An improved synthesis of canthin-6-one

Article abstract of DOI:10.1081/SCC-120017199

An improved route has been devised which provides canthin-6-one in the highest yield from tryptamine to date. Tryptamine is converted to Nb-benzyltryptamine via reaction with benzoylchloride and reduction using LAH. Pictet-Spengler condensation with 2-ketoglutaric acid, removal of the protecting group by CTH, and aromatization with MnO₂ affords canthin-6-one in 48% overall yield.

Full text of DOI:10.1081/SCC-120017199

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An Improved Synthesis of Canthin-6-one
Kevin M. Czerwinski a , Craig A. Zificsak a , John Stevens a , Melissa Oberbeck a , Christopher
Randlett a , Melissa King a & Steve Mennen a
a Department of Chemistry, University of Wisconsin-Stevens Point, Stevens Point, Wisconsin,
USA
Version of record first published: 21 Aug 2006
To cite this article: Kevin M. Czerwinski, Craig A. Zificsak, John Stevens, Melissa Oberbeck, Christopher Randlett, Melissa
King & Steve Mennen (2003): An Improved Synthesis of Canthin-6-one, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:7, 1225-1231
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1225–1231, 2003
An Improved Synthesis of Canthin-6-one
Kevin M. Czerwinski,* Craig A. Zificsak, John Stevens,
Melissa Oberbeck, Christopher Randlett,
Melissa King, and Steve Mennen
Department of Chemistry, University of Wisconsin-
Stevens Point, Stevens Point, Wisconsin, USA
ABSTRACT
An improved route has been devised which provides canthin-6-one in
the highest yield from tryptamine to date. Tryptamine is converted to
Nb-benzyltryptamine via reaction with benzoylchloride and
reduction using LAH. Pictet-Spengler condensation with 2-ketoglu-
taric acid, removal of the protecting group by CTH, and aromatiza-
tionwith MnO affords canthin-6-one in 48% overall yield.
2
Key Words: Canthinone; Canthin-6-one; Pictet-Spengler condensa-
tion; Tryptamine.
*Correspondence: Kevin M. Czerwinski, Department of Chemistry, University
of Wisconsin-Stevens Point, Stevens Point, WI 54481, USA; E-mail: kczerwin@
uwsp.edu.
1225
DOI: 10.1081/SCC-120017199
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1226
Czerwinski et al.
Canthin-6-one (4), first isolated in1952 by Haynes, [1] is a member of
the canthinone indole alkaloidal family which includes some 55 structur-
ally related compounds.[2–7] These compounds are of great interest due to
their broad range of pharmacological activity.[3] Consequently, we were
interested in preparing this compound as well as other members of the
family for further study and biological screening but required a direct and
flexible method of preparation. Previous syntheses of canthin-6-ones have
beencarried out by several groups, however, these routes are either
laborious, comprised of steps of low yield, or require harsh reagents
[8–15]
which may lead to the degradationof substituents.
As such, we
report an improved route to canthin-6-one, which utilizes relatively
mild reaction conditions, proceeds through known intermediates but in
a new route, and provides the highest overall yield from tryptamine to
date.
[16]
As has beenaptly demonstrated by Cook,
the key to utilizing
tryptamines in the synthesis of the canthinone carbon skeleton is to
mono-protect the nitrogen atom of the ethylamine side chain so as to
avoid cyclization at the amino nitrogen atom by the propionic acid
side-chain as opposed to the indole nitrogen. Toward this end, trypta-
mine (1) was reacted with benzoyl chloride in a solution of acetone
and NaOH at ꢀ30ꢁC to provide Nb-benzoyltryptamine in 98%
yield.[17] This amide was easily reduced with LAH inahnydrous
[18]
THF to provide Nb-benzyltryptamine (2) in98% yield. Pictet-
Spengler condensation of 2 with 2-ketoglutaric acid ina mixture of
benzene and dioxane at reflux using a Dean-Stark trap afforded an

