum catalyst resulting in a relative trans-geometry
of the adjacent methine protons. The precursor (±)-16 on
reaction with red-Al directly furnished the desired (±)-ami-
no alcohol 17, but only in 25 to 30% yield. Alane reduction
of (±)-16 resulted into the desired product (±)-amino alco-
hol 17 in 84% yield. Both the ester to alcohol and lactam to
amine reductions took place in one-pot, while the N-tosyl
group remained intact. The coupling constant (J = 8 Hz) for
N
N
H
Ts
OH
O
O
11
12
H
N
O
HN
O
N
N
H
Ts
O
CO2Me
14
(
)-13
O
Figure 4 Keto-lactam and some of the exclusively formed unexpected
products
1
angular methine proton in H NMR also confirmed the as-
Finally the advanced precursor (±)-16 on reaction with
magnesium in methanol plus benzene underwent a smooth
N-detosylation followed by a concomitant intramolecular
cyclization resulting in lactam (±)-23 in 83% yield (Scheme
3). The lactamization process of (±)-16 to (±)-23 with trans-
ring fusion was very fast due to the 1,2-equatorial-equato-
signed trans-stereochemistry of an adjacent methine pro-
tons in compound (±)-17. The N-detosylation of (±)-17 fol-
lowed by selective O-acylation of the formed alcohol (±)-18
resulted in product (±)-19 in 85% yield over two steps. The
product (±)-19 on Fujii oxidation14 [Hg(OAc)2/EDTA·2Na·2H2O;
SOCl2, py
H2, PtO2, EtOH, THF
H
H
N
O
N
O
N
O
N
N
0 to 25 °C, 3 h (81%)
N
25 °C, 12 h (98%)
Ts
HO
Ts
Ts
MeO2C
H
( )-15
( )-16
( )-2
CO2Me
CO2Me
H
H
AlH3, THF
Mg, MeOH–benzene
H
H
Ac2O, py, 25 °C
H
H
N
N
N
N
N
N
25 °C, 2 h (84%)
NH4Cl, 25 °C, 4 h
(97%)
16 h (88%)
H
H
Ts
HO
AcO
HO
( )-17
( )-18
( )-19
Hg(OAc)2
1 step (known)4a
3 steps (known)4a
EDTA.2Na.2H2O
H
H
N
N
N
N
N
H
N
EtOH, H2O
80 °C, 2 h (89%)
HO
( )-eburnaminol (21)
O
AcO
OH
20
( )-larutensine (22)
Scheme 2 Formal synthesis of (±)-eburnaminol and (±)-larutensine
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
P. Mondal, N. P. Argade
Paper
Synthesis
rial orientations of the cyclizing groups (Figure 5) and
hence it was not feasible to stop the reaction at an interme-
diate stage as described earlier for the corresponding cis-
ring fusion system shown in Figure 2. The lactam (±)-23 on
alane reduction supplied the kinetically controlled product
(±)-isovindeburnol (24) in 68% yield. Though the (±)-isovin-
deburnol (24) is known in the literature;7c its analytical and
spectral data have not been reported. The obtained spectral
data for (±)-isovindeburnol (24) was in complete agree-
ment with the assigned structure. Acid-catalyzed epi-
merzation at the gem-aminohydrin center of (±)-isovinde-
burnol (24) to deliver the thermodynamically more stable
(±)-vindeburnol (25) via the dehydration-rehydration path-
way is well known in the literature.7c,8c
were recorded on an FT-IR spectrometer. Column chromatographic
separations were carried out on silica gel (60–120 and 230–400
mesh). Commercially available PtO2, Mg foils, DBU, Lawesson’s re-
agent, AlCl3, LiAlH4, Ac2O, and Hg(OAc)2 were used.
(±)-Methyl 2-(1-Hydroxy-4-oxo-1,2,3,4,6,7,12,12b-octahydroindo-
lo[2,3-a]quinolizin-1-yl)acetate (4)
To stirred solution of N-tosyl-protected β-hydroxy ester (±)-2 (400
mg, 0.83 mmol) in MeOH–benzene mixture (14 mL, 1:1) were se-
quentially added activated Mg turnings (199 mg, 8.30 mmol) and
NH4Cl (444 mg, 8.30 mmol) at 25 °C under an argon atmosphere. The
reaction mixture was stirred for 2 h and the reaction was quenched
with sat. aq NH4Cl (4 mL) and aq 1 N HCl (4 mL). Solvent was removed
in vacuo and the residue was dissolved in EtOAc (40 mL). The organic
layer was washed with brine (20 mL) and dried (Na2SO4). Concentra-
tion of organic layer in vacuo, followed by silica gel column chromato-
graphic purification of the resulting residue using EtOAc–PE (8:2) as
an eluent afforded the major uncyclized compound (±)-4 as a white
solid (215 mg, 79%) and then the minor cyclized compound (±)-3 as a
colorless gummy solid (22 mg, 9%).
