Synthesis of β-carbolines via a silver-mediated oxidation of tetrahydro-β-carbolines

Article abstract of DOI:10.1016/j.tetlet.2017.05.098

The oxidation of tetrahydro-β-carbolines to β-carbolines using silver carbonate was developed as an alternative to current methods. The oxidation is extremely mild and provides the products in modest to good yields after purification. A number of functional groups are tolerated by this methodology, including reduction-sensitive groups which are often cleaved with other methods. Though the mechanism is not fully understood, the reaction proceeds in an open flask, is not sensitive to light or moisture, and provides a viable synthetic route to compounds that are not easily prepared via other methodologies.

Full text of DOI:10.1016/j.tetlet.2017.05.098

Accepted Manuscript
Synthesis of β-Carbolines via a Silver-Mediated Oxidation of Tetrahydro-β-
carbolines
Sierra D. Durham, Brianna Sierra, Maximillian J. Gomez, Jennifer K. Tran,
Marc O. Anderson, Nick A. Whittington-Davis, Scott Eagon
PII:
S0040-4039(17)30709-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.098
TETL 48991
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 April 2017
27 May 2017
31 May 2017
Please cite this article as: Durham, S.D., Sierra, B., Gomez, M.J., Tran, J.K., Anderson, M.O., Whittington-Davis,
N.A., Eagon, S., Synthesis of β-Carbolines via a Silver-Mediated Oxidation of Tetrahydro-β-carbolines,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.098
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Graphical Abstract
Synthesis of β-Carbolines via a Silver-Mediated Oxidation of Tetrahydro-β-
carbolines
Sierra D. Durhama, Brianna Sierraa, Maximillian J. Gomeza, Jennifer K. Trana, Marc O.
Andersonb, Nick A. Whittington-Davisb and Scott Eagona,*
aDepartment of Chemistry and Biochemistry, California Polytechnic State University, 1 Grand
Ave., San Luis Obispo, CA 93407, USA.
bDepartment of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway
Avenue, San Francisco, CA 94132, USA.
* Corresponding author: Department of Chemistry & Biochemistry, California Polytechnic State
University, 1 Grand Avenue, San Luis Obispo, CA 93407, USA. Email: seagon@calpoly.edu
Abstract
The oxidation of tetrahydro-β-carbolines to β-carbolines using silver carbonate was
developed as an alternative to current methods. The oxidation is extremely mild and provides
the products in modest to good yields after purification. A number of functional groups are
tolerated by this methodology, including reduction-sensitive groups which are often cleaved with
other methods. Though the mechanism is not fully understood, the reaction proceeds in an
open flask, is not sensitive to light or moisture, and provides a viable synthetic route to
compounds that are not easily prepared via other methodologies.
Keywords
Oxidation; Silver Carbonate; β-Carboline; Aromatization
Introduction
β-Carbolines are reoccurring molecular motifs in natural products such as hyrtiocarboline
(1), which was isolated from a Papua New Guinea marine sponge Hyrtios reticulatus,1 and
eudistomin V (2), which was isolated from Australian ascidian Pseudodistoma aureum marine
sponges.2 The β-carboline scaffold is also present in modern pharmaceuticals including
Tadalafil (Cialis/Adcirca), a phosphodiesterase-5 inhibitor. In addition, the β-carboline core is

