Synthesis of 6-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine

Article abstract of DOI:10.1002/jhet.3130

An efficient synthesis of 6-oxo-1,2,3,4,5,7,12,12b-octahydroindolo[2,3-α]quinolizine from 2-acetylpyridine and phenylhydrazine is described. This derivative of the natural alkaloid desbromoarborescidine A is an important entry point to the sarpagine-vobas

Full text of DOI:10.1002/jhet.3130

Month 2018
Synthesis of 6-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
David C. Tompkins,a Laurence W. Reilly Jr,b Randall B. Nelson,b Lloyd J. Dolby,a† and Gordon W. Gribble
b
*
aDepartment of Chemistry, University of Oregon, Eugene, OR 97403, USA
bDepartment of Chemistry, Dartmouth College, Hanover, NH 03755, USA
*
E-mail: ggribble@dartmouth.edu
†Deceased May 16, 2014
Received November 29, 2017
DOI 10.1002/jhet.3130
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
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An efficient synthesis of 6-oxo-1,2,3,4,5,7,12,12b-octahydroindolo[2,3-α]quinolizine from 2-
acetylpyridine and phenylhydrazine is described. This derivative of the natural alkaloid
desbromoarborescidine A is an important entry point to the sarpagine-vobasine family of plant alkaloids.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
known [12]. Our initial sequence is depicted in Scheme 1
starting with the known 2-(2-pyridyl)indole (6) [12].
Thus, a Fischer indolization of 2-acetylpyridine phenyl
hydrazone with polyphosphoric acid gave 6 in 91% yield.
Selective reduction of the pyridine ring with either
sodium in ethanol or sodium in liquid ammonia/t-butyl
alcohol afforded 2-(2-piperidyl)indole (7) in 90% and
94% yields, respectively. Acetylation of 7 gave N-acetyl
8, which was directly subjected to a gramine synthesis
with formaldehyde and dimethylamine. This Mannich
reaction at room temperature provided gramine 9 in 95%
yield and some ethoxymethyl 10, both of which were
separated, isolated, and characterized. At higher
temperature (steam bath), the solvent ethanol was
incorporated to give ethoxy derivative 10 in 22% yield.
The mixture of 9 and 10 was treated sequentially with
potassium cyanide, followed by sodium hydroxide and
then acidic methanol to furnish piperidine ester 11 in
34% yield. This ester smoothly underwent lactamization
in refluxing toluene to give the desired indole lactam 5 in
76% yield.
The somewhat low overall yield of amino ester 11 led us
to consider postponing the reduction of the pyridine ring of
6 until later in the synthesis. This assessment and change
led to our improved synthesis of lactam 5 as shown in
Scheme 2. Thus, gramine 12 was prepared from pyridyl
indole 6 in 92% yield. Treatment of 12 under the usual
cyanide displacement and hydrolysis conditions gave
indole-3-acetic acid 13 in 80% yield. Dissolving metal
reduction and in situ esterification led to piperidine ester
11, accompanied by the formation of some lactam 5.
The indolo[2,3-a]quinolizine ring system exemplifies
the framework for myriad indole alkaloids [1]. Moreover,
1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (1)
is an alkaloid per se [2,3]. Several oxo-derivatives of 1
have been prepared (2–5) as advanced synthetic
intermediates in the synthesis of alkaloids [4–8], and
ketone 2 has pronounced biological activity [9–11].
Lactam 5 (6-oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-
a]quinolizine) is of particular interest as providing a
potential route to the sapagine-vobasine family of alkaloids.
Ochiai and Takahashi have prepared 5 in 11 steps from
quinoline (yield unreported) [7]. During the course of
our initial studies, we learned that King prepared 5
from indole-3-acetic acid and 5-aminovaleraldehyde
(5-aminovaleraldehyde diethyl acetal) in 53% overall
yield [8]. Although the overall yield is good, King’s
procedure is complicated by the formation of a hexahydro-
1,3,5-triazine, a trimer from 5-aminovaleraldehyde, which
requires refluxing in dioxane with trifluoromethanesulfonic
acid to form lactam 5.
Refluxing the mixture of 11 and
5
effected
For a synthetic project in our laboratory we required an
efficient, large-scale preparation of lactam 5, which we
now describe. Our approach was to forge the C-ring last
because the 2-(2-pyridyl)indole ring system is well
complete conversion to lactam 5 in 46% yield from 13.