Mg, MeOH–benzene
H
H
N
O
N
O
N
N
NH4Cl, 25 °C
2 h (83%)
Ts
H
O
H
( )-16
CO2Me
( )-23
Major Product (±)-4
AlH3, THF, 2 h
25 °C (68%)
Mp 202–204 °C.
IR (neat): 3376, 1732, 1603 cm–1
.
H
H
1 step (known)7c
H
H
1H NMR (CDCl3, 400 MHz): δ = 2.10–2.20 (m, 3 H), 2.40–2.55 (m, 1 H),
2.54 (d, J = 16 Hz, 1 H), 2.64–2.89 (m, 4 H), 3.66 (s, 3 H), 4.71 (s, 1 H),
4.82 (br s, 1 H), 5.07–5.13 (m, 1 H), 7.12 (dt, J = 8, 2 Hz, 1 H), 7.20 (dt,
J = 8, 2 Hz, 1 H), 7.37 (d, J = 8 Hz, 1 H), 7.52 (d, J = 8 Hz, 1 H), 8.90 (br s,
1 H).
N
N
N
N
HO
HO
( )-isovindeburnol (24)
( )-vindeburnol (25)
Scheme 3 Diastereoselective formal synthesis of (±)-vindeburnol
13C NMR (CDCl3, 100 MHz): δ = 20.7, 29.9, 31.9, 35.2, 40.1, 52.2, 61.2,
72.4, 111.2, 111.3, 118.3, 119.5, 122.3, 126.1, 129.5, 136.1, 168.3,
173.5.
O
MS (ESI): m/z = 351 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H20N2O4Na: 351.1315; found:
H
H
H
fast cyclization
N
N
O
N
N
H
H
351.1310.
O
MeO2C
(
)-16: trans-ring fusion
unisolable intermediate
1,2-equatorial–equatorial orientation
(±)-13a-Hydroxy-1,2,5,6,13,13a-hexahydro-3H-indolo[3,2,1-
de]pyrido[3,2,1-ij][1,5]naphthyridine-3,12(41H)-dione (Minor
Product 3)
Figure 5 Lactamization leading to trans-ring fusion
IR (CHCl3): 3446, 1719, 1634 cm–1
.
1H NMR (DMSO-d6, 400 MHz): δ = 1.50 (dt, J = 16, 4 Hz, 1 H), 1.72 (dd,
J = 12, 4 Hz, 1 H), 2.07 (dd, J = 16, 4 Hz, 1 H), 2.55–2.83 (m, 4 H), 2.76
(d, J = 16 Hz, 1 H), 3.04 (dt, J = 12, 8 Hz, 1 H), 4.71 (dd, J = 12, 8 Hz, 1
H), 4.78 (br s, 1 H), 5.88 (s, 1 H), 7.31 (quint, J = 8 Hz, 2 H), 7.49 (d, J =
8 Hz, 1 H), 8.20 (d, J = 8 Hz, 1 H).
13C NMR (DMSO-d6, 100 MHz): δ = 19.8, 28.2, 29.4, 41.2, 46.5, 59.9,
68.2, 114.2, 115.4, 118.7, 124.1, 124.7, 129.7, 133.2, 133.5, 165.9,
168.6.
In summary, we have demonstrated a facile diastereose-
lective formal synthesis of indole alkaloids via stepwise use
of three different oxygen functions in (±)-3-acetoxyglu-
tarimide in a chemo-, regio-, and stereoselective pathway.
We feel that our present approach is general and will be
useful to synthesize focused mini-library of indole-based
structurally interesting and biologically useful architec-
tures for SAR studies.
MS (ESI): m/z = 297 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O3: 297.1234; found:
297.1231.
Melting points are uncorrected. The 1H NMR spectra were recorded
on 200 MHz NMR, 400 MHz NMR, and 500 MHz NMR spectrometers
using TMS as an internal standard. The 13C NMR spectra were record-
ed on 200 NMR spectrometer (50 MHz), 400 NMR spectrometer (100
MHz), and 500 NMR spectrometer (125 MHz). Mass spectra were tak-
en on MS-TOF mass spectrometer. HRMS (ESI) were taken on Orbitrap
(quadrupole plus ion trap) and TOF mass analyzer. The IR spectra
(±)-Methyl (5-Oxido-1-oxo-2,3,10,11-tetrahydro-1H-4-oxa-5-thia-
5a,11a-diazabenzo[cd] fluoranthen-3a(3a1H)-yl)acetate (5)
To a stirred solution of (±)-4 (150 mg, 0.46 mmol) in pyridine (6 mL)
was added SOCl2 (0.20 mL, 2.76 mmol) at 0 °C. Ice bath was removed
and the reaction mixture was stirred at 25 °C for 30 min. It was then
poured into a mixture of EtOAc (10 mL) and crushed ice. The residue
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
P. Mondal, N. P. Argade
Paper
Synthesis
was extracted with EtOAc (3 × 15 mL) and the combined organic lay-
ers were washed with brine (25 mL) and dried (Na2SO4). Concentra-
tion of organic layer in vacuo, followed by silica gel column chromato-
graphic purification of the resulting residue using EtOAc–PE (6:4) as
an eluent afforded the cyclic sulfuramidite (±)-5 as a yellowish white
solid (152 mg, 89%); mp 148–150 °C.
chromatographic purification of the resulting residue using EtOAc–PE
(7:3) as an eluent yielded conjugated ester (±)-8 as a brownish yellow
gum (5 mg, 55%).
