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

Article abstract of DOI:10.1002/jhet.3251

A short synthesis of 7-oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine from 2-acetylpyridine and phenylhydrazine is described. Ring C is forged using 2-chloro-N,N-dimethylacetamide. This derivative of the natural alkaloid 1,2,3,4,6,7,12,12b-octah

Full text of DOI:10.1002/jhet.3251

Month 2018
Synthesis of 7-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
b
David C. Tompkins,a Randall B. Nelson,b Lloyd J. Dolby,a† and Gordon W. Gribble
*
aDepartment of Chemistry, University of Oregon, Eugene, Oregon 97403, USA
bDepartment of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA
*E-mail: ggribble@dartmouth.edu
†Deceased May 16, 2014.
Received April 6, 2018
DOI 10.1002/jhet.3251
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A short synthesis of 7-oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine from 2-acetylpyridine
and phenylhydrazine is described. Ring C is forged using 2-chloro-N,N-dimethylacetamide. This derivative
of the natural alkaloid 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine is an inhibitor of the ZipA–FtsZ
protein–protein complex, which is a novel antibacterial target.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
prepared in three steps (85% yield) from commercially
available 2-acetylpyridine (3) via 2-(2-pyridyl)indole (5)
obtained by a Fischer indolization followed by Na metal
selective reduction of the pyridine ring [2]. Treatment
of 6 with 2-chloro-N,N-dimethylacetamide in a solution
of acetone and triethylamine afforded amide 7 in 59%
yield. Cyclization of 7 was achieved by heating it with
a mixture of polyphosphoric acid and phosphorus
oxychloride to afford ketone 2 in yields ranging from 48
to 78%. Phosphorus oxychloride alone gave no 2. The
structure of ketone 2 was supported by elemental
analysis, spectral data, and comparison with the literature
[16]. Notably, the carbonyl stretching frequency at
1620 cmꢀ1 is consistent with that of 3-acetylindole [21].
In connection with our interest in the synthesis,
spectroscopy, and chemistry of the alkaloid 1,2,3,4,6,
7,12,12b-octahydroindolo[2,3-a]quinolizine (1) [1–11]
(more recently named as desbromoarborescidine A [12])
and of its keto derivatives [13–15], we now describe
a
convenient synthesis of 7-oxo-1,2,3,4,6,7,12,12b-
octahydroindolo[2,3-a]quinolizine (2).
Likewise, the ultraviolet spectrum is that of
a
During our early work on this project, we became aware
of the first synthesis of ketone 2 by Rosemund [16], and
subsequently, we learned of the discovery by Sutherland
[17–19] that 2 is a novel inhibitor of the ZipA–FtsZ
protein–protein complex. This discovery has led ketone 2
to become a potential target for a new antibiotic strategy.
Thus, the ZipA–FtsZ interaction is crucial for cell division
in Escherichia coli, and ketone 2 and N-substituted
analogues are pronounced inhibitors of this interaction
[19]. We desired our synthesis of ketone 2 to be scalable
and efficient and, in particular, to mimic our reported
synthesis of 6-oxo-1,2,3,4,6,7,12,12b-octahydroindolo
[2,3-a]quinolizine [14] in terms of starting materials and
with the intent of forging ring C at the end.
Our synthesis of ketone 2 is shown in Scheme 1. It
differs from that of Rosemund [16] and Sutherland [18]
in that we avoid using the toxic, lachrymatory, and
carcinogenic [20] bromoacetates and bromoacetic acid
that were used by the previous workers in the key step of
their syntheses. The known 2-(2-piperidyl)indole (6) was
3-acetylindole [21]. Reduction of 2 with LiAlH4 gave the
(racemic) alkaloid 1, identical with a sample prepared in
our laboratory. Similarly, reduction of 2 with NaBH4
gave indole alcohol 8.
In summary, we have synthesized 7-oxo-1,2,3,4,
6,7,12,12b-octahydroindolo[2,3-a]quinolizine (2) in five
steps from commercial 2-acetylpyridine (3) in 24%
overall yield.
EXPERIMENTAL
General.
Melting points were determined in open
capillaries with Mel-Temp Laboratory Devices
apparatus and are uncorrected. Infrared spectra were
recorded on PerkinElmer 257 spectrophotometer
a
a
(PerkinElmer, Inc., Waltham, MA). NMR spectra were
determined on a Jeol JNM-FX60 Q Fourier transform
spectrometer (JEOL, Tokyo, Japan). Ultraviolet spectra
© 2018 Wiley Periodicals, Inc.