This second procedure is shorter in terms of operations,
yield (34% vs. 19% from 6), and time than our Scheme 1
synthesis.
© 2018 Wiley Periodicals, Inc.

D. C. Tompkins, L. W. Reilly Jr, R. B. Nelson, L. J. Dolby, and G. W. Gribble
Vol 000
Scheme 1
Technology and on a Finnegan EI-CI gas chromatograph-
mass spectrometers system. Microanalyses were
performed by Micro-Tech Laboratories, Skokie, IL, USA.
The adsorbent for TLC, both preparative and analytical,
was silica gel PF 254 + 366 (Merck). TLC spots were
visualized either under 254-nm UV light or by spraying
with a solution of 3% ceric ammonium sulfate in 10%
sulfuric acid. Organic solutions were concentrated in
vacuo with a Büchi Rotavaporator. Dry solvents were
obtained by distillation from the following drying agents:
lithium aluminum hydride (THF, dioxane), calcium
hydride (DMSO, DMF), P4O10 (EtOAc), sodium
(t-butanol, benzene, ether), and barium oxide (amines).
2-Acetylpyridine phenylhydrazone.
A solution of
39.9 g (0.33 mol) of 2-acetylpyridine, 35.6 g (0.33 mol)
of phenylhydrazine, and 24 mL of ethanol was heated to
approximately 50°C for 90 min. At the end of this time, a
solid mass of yellow crystals formed. These crystals
were collected and dried to give 70.4 g (quant.) of
2-acetylpyridine phenylhydrazone: mp 149–154°C (lit.
[12] mp 155°C).
Scheme 2
2-(2-Pyridyl)indole (6). A mixture of 25.5 g (0.121 mol)
of 2-acetylpyridine phenylhydrazone and approximately
85 g of polyphosphoric acid was heated to 130°C with
constant stirring. After a few minutes, a vigorous,
exothermic reaction ensued and increased the temperature
of the solution to above 200°C. The reaction mixture was
cooled to 70–80°C and basified to pH >10 by dilution
with H2O and addition of NaOH pellets. Much NH3 gas
was evolved during the basification. Exhaustive
extraction with CH2Cl2, washing of the organic phase
with H2O (3X) and brine (1X), drying over anhydrous
K2CO3, and concentration in vacuo afforded 21.5 g
(91%) of 6. TLC (5% Et3N in EtOAc) showed a single,
high Rf spot. Column chromatography (activity III basic
alumina, elution with benzene) gave pure material: mp
95% EtOH
max
151–152.5°C (lit. [12] mp 154°C); UV (λ
)
325 nm; IR (CHCl3) 3550 cmÀ1; NMR (CDCl3) δ
6.96–7.43 (m, 6H), 7.53–7.81 (m, 2H), 8.58 (d, 1H), and
In conclusion, we have synthesized 6-oxo-1,2,3,4,
6,7,12,12b-octahydroindolo[2,3-a]quinolizine (5) in five
steps from readily available 2-acetylpyridine.
10.10 ppm (broad s, 1H).
2-(2-Piperidyl)indole (7) using Na/EtOH. To a solution of
10.00 g (0.052 mol) of 6 in 500 mL of absolute ethanol was
added freshly cut Na (~50 g) in portions so as to keep the
solution at reflux. After the final addition, the solution
was refluxed for 90 min. After cooling, the solid mass of
sodium ethoxide was dissolved in H2O and extracted
with benzene. The organic phase was washed with brine,
dried over anhydrous K2CO3, and concentrated in vacuo
to yield 9.35 g (90%) of 7 as white crystals. TLC (5%
Et3N in EtOAc) showed a single spot of much lower Rf
than 6. Recrystallization from ether-petroleum ether gave
EXPERIMENTAL
General.
Melting points were determined in open
capillaries with Mel-Temp Laboratory Devices
a
apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin-Elmer 257 spectrophotometer.