IR (CHCl3): 3275, 1706, 1645 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 1.75–1.95 (m, 2 H), 2.70–2.82 (m, 2 H),
2.90 (br s, 1 H), 2.95–3.12 (m, 4 H), 3.25–3.35 (m, 1 H), 3.73 (s, 3 H),
4.62 (s, 1 H), 5.89 (s, 1 H), 7.13 (t, J = 10 Hz, 1 H), 7.19 (t, J = 10 Hz, 1
H), 7.34 (d, J = 10 Hz, 1 H), 7.52 (d, J = 10 Hz, 1 H), 7.81 (br s, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 18.7, 25.4, 26.6, 49.9, 50.4, 51.3, 63.0,
108.8, 111.1, 116.9, 118.4, 119.7, 122.1, 127.1, 135.9, 166.6.
IR (neat): 1731, 1649 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.06 (d, J = 16 Hz, 1 H), 2.35 (q, J = 8 Hz,
1 H), 2.60–2.95 (m, 6 H), 3.03 (dt, J = 12, 4 Hz, 1 H), 3.69 (s, 3 H), 4.89
(dd, J = 12, 4 Hz, 1 H), 5.14 (s, 1 H), 7.30–7.45 (m, 2 H), 7.57 (d, J = 8 Hz,
1 H), 7.69 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 20.2, 29.8, 30.6, 34.3, 37.8, 52.4, 56.3,
84.4, 112.6, 115.0, 119.5, 123.7, 124.7, 128.6, 129.0, 137.8, 168.1,
168.4.
MS (ESI): m/z = 297 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2O2: 297.1598; found:
297.1589.
MS (ESI): m/z = 397 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18N2O5SNa: 397.0829; found:
(±)-12b-Hydroxy-6,7,12,12b-tetrahydroindolo[2,3-a]quinolizine-
1,4-dione (12)
397.0826.
To a stirred solution of ketone (±)-11 (50 mg, 0.12 mmol) in THF (2
mL) at 25 °C was added dropwise Bu4NF (1.0 M in THF, 0.18 mL, 0.18
mmol) and the reaction mixture was stirred for 3 h. The reaction was
quenched with sat. aq NH4Cl (2 mL) and the solvent was removed in
vacuo. The residue was dissolved in EtOAc (25 mL) and the organic
layer was washed with brine (15 mL), and dried (Na2SO4). Concentra-
tion of organic layer in vacuo, followed by silica gel column chromato-
graphic purification of the resulting residue using PE–EtOAc (6:4) as
an eluent afforded the oxidized compound (±)-12 as a yellow solid (19
mg, 58%); mp 175–177 °C.
(±)-Methyl (E)-2-(4-Oxo-3,4,6,7,12,12b-Hexahydroindolo[2,3-
a]quinolizin-1(2H)-ylidene)acetate (6)
To a stirred solution of compound (±)-5 (50 mg, 0.13 mmol) in CH2Cl2
(4 mL) was added DBU (0.03 mL, 0.20 mmol) at –60 °C under an argon
atmosphere. The reaction mixture was stirred at the same tempera-
ture for 1 h. The reaction was quenched with sat. aq NH4Cl (2 mL) and
the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic layers were washed with H2O (15 mL) and brine (15 mL), and
dried (Na2SO4). Concentration of the dried organic layer in vacuo fol-
lowed by the silica gel column chromatographic purification of the
resulting residue using PE–EtOAc (1:1) as an eluent yielded the conju-
gated ester (±)-6 as a brownish yellow solid (30 mg, 73%); mp 171–
173 °C.
IR (neat): 3284, 1724, 1676 cm–1
.
1H NMR (DMSO-d6, 400 MHz): δ = 2.05–2.18 (m, 1 H), 2.40–2.55 (m, 1
H), 2.58–2.72 (m, 1 H), 3.03–3.20 (m, 1 H), 6.70 (d, J = 12 Hz, 1 H), 6.82
(d, J = 12 Hz, 1 H), 6.88 (s, 1 H, D2O exchangeable), 7.16 (t, J = 8 Hz, 1
H), 7.37 (t, J = 8 Hz, 1 H), 7.47 (d, J = 8 Hz, 1 H), 7.96 (d, J = 8 Hz, 1 H),
11.96 (s, 1 H, D2O exchangeable).