D. C. Tompkins, R. B. Nelson, L. J. Dolby, and G. W. Gribble
Vol 000
Scheme 1
were recorded on a Unicam SP-800A spectrophotometer.
UV λmax (95% EtOH) 325 nm; IR (CHCl3) 3550 cmꢀ1
;
Microanalyses were performed by Micro-Tech
Laboratories, Skokie, IL. The adsorbent for thin-layer
chromatography (TLC) was silica gel PF 254 + 366
(Merck, Kenilworth, NJ). TLC spots were visualized
either under 254-nm UV light or by spraying with a
solution of 3% (NH4)4Ce (SO4)4-2H2O in 10% aqueous
H2SO4. Organic solutions were concentrated in vacuo
with a Büchi Rotavaporator. Dry solvents were obtained
by distillation from the following drying agents: LiAlH4
(THF), CaH2 (DMSO and DMF), P4O10 (EtOAc), Na (t-
BuOH, benzene, and Et2O), and BaO (amines).
2-Acetylpyridine phenylhydrazone (4). A solution of
39.9 g (0.33 mol) of 2-acetylpyridine (3), 35.6 g
(0.33 mol) of phenylhydrazine, and 24 mL of EtOH was
heated to approximately 50°C for 90 min. At the end of
this time, a solid mass of yellow crystals that formed was
NMR (CDCl3) δ 6.96–7.43 (m, 6H), 7.53–7.81 (m, 2H),
8.58 (d, 1H), and 10.10 ppm (broad s, 1H).
2-(2-Piperidyl)indole (6) using Na/EtOH. To a solution
of 10.00 g (0.052 mol) of 5 in 500 mL of absolute EtOH,
freshly cut Na (~50 g) in portions was added 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 NaOEt was dissolved in H2O and extracted with
benzene. The organic phase was washed with brine, dried
over K2CO3, and concentrated in vacuo to yield 9.35 g
(90%) of 6 as white crystals. Recrystallization from
Et2O–petroleum ether gave material with mp 134–135°C;
(lit [2], mp 128–129°C); UV λmax (95% EtOH) 271, 278,
281, and 289 nm; NMR (CDCl3) δ 1.16–2.21, 2.56–3.38,
3.73–4.04 (m, 10H), 6.30 (broad s, 1H), 6.95–7.67 (m,
4H), and 8.88 ppm (broad s, 1H).
2-(2-Piperidyl)indole (6) using Na/NH3. Sodium spheres
(1.03 g, 56.5 mmol) were added to a flask equipped with
a dry ice–acetone condenser and containing liquid NH3
(125 mL), 2-(2-pyridyl)indole (5) (1.18 g, 6.03 mmol),
and dry t-BuOH (20 mL). After the blue color had
disappeared, EtOH (50 mL) was added, and the NH3 was
allowed to evaporate. The mixture was poured into H2O
and extracted with CHCl3. The combined extracts were
dried (K2CO3), and the solvent was removed to give 6
(1.15 g, 94%) as a fluffy white solid. This material was
identical to that prepared using Na and EtOH (vide
supra) and was sufficiently pure to be used in the next
reaction.
collected and dried to give 70.4 g (quant.) of 4: mp 149–
154°C (lit [22], mp 155°C).
2-(2-Pyridyl)indole (5). A mixture of 25.5 g (0.121 mol)
of 4 and approximately 85 g of PPA acid was heated to
130°C with efficient stirring. After a few minutes, a
vigorous, exothermic reaction ensued that rapidly
increased the temperature of the mixture to >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, followed
by washing of the organic phase with H2O (3×) and brine
(1×), drying (K2CO3), and concentration in vacuo
afforded 21.5 g (91%) of 5. TLC (5% Et3N in EtOAc)
showed a single, high Rf spot. Column chromatography
(activity III basic alumina, elution with benzene) gave
material having mp 151–152.5°C (lit [22], mp 154°C);
N,N-[2-(2-Indolyl)-1-piperidineacetyl]dimethylamine (7).
A
mixture of (6) (9.50 g, 0.0474 mol), Et3N
(20 mL), and 2-chloro-N,N-dimethylacetamide (10.5 g,
0.0864 mol) in acetone (500 mL) was stirred at room
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of 7-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
temperature for 12 h. The solvent was removed in vacuo,
and the residue was distributed between 10% K2CO3 and
CHCl3. The combined CHCl3 extracts were washed with
10% K2CO3 and dried (K2CO3), and the solvent was
removed in vacuo to give a brown oil (20 g), which was
chromatographed over 294 g of Woelm activity III
neutral alumina. Elution with benzene (300 mL) and 25%
CHCl3-benzene (600 mL) gave an oil (16.1 g), which