Proton and carbon NMR spectra were determined on a
Jeol JNM-FX60
Q Fourier transform spectrometer.
pure material: mp 134–135°C; (lit. [13] mp 128–129°C)
uv (λ
(CDCl3) δ 1.16–2.21, 2.56–3.38, 3.73–4.04 (m, 10H),
Ultraviolet spectra were recorded on a Unicam SP-800A
spectrophotometer. Mass spectra were obtained at the
NIH Regional Facility at the Massachusetts Institute of
95%
max
EtOH) 271, 278, 281, and 289 nm; NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of 6-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
6.30 (broad s, 1H), 6.95–7.67 (m, 4H), and 8.88 ppm
(broad s, 1H). All physical and spectral data matched the
literature [13] values.
acetyl-2-piperidyl)indole (8) (1.261 g, 5.30 mmol)
dissolved in 35 mL of warm 95% ethanol. The solution
was heated overnight on a steam bath. After reducing the
volume of solvent by rotary evaporation, the solution was
made alkaline with aqueous potassium hydroxide and
was extracted with chloroform. The combined extracts
were washed with water, dried (potassium carbonate),
and the solvent was removed to give a yellow oil.
Chromatography over 50 g of Woelm activity III neutral
alumina gave upon elution with benzene (200 mL) the
crystalline ethoxy derivative 10 (349 mg, 22%).
Recrystallization from 95% ethanol gave material with
mp 165–166°C. The NMR spectrum had signals at δ
7.8–7.1 (m, 4, aromatic H), 4.4 (s, 2, CH2OC2H5), 3.62
(q, 2, J = 7 Hz, OCH2CH3), 2.13 (s, 3, COCH3), and
1.22 (t, 3, J = 7 Hz, OCH2CH3).
2-(2-Piperidyl)indole (7) using Na/NH3. Metallic sodium
spheres (1.3 g, 56.5 mmol) were added to a flask equipped
with a dry-ice-acetone condenser and containing liquid
ammonia (125 mL), 2-(2-pyridyl)indole (6) (1.180 g,
6.03 mmol), and dry t-butyl alcohol (20 mL). After the
blue color had disappeared, ethanol (50 mL) was added
and the ammonia was evaporated. The mixture was
poured into water and extracted with chloroform. The
combined extracts were dried (potassium carbonate), and
the solvent was removed to give 7 (1.150 g, 94%) as a
fluffy white solid. This material was identical to that
prepared above by sodium and alcohol reduction.
2-(1-Acetyl-2-piperidyl)indole (8). A solution of 0.87 g
(4.35 mmol) of 2-(2-piperidyl)indole (7), 7 mL of acetic
anhydride, and 7 mL of dry pyridine was allowed to
stand at 25°C for 2 days. The dark solution was poured
into water and extracted with methylene chloride. The
organic extract was repeatedly washed with water and
then dried over sodium sulfate. Concentration gave crude
brown solid, which was purified by filtration through
activity III neutral alumina. Elution with benzene gave
0.89 g (85%) of a yellow glassy material that slowly
crystallized. The infrared spectrum showed absorption at
1613 cmÀ1 (C═O) while the NMR spectrum exhibited a
sharp singlet at 2.12 ppm (acetyl methyl) and a multiplet
at 6.38 ppm (3-indole proton). The ultraviolet spectrum
showed absorption at 270, 277, 280, and 288 nm. This
crude material was carried on directly in the next step.
Anal. Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33.
Found: C, 71.84; H, 7.78; N, 9.17.
Elution with 25% benzene-chloroform (125 mL) and
then chloroform (100 mL) gave the crystalline
dimethylaminomethyl derivative (9) (207 mg).
Intermediate fractions (275 mL of 10% and 175 mL of
50% chloroform-benzene) afforded 990 mg of a mixture
of 9 and 10.
Methyl 2-(2-piperidyl)indole-3-acetate (11) from piperidine
compounds 9 and 10. A mixture (0.712 g, 2.38 mmol)
of 9 and 10, and potassium cyanide (1.337 g, 20.6 mmol)
in 95% ethanol (70 mL), and water (10 mL) was heated
at reflux for 138 h. The solvent was removed, and the
resulting residue was suspended in water and extracted
with chloroform. The combined chloroform extracts were
washed with water, dried (magnesium sulfate), and the
solvent was removed to give 0.620 g of a white foam.