IR (neat): 3272, 1709, 1625 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.32 (dt, J = 12, 4 Hz, 1 H), 2.46 (dt, J =
16, 4 Hz, 1 H), 2.60–2.70 (m, 1 H), 2.75 (d, J = 12 Hz, 1 H), 2.90–3.06
(m, 2 H), 3.80 (s, 3 H), 3.80–3.85 (m, 1 H), 5.03 (q, J = 8 Hz, 1 H), 5.31
(s, 1 H), 6.14 (s, 1 H), 7.13 (t, J = 8 Hz, 1 H), 7.19 (t, J = 8 Hz, 1 H), 7.32
(d, J = 8 Hz, 1 H), 7.50 (d, J = 8 Hz, 1 H), 7.96 (s, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 20.7, 23.0, 32.4, 41.4, 51.7, 61.1, 110.9,
111.2, 117.1, 118.5, 120.0, 122.6, 127.4, 129.4, 135.8, 153.1, 165.8,
168.9.
13C NMR (DMSO-d6, 100 MHz): δ = 27.7, 28.1, 90.0, 104.5, 112.5,
119.4, 119.9, 120.3, 120.8, 125.2, 126.6, 130.2, 137.6, 174.6, 180.8.
MS (ESI): m/z = 269 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2O3: 269.0921; found:
269.0915.
(±)-12-Tosyl-2,3,6,7,12,12b-hexahydro-4H-spiro[indolo[2,3-
a]quinolizine-1,2′-oxetane]-4,4′-dione (13)
MS (ESI): m/z = 311 [M + H]+.
To a stirred solution of (±)-2 (20 mg, 0.04 mmol) in anhyd toluene (3
mL) was added anhyd p-TSA (8 mg, 0.05 mmol) at 25 °C and the reac-
tion mixture was refluxed for 4.5 h. Toluene was removed in vacuo
and the residue was dissolved in EtOAc (15 mL). The organic layer was
washed with sat. aq NaHCO3 (10 mL) and brine (10 mL), and dried
(Na2SO4). Concentration of organic layer in vacuo, followed by silica
gel column chromatographic purification of the resulting residue us-
ing EtOAc–PE (6:4) as an eluent afforded the spirolactone (±)-13 as a
gummy solid (16 mg, 85%).
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O3: 311.1390; found:
311.1386.
(±)-Methyl (E)-2-(3,4,6,7,12,12b-Hexahydroindolo[2,3-a]quinoliz-
in-1(2H)-ylidene)acetate (8)
To a stirred solution of compound (±)-6 (10 mg, 0.03 mmol) in anhyd
toluene was added Lawesson’s reagent (12 mg, 0.03 mmol) at 25 °C
under an argon atmosphere. The reaction mixture was refluxed for 1
h and cooled to 25 °C. Toluene was removed in vacuo and the ob-
tained residue was quickly purified by silica gel (230–400 mesh) col-
umn chromatography by using PE–EtOAc (6:4) to provide the thiolac-
tam (±)-7 (8 mg, 0.02 mmol), which was immediately used in the next
step. A solution of (±)-7 in anhyd THF (1 mL) was added dropwise to a
stirred solution of freshly prepared Raney nickel (100 mg) suspension
in anhyd THF (2 mL) at 25 °C. The reaction mixture was vigorously
stirred for 6 h at 25 °C under 1 atmosphere of H2 pressure and filtered
through a pad of Celite by washing with EtOAc (15 mL). Concentration
of filtrate under vacuo followed by silica gel (230–400 mesh) column
IR (neat): 1783, 1698 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 2.27 (s, 3 H), 2.30–2.80 (m, 6 H), 2.84
(d, J = 16 Hz, 1 H), 2.95–3.20 (m, 1 H), 3.35–3.55 (m, 1 H), 4.45–4.65
(m, 1 H), 5.59 (s, 1 H), 7.05 (d, J = 8 Hz, 2 H), 7.15–7.45 (m, 5 H), 8.08
(d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 21.5, 22.5, 28.1, 28.8, 37.2, 45.7, 63.7,
89.1, 117.3, 119.1, 125.4, 126.1, 126.8, 128.6, 129.2, 129.3, 130.9,
131.3, 138.7, 145.3, 170.1, 175.2.
MS (ESI): m/z = 473 [M + Na]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
P. Mondal, N. P. Argade
Paper
Synthesis
HRMS (ESI): m/z [M + Na]+ calcd for C24H22N2O5SNa: 473.1142; found:
(±)-Methyl 4-Oxo-12-tosyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-
473.1145.
a]quinolizin-1-yl)acetate (16)
To a stirred solution of conjugated ester (±)-15 (200 mg, 0.43 mmol)
in EtOH and THF mixture (8 mL, 1:1) was added a catalytic amount of
PtO2 (10 mg, 0.04 mmol) at 25 °C. The resulting mixture was stirred
under the balloon pressure of H2 atmosphere for 12 h and filtered
through a pad of Celite by washing with EtOAc (40 mL). The mixture
was concentrated in vacuo to afford the hydrogenated compound (±)-
16 as a gummy solid (197 mg, 98%).