was dissolved in Et2O and hexane and stored at 0°C. The
resulting crystalline 7 (6.4 g) was collected. Elution with
50% CHCl3-benzene (600 mL), CHCl3 (300 mL), and
0.3% MeOH–CHCl3 (300 mL) afforded additional 7
(1.6 g). Further elution with 0.3% MeOH–CHCl3
(600 mL) gave a mixture (441 mg) of 7 and starting
material 6, which was not further separated. The total yield
of 7 was 8.0 g (59%). Recrystallization from EtOAc give
mp 156–157°C; IR 1645 (C¼O), and 3500 cmꢀ1 (NH);
NMR δ 9.22 (m, 1H), 7.6–6.9 (m, 4H), 6.35 (s, 1H), 3.22
(s, 1H, CH2C¼O), 3.00 (s, 1H, CH2C¼O), 2.83 (s, 3H, N
(CH3)2), 2.78 (s, 3H, N (CH3)2), and 3.5–1.5 (m, 9H).
Anal. Calcd for C17H23N3O: C, 71.55; H, 8.12; N,
14.72. Found: C, 71.65; H, 8.14; N, 14.99.
After filtering and washing the filter cake with acetone,
the solvent was evaporated to afford a residue that was
partitioned between CHCl3 and 10% K2CO3. The CHCl3
extracts were dried (K2CO3), and the solvent was
removed to give 84 mg (83%) of off-white crystals
identical with that of authentic tetracyclic base (1)
prepared in our laboratory [4].
7-Hydroxy-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]
quinolizine (8). Sodium borohydride (180 mg) was added
to a solution of ketone (2) (94 mg, 0.39 mmol) in EtOH
(100 mL). After stirring at room temperature for 21 h, the
EtOH was removed, and the residue was suspended in
water. The insoluble material was filtered and washed
with H2O (2×) and with CHCl3 (3×). After drying the
white powder (61 mg, 64%), it had mp 215–216°C dec.
Material crystallized from hot DMF had mp 210–211°C
dec; UV λmax (95% EtOH) (log ε) 282 (3.88) and 289
(3.30) nm. This material was too insoluble to obtain
satisfactory NMR spectra.
Anal. Calcd for C15H18N2O: C, 74.35; H, 7.49; N,
11.56. Found: C, 74.25; H, 7.55; N, 11.73.
7-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine
(2). A mixture of amide 7 (3.25 g, 0.0114 mol), PPA
(50 g), and freshly distilled POCl3 (100 mL) was heated
Acknowledgment. We thank Dartmouth College for support.
at reflux under nitrogen for 0.5 h. The reaction was
cooled, and the excess POCl3 was decanted and
discarded. The remaining purple sludge was decomposed
with H2O and ice. The resulting mixture was made
alkaline with NaOH (70 g in 400 mL of H2O), and the
precipitate was isolated by filtration, washed with CHCl3
(3×), and dried (K2CO3), and evaporated in vacuo to give
775 mg of ketone 2. The aqueous filtrate was extracted
with CHCl3. The combined CHCl3 extracts and filter
cake washings (about 500 mL) were dried (K2CO3) and
chromatographed (without reducing the volume of
solvent) over 70 g of Woelm activity III basic alumina.
Elution with CHCl3 (920 mL) gave 539 mg of ketone
(2). The total yield of 2 that was homogeneous by TLC
was 1.314 g (48%). Material crystallized from n-BuOH
had mp 251°C (lit [16], mp 260°C); UV λmax (95%
MeOH) (log ε) 241 (4.21), 263 (4.09), and 295 (4.02) nm
(lit [16]; λmax (MeOH) (log ε) 243 (4.22), 262 (4.07), and
297 (4.00) nm); IR (KBr) 1580 (C¼C), 1620 cmꢀ1
(C¼O). A smaller scale reaction (0.005 mol of amide 7)
afforded 2 in 78% yield.
REFERENCES AND NOTES
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Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71; N,
11.66. Found: C, 74.82; H, 6.64; N, 11.75.
Reduction of ketone 2 with lithium aluminum hydride
to afford alcohol 1.
A mixture of ketone 2 (108 mg,
0.449 mmol) and LiAlH4 (107 mg) in dry THF (70 mL)
was heated at reflux for 4 h. The reaction mixture was
cooled, and the lithium compounds were decomposed by
successively adding H2O, 40% NaOH, and then H2O.
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D. C. Tompkins, R. B. Nelson, L. J. Dolby, and G. W. Gribble
Vol 000
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Journal of Heterocyclic Chemistry
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