found in numerous molecules with antiviral3,4 and anticancer5 activities, and also displays
inhibitory effects against kinases6 and acetylcholinesterases,7 among others.
Figure 1. Structure of hyrtiocarboline (1) and eudistomin V (2).
Given their utility, a variety of methods have been developed to synthesize β-carbolines.
Many synthetic routes begin with the Pictet-Spengler reaction with a tryptamine derivative and
an aldehyde to form the corresponding tetrahydro-β-carboline intermediate. This initial reaction
is most commonly followed by a palladium8 oxidation reaction to form the final β-carboline
product. However, palladium-mediated oxidation has several drawbacks including catalyst cost,
the reduction or cleavage of numerous functional groups and exhaustive purification required to
remove the toxic metal to acceptable levels for use in biological studies. Alternative carboline
oxidation methods such as potassium permanganate,9 DDQ10 and chromium reagents11 have
similar limitations and toxicity to palladium, while hypervalent iodine reagents like IBX12 are
usually required in superstoichiometric amounts and/or often require the presence of certain
functional groups13 to achieve successful β-carboline oxidation.
Our group has recently focused on the synthesis of β-carbolines after Harmine, a
naturally occurring β-carboline which was found to be a selective inhibitor of the Plasmodium
falciparum heat shock 90 protein (PfHsp90).14 In order to better understand this activity and
develop a structure-activity relationship (SAR) model, we began to synthesize a library of β-
carboline derivatives of harmine, including numerous analogs containing aromatic halogens.
Results and Discussion
Initially, our group synthesized several β-carbolines using a Pictet-Spengler reaction
under microwave conditions to precipitate the tetrahydro-β-carboline intermediate, followed by
oxidation over palladium on carbon in the microwave to give the final product.15 Though this
procedure could be used to rapidly generate compounds in good yields and excellent purity, a
number of functional groups did not survive the palladium-mediated oxidation. We began to test
a variety of other palladium and related hydrogenation catalysts to see if we could modulate the
oxidation reaction versus the cleavage of sensitive moieties. During these tests, an
undergraduate researcher accidently utilized silver carbonate instead of a traditional
hydrogenation metal. Much to our surprise, TLC indicated the presence of a β-carboline
product which was isolated and confirmed by NMR (Table 1, entry 1). After confirming these
surprising results, we scoured the literature and could find no reports of similar silver(I)-
mediated carboline oxidations, although silver carbonate has been used with other transition
metal systems as an oxidant.16,17 Given that silver is a fairly mild reagent, we sought to discover
if this methodology could be further developed to provide a new route to prepare β-carbolines
with reduction-sensitive functional groups.

We first began our methodological studies using 1-phenyl-2,3,4,9-tetrahydro-1H-β-
carboline HCl salt (Table 1) and testing various solvents and reagent equivalents.
Table 1. Silver(I) carbonate-mediated oxidation studies.
Isolated
Equiv.
Ag2CO3
Yield 3a
(%)
< 5
35
Entry
Solvent Time
1
2
3
4
5
6
0.1
1
1.5
2
4
2
DMF
DMF
DMF
DMF
DMF
DMSO
1 d
16 h
16 h
16 h
3 h
35
70
40
54
5 h
7
8
2
2
2
2
Dioxane 6 h
n.r.
—
—
a
EtOH
H2O
4 h
4 h
a
9
10b
Toluene 1 d
56
aComplex mixture of by-products observed by TLC.
bStarting material run as a free base in the absence of
Li2CO3.
Using catalytic Ag2CO3 gave poor yields, but stoichiometric and superstoichiometric amounts
resulted in modest to good yields in DMF, with 2 equivalents giving optimal yields after
purification by column chromatography (Table 1, entries 1-5). A variety of other solvents were
tested as well, with DMSO and toluene also giving satisfactory results, while protic solvents
gave a mixture of by-products (Table 1, entries 6-10). We found that 2 equivalents of Ag2CO3 in
DMF gave optimal yields, although heating for 16 hours at reflux was required. Using DMSO or
larger quantities of Ag2CO3 gave shorter reaction times but resulted in noticeably lower yields.
In addition to the methodological studies described in Table 1, we also tested various
other conditions to probe the reaction mechanism. Silver(I) oxide, silver(I) nitrate, and silver(I)
tetrafluoroborate were also found to provide product (3a) when reacted with the hydrochloride
salt of 1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline, but with lower observed yields (data not
shown). Running the reaction under argon, in the dark, or in a pure oxygen environment had no
effect on the observed rate as indicated by TLC. Moreover, the reaction produces small, round
metallic solids hypothesized to be Ag(0) based on XRF analysis (data not shown). While the
overall mechanism is unclear, these results suggest that neither oxygen nor light participate in
this reaction, but that silver alone is reduced during ring oxidation via an unknown redox
mechanism. This may also explain why two equivalents are required for maximal yields, as two
double bonds are formed during the oxidation. While much remains unknown about the
mechanism, our studies show that the reaction does not require an inert atmosphere and is not
sensitive to light or atmospheric water.
We next decided to investigate whether our optimized conditions would work with a
series of oxidation and reduction-sensitive functional groups (Table 2).