(±)-Methyl (E)-2-(4-Oxo-12-tosyl-3,4,6,7,12,12b-hexahydroindo-
lo[2,3-a]quinolizin-1(2H)-ylidene)acetate (15)
To a stirred solution of (±)-2 (600 mg, 1.24 mmol) in pyridine (8 mL)
was added SOCl2 (0.45 mL, 6.22 mmol) at 0 °C. Ice bath was removed
and the reaction mixture was stirred at 25 °C for 3 h. It was then
poured into a mixture of EtOAc (15 mL) and crushed ice. The aqueous
layer was extracted with EtOAc (3 × 25 mL) and the combined organic
layers were washed with brine (50 mL), and dried (Na2SO4). Concen-
tration of organic layer in vacuo, followed by silica gel column chro-
matographic purification of the resulting residue using EtOAc–PE
(1:1) as an eluent afforded the conjugated ester (±)-15 as a yellowish
white solid (468 mg, 81%); mp 150–152 °C.
IR (CHCl3): 1734, 1642 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 1.73 (t, J = 4 Hz, 1 H), 1.78 (t, J = 4 Hz, 1
H), 2.27 (s, 3 H), 2.30–2.80 (m, 6 H), 2.96 (dd, J = 16, 6 Hz, 1 H), 3.11
(sext, J = 6 Hz, 1 H), 3.68 (s, 3 H), 4.96 (dd, J = 12, 4 Hz, 1 H), 5.01–5.08
(m, 1 H), 7.04 (d, J = 8 Hz, 2 H), 7.20–7.35 (m, 3 H), 7.34 (d, J = 8 Hz, 2
H), 8.11 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 21.5, 21.8, 22.9, 28.8, 36.3, 36.8, 41.4,
51.7, 59.8, 117.2, 118.6, 125.0, 125.5, 126.6, 127.4, 129.2, 131.1, 132.1,
135.4, 138.7, 145.0, 170.9, 172.4.
IR (neat): 1791, 1713, 1652 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.33 (s, 3 H), 2.55–3.00 (m, 5 H), 3.14
(dd, J = 18, 8 Hz, 1 H), 3.30–3.45 (m, 1 H), 3.61 (s, 3 H), 4.60–4.70 (m, 1
H), 5.22 (s, 1 H), 5.94 (s, 1 H), 7.18 (d, J = 8 Hz, 2 H), 7.32 (t, J = 8 Hz, 1
H), 7.40 (t, J = 8 Hz, 1 H), 7.47 (d, J = 8 Hz, 1 H), 7.57 (d, J = 8 Hz, 2 H),
8.19 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 20.2, 21.6, 25.7, 31.3, 38.5, 51.1, 56.0,
114.6, 115.3, 118.9, 122.9, 124.2, 125.7, 126.3, 128.7, 129.1, 129.9,
134.6, 136.9, 145.3, 156.8, 166.5, 172.3.
MS (ESI): m/z = 489 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H26N2O5SNa: 489.1445; found:
489.1444.
(±)-(12-Tosyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-
1-yl)ethan-1-ol (17)
MS (ESI): m/z = 487 [M + Na]+.
A flame dried round-bottomed flask was charged with AlCl3 (28 mg,
0.21 mmol) and THF (2 mL) under an argon atmosphere. The stirred
reaction mixture was cooled to 0 °C and a suspension of LiAlH4 (24
mg, 0.63 mmol) in THF (2 mL) was added dropwise. After stirring for
10 min at 0 °C, a solution of lactam ester (±)-16 (100 mg, 0.21 mmol)
in THF (4 mL) was added dropwise to the above mixture. It was
stirred for 2 h at 25 °C and quenched by the addition of sat. aq Na2SO4
(2 mL). The mixture was filtered through Celite and the solid residue
was washed with EtOAc (20 mL). The filtrate was dried (Na2SO4) and
concentrated in vacuo. The silica gel column chromatographic purifi-
cation of the resulting residue using CH2Cl2–MeOH (96:04) as an elu-
ent afforded the alcohol (±)-17 as a gummy solid (76 mg, 84%).
HRMS (ESI): m/z [M + Na]+ calcd for C25H24N2O5SNa: 487.1298; found:
487.1299.