The foam was heated for 7 h at reflux in a solution of
potassium hydroxide (3 g) in water (20 mL). After
cooling, the solution was neutralized with dilute
hydrochloric acid, filtered, and the filtrate was evaporated
to dryness. The resulting white powder was suspended in
methanol (50 mL) and sulfuric acid (1 mL) and heated at
reflux for 7 h. After filtration, the methanol was removed
and the residue was suspended in 10% potassium
carbonate and was extracted with chloroform. The
combined extracts were washed with water, dried
(potassium carbonate), and the solvent was removed to
yield crystals of piperidine ester 11 (0.250 g, 34%). This
material could not be recrystallized and was directly
converted to lactam 5. It showed infrared absorptions at
1735 (ester C═O) and 3500 cmÀ1 (NH). The NMR
spectrum showed signals at δ 9.00 (NH), 3.75 (s,
2-(1-Acetyl-2-piperidyl)-3-(dimethylaminomethyl)indole
(9). A solution prepared by successively adding acetic
acid (0.5 mL) and 37% aqueous formaldehyde (130 mg)
to 25% aqueous dimethylamine (0.22 mL) was added to
2-(1-acetyl-2-piperidyl)indole (8) (224 mg, 0.941 mmol)
dissolved in 45 mL of ethanol. The mixture was stirred at
room temperature overnight. After reducing the volume
of solvent by rotary evaporation, the reaction mixture was
made alkaline with aqueous potassium hydroxide and
was extracted with chloroform. The combined chloroform
extracts were washed with water, dried (potassium
carbonate), and the solvent was removed to give 9 as
yellow foam (267 mg, 95%), which crystallized from
acetone-hexane, mp 144–145°C. The NMR spectrum
showed signals at δ 7.90–7.14 (m, 4, aromatic H), 3.60
(s, 2, CH2N(CH3)2), 2.25 (s, 6, N(CH3)2), 2.17 (s, 3,
COCH3), and 1.8–1.5 (m, 6, CH2CH2CH2).
Anal. Calcd for C18H25N3O: C, 72.21; H, 8.42; N,
14.03. Found: C, 72.15; H, 8.20; N, 13.91.
CH2COCH3), and 3.64 (s, COCH3). The UV spectrum
EtOH
max
2-(1-Acetyl-2-piperidyl)-3-(ethoxymethyl)indole (10).
A
had maxima at λ
280 mμ and 289.
solution prepared by successively adding acetic acid
(794 mg) and 37% aqueous formaldehyde (481 mg) to
25% aqueous dimethylamine (1.2 mL) was added to 2-(1-
6-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
(5). The crude ester (11) (7.6 g) was dissolved in 75 mL
of hot toluene and heated at reflux under nitrogen for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. C. Tompkins, L. W. Reilly Jr, R. B. Nelson, L. J. Dolby, and G. W. Gribble
Vol 000
3.5 days. The lactam (5) (4.8 g) that had precipitated was
collected by filtration. Hexane was added to the filtrate to
yield an additional 0.3 g (5). The material (5.1 g, 76%)
upon crystallization from ethanol had mp 251–253°C;
and recrystallization from ethanol yielded pure 5: mp
254.5–255.5°C (lit. [7] mp 254–255°C). The infrared
spectrum (KBr) showed a peak at 1600 cmÀ1 (C═O) and
was identical to that prepared in Scheme 2, vide infra. A
sample of 5 was reduced with lithium aluminum hydride
11.38 (s, disappears with D2O), 8.70 (m), 8.1–6.6 (m),
and 5.23 (s), (rel ratio 1:1:7:1).
The volume of the filtrate was reduced, and water
(600 mL) was added producing a brown precipitate that
was collected by filtration (6.9 g). TLC indicated a
mixture of 13 and the same unknown compound
mentioned previously. The filtrate was acidified by the
dropwise addition of 50% sulfuric acid until a yellow
precipitate ceased to be formed (about pH 6). The
collected dry yellow material (220–250 g) was placed in
a Soxhlet extractor for 3 h using acetone as the solvent.
Removal of the acetone gave 55.5 g (79%) of yellow
pyridine acid 13, mp 180–187°C. Crystallization from
ethanol gave material which showed mp 194–195°C (lit.
(THF,
reflux)
to
give
1,2,3,4,6,7,12,12b-
octahydroindolo[2,3-a]quinolizine (1) in 72% yield.