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Synthesis of Canthin-6-one
1227
80% yield of Nb-benzylhexahydrocanthin-6-one (3).[19] Debenzylation
of 3 by catalytic transfer hydrogenation (CTH) utilizing ammonium
formate and 10% Pd/C in anhydrous methanol provided hexahydro-
canthin-6-one (83%).[20] Subsequent reaction of freshly prepared
[21]
MnO2
in anhydrous benzene with this intermediate provided a
78% yield of 4 which affords an overall yield of canthin-6-one (4)
from tryptamine of 48%. This improves the yield by greater than
100% (48% versus 18% overall from tryptamine) and is a marked
increase in molecular efficiency.
EXPERIMENTAL SECTION
All starting materials were purchased from Aldrich Chemical
Company unless otherwise noted. Thin layer chromatography was
performed onMerck silica gel 60 F-254 TLC plates. Unless otherwise
1
noted, all H NMR spectra were measured at a resonance frequency of
200 MHz and all 13C NMR spectra at 50 MHz. Chemical shifts are
reported in ppm relative to the indicated solvent. Coupling constants
(J values) are inHertz. Mass spectrometry was performed usign
a Hewlett-Packard 5985B GC–Mass Spectrometer.
Nb-benzoyltryptamine.[22,23] To a stirred solutionof tryptamine ( 1)
(10.0 g, 0.0624 mol), NaOH(S) (6.15 g, 0.154 mol), and anhydrous acetone
(300 mL) at ꢀ30ꢁC was added benzoyl chloride (8.0 mL, 0.069 mol) drop-
wise. The reactionwas allowed to stir until complete (TLC–silica, methy-
lene chloride/ethyl acetate, 9:1, v/v) and then quenched with H2O
(100 mL, 5 mol). Additional water (600 mL) was added and the suspen-
sionfiltered to yield white crystals. The filtrate was extracted with diethyl
ether (5 ꢂ 200 mL), dried over anhydrous K2CO3, and the solvent
removed under vacuum. Successive recrystallization of the mother
liquors from dichloromethane provided Nb-benzoyltryptamine
(15.608 g, 59.093 mmol –95%) as a white solid: M.p. 130.7–131.5ꢁC;
1H NMR (DMSO-d6) ꢀ 2.9 (t, J ¼ 10.0, 2H); 3.5 (m, 2H); 6.9–7.7
(m, 10H); 8.5 (s, 1H); 10.7 (s, 1H).
Nb-benzyltryptamine (2).[19] A solutionof Nb-benzoyltryptamine
(1.10 g, 4.17 mmol) inanhydrous THF (25 mL) was cooled to 0 ꢁC an d
LiAlH4 (95%, 1.3 g, 34.5 mmol) was added cautiously to the solution.
The reaction was heated to reflux and monitored by TLC (silica, ethyl
acetate, NH3 vapor). Uponcompletion, the reactionwas cooled to 0 ꢁC
and quenched by addition of 10% THF/H2O (1 mL), 10% NaOH (3 mL),
and H2O (1 mL). Heating the light gray mixture to reflux (1.5 h) induced
precipitation of a white solid. Gravity filtration and solvent removal