(±)-Methyl (E)-2-(4-Oxo-1,2,3,4,5,6,8,9-octahydro-7H-azecino[5,4-
b]indol-7-ylidene)acetate (14)
To a stirred solution of naphthalene (108 mg, 0.85 mmol) in THF (4
mL) at 25 °C was carefully added a piece of Na metal (12 mg, 0.52
mmol) under an argon atmosphere. The reaction mixture was stirred
for 30 min to form a greenish blue solution. THF solution (2 mL) of
conjugated ester (±)-15 (60 mg, 0.13 mmol) was dropwise added to
the reaction mixture at –78 °C. After 20 min, the reaction was
quenched with sat. aq NH4Cl (2 mL). The mixture was extracted with
EtOAc (3 × 15 mL) and the combined organic layers were washed with
brine (25 mL), and dried (Na2SO4). Concentration of organic layer in
vacuo, followed by silica gel column chromatographic purification of
the resulting residue using EtOAc–PE (7:3) as an eluent afforded the
macrolactam (±)-14 as a gummy solid (23 mg, 56%).
IR (CHCl3): 3377, 1658, 1600 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 1.30–1.57 (m, 2 H), 1.73–1.90 (m, 2 H),
1.80–2.00 (m, 1 H), 2.00–2.15 (m, 1 H), 2.24 (s, 3 H), 2.15–2.60 (m, 2
H), 2.65–2.80 (m, 2 H), 2.85–2.95 (br s, 1 H), 3.00–3.22 (m, 2 H), 3.45–
3.55 (m, 1 H), 3.55–3.68 (m, 1 H), 3.73 (quint, J = 8 Hz, 1 H), 4.56 (d, J =
8 Hz, 1 H), 7.06 (d, J = 8 Hz, 2 H), 7.18 (t, J = 8 Hz, 1 H), 7.20 (t, J = 8 Hz,
1 H), 7.25 (d, J = 8 Hz, 1 H), 7.44 (d, J = 8 Hz, 2 H), 8.04 (d, J = 8 Hz, 1 H).
IR (neat): 3301, 3262, 1722, 1649 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.10–2.35 (m, 3 H), 2.46 (br s, 1 H),
2.83 (br s, 2 H), 3.22 (br s, 2 H), 3.42 (br s, 1 H), 3.69 (d, J = 16 Hz, 1 H),
3.77 (s, 3 H), 5.53 (br s, 1 H), 6.42 (s, 1 H), 7.11 (t, J = 8 Hz, 1 H), 7.18 (t,
J = 8 Hz, 1 H), 7.31 (d, J = 8 Hz, 1 H), 7.52 (d, J = 8 Hz, 1 H), 8.04 (br s, 1
H).
13C NMR (CDCl3, 100 MHz): δ = 24.1, 30.4, 34.6, 38.9, 40.5, 52.2, 110.8,
110.9, 118.2, 119.4, 121.9, 123.5, 127.3, 132.1, 135.7, 141.9, 172.5,
172.9.
13C NMR (CDCl3, 100 MHz): δ = 20.0, 20.5, 21.5, 29.8, 33.3, 35.8, 43.4,
53.4, 60.0, 60.4, 116.5, 118.4, 120.7, 124.2, 124.5, 126.7, 129.3, 131.3,
133.4, 137.6, 137.7, 144.4.
MS (ESI): m/z = 447 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C24H29N2O3S: 425.1893; found:
425.1893.
(±)-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizin-1-
yl)ethan-1-ol (18)
MS (ESI): m/z = 313 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2O3: 313.1547; found:
To stirred solution of N-tosyl-protected amino alcohol (±)-17 (75 mg,
0.18 mmol) in MeOH–benzene (4 mL, 1:1) were sequentially added
activated Mg turnings (200 mg, 8.30 mmol) and NH4Cl (200 mg, 3.74
mmol) at 25 °C. The reaction mixture was stirred for 4 h and the reac-
tion was quenched with sat. aq NH4Cl (5 mL) and aq 1 N HCl (2 mL).
Solvent was removed in vacuo and the residue was extracted with
EtOAc (3 × 5 mL). The combined organic layer was washed with brine
313.1547.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
P. Mondal, N. P. Argade
Paper
Synthesis
(10 mL) and dried (Na2SO4). Concentration of organic layer in vacuo,
followed by silica gel column chromatographic purification of the re-
sulting residue using CH2Cl2–MeOH (92:8) as an eluent afforded the
N-tosyl deprotected amino alcohol (±)-18 as a brownish white solid
(46 mg, 97%); mp 178–180 °C.
13C NMR (CDCl3, 100 MHz): δ = 21.1, 21.8, 22.4, 30.0, 33.2, 52.0, 52.2,
63.5, 103.8, 111.5, 111.8, 118.1, 119.1, 122.3, 125.9, 129.3, 135.2,
137.4, 172.9.
MS (ESI): m/z = 311 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H23N2O2: 311.1754; found:
IR (Nujol): 3375, 3126 cm–1
.
311.1750.
1H NMR (CD3OD, 400 MHz): δ = 1.35–1.47 (m, 1 H), 1.55–1.85 (m, 4
H), 1.98–2.10 (m, 1 H), 2.25 (br s, 1 H), 2.75–3.10 (m, 5 H), 3.40–3.50
(m, 1 H), 3.63–3.78 (m, 2 H), 3.88 (d, J = 8 Hz, 1 H), 6.98 (t, J = 8 Hz, 1
H), 7.06 (t, J = 8 Hz, 1 H), 7.31 (d, J = 8 Hz, 1 H), 7.40 (d, J = 8 Hz, 1 H).
