Short Synthesis of 2-oxo-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine

Full text of DOI:10.1080/00304948.2018.1525985

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
Short Synthesis of 2-oxo-1,2,3,4,6,7,12,12b-
Octahydroindolo[2,3-a]quinolizine
Laurence W. Reilly Jr.,, Randall B. Nelson, & Gordon W. Gribble
To cite this article: Laurence W. Reilly Jr.,, Randall B. Nelson, & Gordon W. Gribble (2018) Short
Synthesis of 2-oxo-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine, Organic Preparations and
Procedures International, 50:5, 509-511, DOI: 10.1080/00304948.2018.1525985
To link to this article: https://doi.org/10.1080/00304948.2018.1525985
Published online: 04 Jan 2019.
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Organic Preparations and Procedures International, 50:509–511, 2018
# 2018 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1525985
OPPI BRIEF
Short Synthesis of 2-oxo-1,2,3,4,6,7,12,12b-
Octahydroindolo[2,3-a]quinolizine
Laurence W. Reilly Jr., Randall B. Nelson, and
Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
The title compound, 2-oxo-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine (1), was
first synthesized in 1952 by Groves and Swan1 as an entry point to the yohimbine-reser-
pine-corynantheine family of alkaloids. Subsequently, this indole ketone was prepared by
several groups,2–14 and Kametani parlayed 1 into a synthesis of yohimbine.5 In connection
with a project in our laboratory we required a short, efficient, and atom-economical prepar-
ation of 1. Of the several known syntheses of 1 only the method of Potts and Nasri4
seemed suitable for us. We now describe a modification of this synthesis that involves the
coupling of 3-acetylindole (2) and 4-methoxypyridine (3) (Scheme 1).
Scheme 1. Retrosynthesis of 1.
Our synthesis of 1 is shown in Scheme 2. Whereas Potts and Nasri employed brom-
ine in their process,4 we found that iodine is superior in the reaction between 3-acetylin-
dole (2) and 4-methoxypyridine (3) to give pyridinium salt 4, in modest yield after
crystallization. Reduction of pyridinium salt 4 with LiAlH4 in THF and acid treatment
of the intermediate dihydropyridine 5 resulted in Pictet-Spengler cyclization and
hydrolysis of the enol ether to give 1 in 59% yield after chromatography. Although the
overall yield is only 20–25%, this process satisfies our aforementioned criteria.
Received December 4, 2017; in final form February 21, 2018.
Address correspondence to Gordon W. Gribble, Department of Chemistry, Dartmouth College,
Hanover, NH 03755, USA. E-mail: gordon.w.gribble@dartmouth.edu
509

510
Gribble et al.
Moreover, both 3-acetylindole (2)15 and 4-methoxypyridine (3)16 are commercially
available or easily synthesized.
Scheme 2. Synthesis of 1.
Experimental Section
4-Methoxypyridine (3).16 To a solution of 45.0 g (0.360 mol) of 4-methoxypyridine-N-
oxide (Olin) in 1.5 L of 2M H2SO4 was added over 135 min 90.0 g (1.38 mol) of zinc
dust. The solution was heated at 98 ꢀC for 16 h before it was cooled and basified with
concentrated NH4OH. Decanting and filtering the aqueous solution from unreacted zinc
and extraction with ether gave, after drying over anhydrous K2CO3 and concentration
in vacuo, a cloudy yellow oil. Distillation at H2O aspirator pressure gave 17.6 g (45%)
of 3 as a colorless oil: bp 150–160 ꢀC with external heating from a heat gun (lit.17 bp
185 ꢀC (712 Torr)).
4-Methoxy-1-(2-(3-indolyl)-2-oxoethyl)pyridinium iodide (4). A mixture of 5.00 g
(0.031 mol) of 2 (Sigma) and 7.02 g (0.064 mol) of 3 in 50 mL of dry dioxane was
heated on a steam bath until solution was complete. Iodine (4.82 g) was added and heat-
ing was continued for 10 min. More iodine (3.15 g) was added (a total of 7.97 g;
0.031 mol) and the solution was heated for 1 h with occasional swirling. The reaction
mixture was cooled to room temperature and 50 mL of absolute ethanol was added.
Upon cooling to 0 ꢀC there was deposited in several crops 4.51 g (37%) of crystalline 4.
Recrystallization from ethanol yielded 4 as golden needles: mp >250 ꢀC; TLC (40%
CH3OH in CHCl3) Rf ¼ 0.10, stains purple.
Anal. Calcd. for C16H15N2O2I: C, 48.75; H, 3.84; N, 7.11. Found: C, 48.24; H,
3.36; N, 7.11.
2-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (1). To a suspension of
2.43 g (0.064 mol) of LiAlH4 in 250 mL of THF under dry nitrogen at 0–5 ꢀC was added
4.48 g (0.011 mol) of 4. The reaction mixture was refluxed for 4 h before it was cooled
to 0–5 ꢀC and treated with 25 mL of H2O. The gelatinous mixture was filtered through
Celite and the filter cake was washed with THF. This solution was made strongly acidic
with 25 mL of 9M HCl and allowed to stand at room temperature for 15 h. Ice was
added and the aqueous solution was basified with concentrated NH4OH and extracted
with CH2Cl2. The organic phase was washed with H2O and brine, dried over anhydrous

2-oxo-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine
511
K2CO3, and concentrated in vacuo. Column chromatography of the resultant red gum
(activity III neutral alumina, elution with benzene-ether (1:1) and then CHCl3) yielded
1.57 g (59%) of 1 as tan crystals. Recrystallization from 15% hexane in toluene yielded
1 as yellow needles: mp 185–185.5 ꢀC (lit.4 mp 181–182 ꢀC).
Acknowledgment
We gratefully acknowledge support from Dartmouth College.
ORCID
Gordon W. Gribble
http://orcid.org/0000-0002-7573-0927
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