3-(Dimethylaminomethyl)-2-(2-pyridyl)indole (12).
To
25.0 g (0.129 mol) of 6 was added a solution of 21 mL
of acetic acid, 11.25 g of 40% aqueous formaldehyde,
and 28 mL of 25% aqueous dimethylamine. An
additional 300 mL of acetic acid was added ,and the
reaction mixture was poured into a solution of 500 g of
KOH in 2.5 L of H2O. After the mixture had been
chilled at 0°C for 2.5 h, the precipitate was collected
and subjected to column chromatography (activity III
basic alumina, elution with benzene) to yield 29.8 g
(92%) of 12 as yellow crystals. A pure sample was
obtained by recrystallization from EtOAc: mp 110–111°C;
13C NMR (CD3COCD3) δ 43.5, 52.5, 110.6, 118.1, 118.3,
120.7, 121.6, 122.1, 129.4, 134.0, 134.7, 135.5, 148.0,
and 149.9 ppm. The signal at δ 52.5 ppm integrated for 2
carbons (─N(CH3)2). Fortuitously and interesting so, two
quaternary carbons have the same 13C chemical shift.
Anal. Calcd for C16H17N3: C, 76.46; H, 6.82; N, 16.72.
Found: C, 76.27; H, 6.84; N, 16.83.
[12] mp 194°C).
6-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
(5) from pyridyl acid 13. A 30-mL liquid NH3 was added
to 1.524 g (6.05 mmol) of 13. To this solution was
added 5 mL of dry t-butanol followed by 1.7 g
(74 mmol) of freshly cut Na in small portions. After the
final Na addition, the reaction mixture was stirred for
90 min and the blue color was discharged with 20 mL of
methanol. The NH3 was allowed to evaporate, 20 mL of
additional methanol was added, and HCl gas was
bubbled into the solution until it was strongly acidic. The
reaction mixture was refluxed for 3 h. After cooling, the
solution was filtered from residual NH4Cl, concentrated
in vacuo and the residue partitioned between H2O and
CHCl3. The organic phase was washed with 15% H3PO4
(saved) and 10% K2CO3 and dried over anhydrous
K2CO3. Concentration in vacuo left 0.813 g of tan
crystals. The H3PO4 extract was basified and extracted
with CHCl3. The organic phase was dried over anhydrous
K2CO3 and concentrated in vacuo to yield 0.346 g of tan
crystals. Both products contained lactam 5 and ester 11
(TLC, 5% Et3N in EtOAc). Total yield of ester 11 is about
67% from 13. The products were combined and 0.812 g
was refluxed in 10 mL of toluene for 3 days. The reaction
mixture was cooled and the resultant precipitate was
collected to yield 0.669 g of 5 in 46% yield from 13,
identical to material prepared via Scheme 1.
2-(2-Pyridyl)indole-3-acetic acid (13).
A solution of
19.3 g (0.077 mol) of 12 in 450 mL of ethanol was
brought to reflux. At reflux, a solution of 45 g (0.692 mol)
of KCN in 135 mL of H2O was added. After refluxing for
48 h, 250 mL of 20% KOH was added. After further
refluxing for 22 h, the reaction mixture was cooled,
neutralized to pH 6 with concentrated H2SO4 and ice, and
the resultant precipitate was collected. The precipitate was
extracted with acetone for 2 h in a Soxhlet extractor.
Concentration of the acetone in vacuo yielded 15.6 g
(80%) of 13 as yellow crystals. Recrystallization from
ethanol gave pure 13: mp 197–198°C (lit. [12] mp 194°C).
2-(2-Pyridyl)indole-3-acetic acid (13) (large scale). To a
solution of 12 (70 g, 0.27 mol) in hot 95% ethanol (1 L)
was added 100 g of potassium cyanide in 130 mL of
water. The reaction mixture was heated at reflux for
8 days. Potassium hydroxide (60 g) was added, and the
reaction mixture was warmed for an additional 10 days.
The tan crystals which had formed were collected by
filtration, washed with water and dried to give an
unidentified compound (4.4 g), mp 214–217°C, which
was recrystallized from ethanol; mp 221–222°C. The
Acknowledgment. We thank Dartmouth College for support.
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DOI 10.1002/jhet

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Synthesis of 6-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
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