13C NMR (CD3OD, 100 MHz): δ = 20.76, 20.81, 21.7, 34.2, 36.2, 49.61,
49.64, 60.5, 61.9, 108.1, 112.0, 118.6, 119.8, 122.2, 128.3, 134.8, 137.8.
(±)-1,2,5,6,13,13a-Hexahydro-3H-indolo[3,2,1-de]pyrido[3,2,1-
ij][1,5]naphthyridine-3,12(41H)-dione (23)
Activated Mg turnings (62.40 mg, 2.60 mmol) and NH4Cl (65 mg, 1.22
mmol) were sequentially added to stirred solution of N-tosyl protect-
ed lactam (±)-16 (60 mg, 0.13 mmol) in MeOH–benzene (1:1; 4 mL) at
25 °C. The reaction mixture was stirred for 2 h and quenched with sat.
aq NH4Cl (1 mL) and aq 1 N HCl (1 mL). MeOH and benzene were re-
moved in vacuo and the residue was extracted with EtOAc (3 × 25
mL). The combined organic layers were washed with brine (40 mL)
and dried (Na2SO4). Concentration of organic layer in vacuo, followed
by silica gel (230–400 mesh) column chromatographic purification of
the resulting residue using EtOAc–PE (7:3) as an eluent afforded the
pentacyclic compound (±)-23 as a white solid (30 mg, 83%); mp 172–
174 °C.
MS (ESI): m/z = 271 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H23N2O: 271.1805; found:
271.1797.
(±)-(1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizin-1-yl)eth-
yl Acetate (19)
To a stirred solution of (±)-18 (40 mg, 0.15 mmol) in pyridine (2 mL)
was added Ac2O (0.30 mL, 3.18 mmol) at 25 °C. After stirring for 16 h,
the reaction was quenched with H2O (5 mL) and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed with
sat. aq NaHCO3 (15 mL) and brine (15 mL), and dried (Na2SO4). Con-
centration of organic layer in vacuo, followed by silica gel column
chromatographic purification of the resulting residue using CH2Cl2–
MeOH (94:6) as an eluent afforded the ester (±)-19 as a gummy solid
(41.0 mg, 88%).
IR (CHCl3): 1709, 1644 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 1.77 (ddd, J = 18, 10, 5 Hz, 1 H), 2.03
(dd, J = 10, 5 Hz, 1 H), 2.21 (tq, J = 10, 5 Hz, 1 H), 2.55 (ddd, J = 15, 10, 5
Hz, 1 H), 2.65 (d, J = 15 Hz, 1 H), 2.69 (dt, J = 15, 5 Hz, 1 H), 2.77–2.84
(m, 2 H), 2.93 (dd, J = 15, 5 Hz, 1 H), 2.96–3.05 (m, 1 H), 4.27 (d, J = 10
Hz, 1 H), 5.09 (td, J = 10, 5 Hz, 1 H), 7.32 (dt, J = 10, 5 Hz, 1 H), 7.36 (dt,
J = 10, 5 Hz, 1 H), 7.46 (d, J = 10 Hz, 1 H), 8.36 (d, J = 10 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 20.4, 25.9, 32.1, 37.2, 38.2, 38.9, 55.1,
112.6, 116.2, 118.6, 124.3, 125.0, 129.1, 132.1, 135.2, 166.7, 168.3.
MS (ESI): m/z = 281 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O2: 281.1285; found:
IR (CHCl3): 3429, 1737 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 1.65–1.82 (m, 3 H), 1.85–2.05 (m, 3 H),
2.10 (s, 3 H), 2.05–2.18 (m, 1 H), 2.80–3.15 (m, 5 H), 3.35–3.45 (m, 1
H), 3.94–4.05 (m, 1 H), 4.10–4.20 (m, 1 H), 4.25–4.37 (m, 1 H), 7.08 (t,
J = 8 Hz, 1 H), 7.17 (t, J = 8 Hz, 1 H), 7.37–7.45 (m, 2 H), 9.28 (br s, 1 H).
281.1281.
13C NMR (CDCl3, 100 MHz): δ = 19.5, 20.9, 21.0, 28.2, 31.1, 34.4, 49.2,
51.6, 60.0, 62.3, 107.8, 111.3, 118.0, 119.4, 121.9, 126.6, 131.5, 136.4,
171.8.
(±)-2,3,41,5,6,12,13,13a-Octahydro-1H-indolo[3,2,1-de]pyri-
do[3,2,1-ij][1,5]naphthyridin-12-ol [Isovindeburnol, (±)-24]
MS (ESI): m/z = 313 [M + H]+.