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1228
Czerwinski et al.
under reduced pressure yielded a brown oil. The oil was subjected to
columnchromatography (silica, (ethyl acetate/NH 4OH) ¼ 54:1, v/v)
which yielded Nb-benzyltryptamine (2) (1.02 g, 4.09 mmol –98%) as a
yellow oil: 1H NMR (DMSO-d6) ꢀ 2.8 (m, 4H); 3.6 (s, 2H); 7.4 (m,
11H); 10.7 (s, 1H); MS (CI, CH4) m/z (relative intensity) 251 (Mþ1,
100%).
Nb-benzyl-1,2,3,3a,4,5-hexahydrocanthin-6-one (3).[19] Nb-benzyltryp-
tamine (1.28 g, 5.10 mmol), a-ketoglutaric acid (0.9 g, 5.8 mmol), and a
solution of benzene:dioxane (100 mL 6:4 v/v) were heated to reflux under
a N2(g) atmosphere using a Dean-Stark trap for water removal.
The reactionwas monitored by TLC (silica, ethyl acetate) and upon
completion, allowed to cool and the volatiles removed under reduced
pressure. The residue was dissolved ina mixture of CH 2Cl2 (30 mL)
and saturated aqueous NaHCO3 (60 mL). Extractionwith CH 2Cl2
(3 ꢂ 25 mL) and drying over anhydrous Na2CO3 followed by solvent
removal under reduced pressure yielded a dark green residue. Flash chro-
matography (silica, hexanes:ethyl acetate:NH4OH, 2:1:0.15, v/v/v)
yielded Nb-benzyl-1,2,3,3a,4,5-hexahydrocanthin-6-one ꢁ(3) (1.29 g,
1
4.08 mmol, 80%) as a light greensolid: M.p. 173.3–173.9 C; H NMR
(CDCl3)ꢀ 1.8 (m, 1H); 2.6 (m, 6H); 3.2 (m, 1H); 3.4 (d, 1H, J ¼ 14); 4.2 (d,
1H, J ¼ 14); 7.1–7.5 (m, 8H); 8.4 (m, 1H).
1,2,3,3a,4,5-hexahydrocanthin-6-one.[24] To
a
slurry of Pd/C
(10%–0.500 g), HCO2NH4 (0.65 g), and anhydrous CH3OH (10 mL)
was added Nb-benzyl-1,2,3,3a,4,5-hexahydrocanthin-6-one (0.250 g,
0.790 mmol) dissolved inbenzene (10 mL). The mixture was heated to
reflux and monitored by TLC (silica gel, 3:2 acetone:EtOAc, 5 min
NH3 exposure) with additions of HCO2NH4 (0.500 g) every 6 h and
Pd/C (0.500 g) every 12 h. After 36 h the reactionmixture was filtered
through Celite and the filter cake rinsed with copious amounts of
CH2Cl2 until TLC indicated complete removal of the product. The
organic phase was brought to a pH of 10 (NH3(aq)), and the aqueous
phase extracted with CH2Cl2 (3 ꢂ 25 mL). The organic extracts were
dried over anhydrous K2CO3 and gravity filtered. The solvent was
removed under reduced pressure to provide 1,2,3,3a,4,5-hexahydro-
canthin-6-one (0.148 g, 0.656 mmol, 83%): 1H NMR (CDCl3) ꢀ 1.827
(m, 2H); 2.431 (m, 1H); 2.745 (m, 4H); 3.193 (m, 1H); 3.517 (m, 1H);
3.993 (m, 1H); 7.329 (m, 3H); 8.365 (m, 1H); 13C NMR (CDCl3) ꢀ 21.271,
28.612, 32.649, 43.017, 49.730, 110.700, 113.957, 115.838, 121.557,
122.077, 127.353, 132.017, 133.393, 164.941.
Canthin-6-one (4).[19] Freshly prepared MnO2 (0.080 g) and
1,2,3,3a,4,5-hexahydrocanthin-6-one (0.071 g, 0.314 mmol) were vigor-
ously stirred ina solutionof bezneen:tolueen (4.5 mL:1.5 mL) at

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Synthesis of Canthin-6-one
1229
reflux, under an atmosphere of N2(g). Additional manganese dioxide
(0.080 g) was added after 20 h and 48 h. The reaction was judged com-
plete after 60 h (TLC–silica gel, 3:2 acetone:EtOAc, NH3 vapor). The
reaction slurry was subjected to gravity filtration twice and the filtrant
rinsed with hot benzene. Removal of the solvent under reduced pressure
afforded canthin-6-one (4) (0.054 g, 0.245 mmol–78%): M.p. 161.2–
162.9, lit. 161.0–161.5; 1H NMR (CDCl3) ꢀ 6.988 (d, 1H, J ¼ 10);
7.533 (t, 1H, J ¼ 8); 7.713 (t, 1H, J ¼ 8); 7.963 (d, 1H, J ¼ 5); 8.026
(d, 1H, J ¼ 10); 8.116 (d, 1H, J ¼ 8); 8.682 (d, 1H, J ¼ 8); 8.832 (d,
1H, J ¼ 5); 13C NMR (CDCl3) ꢀ 114.605, 115.526, 120.806, 122.526,
123.354, 123.723, 126.240, 126.348, 126.962, 127.039, 128.881, 137.523,
143.647, 157.110.
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