A flame dried round-bottomed flask was charged with AlCl3 (12 mg,
0.09 mmol) and THF (1 mL) under an argon atmosphere. The stirred
reaction mixture was cooled to 0 °C and a suspension of LiAlH4 (10
mg, 0.27 mmol) in THF (1 mL) was added dropwise. After stirring for
10 min at 0 °C, a solution of lactam (±)-23 (25 mg, 0.09 mmol) in THF
(2 mL) was added dropwise to the above reaction mixture. Then it
was stirred for 2 h at 25 °C and quenched by the addition of sat. aq
Na2SO4 (2 mL). The mixture was filtered through Celite and the solid
residue was washed with EtOAc (3 × 10 mL). The filtrate was dried
(Na2SO4) and concentrated in vacuo. Silica gel (230–400 mesh) col-
umn chromatographic purification of the resulting residue using
CH2Cl2–MeOH (96:04) as an eluent afforded the isovindeburnol [(±)-
24] as a brownish solid (16 mg, 68%); mp 246–248 °C (Lit.7c mp 254 °C).
HRMS (ESI): m/z [M + H]+ calcd for C19H25N2O2: 313.1911; found:
313.1908.
(±)-2-(2,3,4,6,7,12-Hexahydroindolo[2,3-a]quinolizin-1-yl)ethyl
Acetate (20)
To a stirred solution of acetate (±)-19 (25 mg, 0.08 mmol) in EtOH (2
mL) were added a solution containing EDTA disodium salt dihydrate
(70 mg, 0.24 mmol) and Hg(OAc)2 (76 mg, 0.24 mmol) in H2O (3 mL)
and the resulting solution was gently heated at 80 °C for 2 h. After
cooling, CH2Cl2 was added to the reaction mixture and the two-phase
mixture was basified to pH 11 with 5% aq ammonia. The organic layer
was separated and the aqueous layer was extracted with CH2Cl2 (2 ×
10 mL). The combined organic layers were washed with sat. aq
NaHCO3 (10 mL) and brine (10 mL), and dried (Na2SO4). Filtration and
concentration of organic layer in vacuo afforded the enamine (±)-20
as a brown gummy solid (22 mg, 89%).
IR (CHCl3): 3345, 1720, 1645 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 0.77–0.94 (m, 1 H), 1.10–1.23 (m, 1 H),
1.23–1.34 (m, 1 H), 1.38–1.54 (m, 1 H), 1.57–1.67 (m, 1 H), 1.67–1.80
(m, 1 H), 2.01–2.15 (m, 2 H), 2.15–2.27 (m, 1 H), 2.40–2.60 (m, 1 H),
2.60–2.75 (m, 1 H), 2.86–3.00 (m, 2 H), 3.00–3.10 (m, 1 H), 5.36 (t, J =
8 Hz, 1 H), 7.00–7.25 (m, 2 H), 7.43 (d, J = 8 Hz, 1 H), 7.67 (d, J = 8 Hz, 1
H).
13C NMR (CDCl3, 100 MHz): δ = 21.3, 24.9, 29.5, 35.6, 39.5, 52.4, 54.5,
62.9, 79.0, 105.2, 112.3, 118.2, 120.1, 121.3, 128.6, 134.5, 138.0.
MS (ESI): m/z = 269 [M + H]+.
IR (CHCl3): 3361, 1728, 1634 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 1.95–2.02 (m, 4 H), 2.02–2.20 (m, 1 H),
2.18 (s, 3 H), 2.22–2.30 (m, 1 H), 2.77 (dd, J = 8, 8 Hz, 1 H), 2.97 (t, J = 8
Hz, 2 H), 3.03–3.15 (m, 3 H), 4.24 (dd, J = 8, 8 Hz, 2 H), 7.10 (t, J = 8 Hz,
1 H), 7.21 (t, J = 8 Hz, 1 H), 7.51 (d, J = 8 Hz, 1 H), 7.56 (d, J = 8 Hz, 1 H),
10.13 (br s, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
P. Mondal, N. P. Argade
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C17H21N2O: 269.1648; found:
269.1645.
(3) (a) Wee, A. G. H.; Yu, Q. J. Org. Chem. 2001, 66, 8935. (b) Ghosh,
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Acknowledgment
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(b) Smith, M. W.; Hunter, R.; Patten, D. J.; Hinz, W. Tetrahedron
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P.M. thanks CSIR, New Delhi, for the award of a research fellowship.
N.P.A. thanks Science and Engineering Research Board (SERB), New
Delhi for financial support.
(5) (a) England, D. B.; Padwa, A. J. Org. Chem. 2008, 73, 2792.
(b) Deiters, A.; Pettersson, M.; Martin, S. F. J. Org. Chem. 2006,
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588386. NMR spectra of all the
synthesized compounds are included.
S
u
p
p
ortioInfgrmoaitn
S
u
p
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(6) Lancefield, C. S.; Zhou, L.; Lébl, T.; Slawin, A. M. Z.; Westwood,
N. J. Org. Lett. 2012, 14, 6166.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H