Table 2. Oxidation of substituted tetrahydro-β-carbolines using silver(I) carbonate.
Isolated
Yield 3
(%)
Isolated
Yield 3
(%)
Entry
1
Product
Time
16 h
Entry
9
Product
Time
70
2 d
25
2
3 d
44
10
23 h
26
3c
19 h
19 h
1 h
31
53
34
11
12c
13
14 h
15 h
18 h
47
54
27
4
5c
6c
6 h
40
26
57
14
15
16
2 d
32
38
24
7
3 d
23 h
22 h
8
20 h
cStarting material used in the form of a TFA salt
We were pleased to find that most functional groups were well tolerated by our
methodology, and that the products could be isolated in modest to good yields. Medicinally
attractive heteroatom-containing substituents including pyridine (3i), thiophene (3g) and 1,3-
benzodioxyl (3h) were also isolated in modest to satisfactory yields. Various reduction-sensitive
functional groups were well tolerated by this procedure. Aromatic chlorine (3b, 3m, 3n), bromine

(3o) and iodine (3p) groups were all successfully oxidized without cleavage of the aromatic-
halogen bond as would be seen with many traditional oxidation methods. In addition, β-
carbolines bearing either a chloro (3b) or methoxy (3c) group on the indole were prepared,
demonstrating that both electron rich and electron withdrawing groups are tolerated on the
indole ring. β-Carbolines containing a variety of alkyl groups were also successfully synthesized
using this oxidation, including a cyclopropyl-substituted β-carboline (3g). The unsubstituted β-
carboline, norharmane (3d) was also successfully oxidized using this method, demonstrating
that the reaction is not limited by the absence of an electron withdrawing or donating group.
While a number of functional groups were compatible with our procedure, a few key
limitations were identified. The oxidation reactions of tetrahydo-β-carbolines with ortho-
substituted phenyl groups in the R1 position failed to produce significant yields of the product.
The synthesis of β-carbolines bearing an o-chlorophenyl, o-iodophenyl and o-cyanophenyl were
attempted, but all three reactions yielded a mixture of the starting tetrahydro-β-carboline salt,
the dihydro-β-carboline intermediate and only traces of the desired β-carboline product. When
these substituents were tested at the meta or para position, however, the reaction proceeded
smoothly and resulted in successful isolation of the desired product (3k, 3m, 3n, 3p). These
results led us to conclude that adding a substituent to the ortho-position likely hinders the
reaction progression via some unknown steric interaction.
Conclusion
The synthesis of this 16 molecule library demonstrates that this procedure is effective for
β-carbolines with a wide range of substituents. This silver-mediated procedure allows for the
oxidation of tetrahydro-β-carbolines containing alkyl or aryl substituents with both electron
donating and electron withdrawing properties. Although this method produces the β-carboline
products in only modest to good yields, the ability to introduce functional groups to these
systems that would otherwise be reduced or cleaved is a notable advantage of using this silver-
mediated oxidation over traditional methodologies.
Acknowledgements
The authors gratefully acknowledge Dr. Megan Grabenauer of the Triangle Research
Institute for performing the HRMS analysis of all novel compounds. We would also like to thank
Dr. Ihsan Erden at San Francisco State University for his helpful discussions, as well as Dr.
Pete Palmer of San Francisco State University for his assistance with our XRF analysis. This
research did not receive any specific grant from funding agencies in the public, commercial or
not-for-profit sectors. The authors declare no competing financial interests.
Supplementary Data
Supplementary data including synthetic procedures and characterization data for all
reported compounds can be found at (INSERT WEB ADDRESS HERE)
References
1.
Inman, W. D.; Bray, W. C.; Gassner, N. C.; Lokey, R. S.; Tenney, K.; Shen, Y. Y.;
TenDyke, K.; Suh, T.; Crews, P. J. Nat. Prod. 2010, 73, 161-171.
2.
3.
Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod., 1998, 61, 959-960.
Quintana, M.; Piccini, L. E.; Zenere, J. D. P.; Damonte, E. B. Antiviral Res. 2016, 134,

26–33.
4.
5.
6.
Brahmbhatt, K. G.; Ahmed, N.; Sabde, S.; Mitra, D.; Pal, I.; Bhutani, K. K. Bioorg. Med.
Chem. Lett. 2010, 20 (15), 4416–4419.
Chatwichien, J.; Basu, S.; Budina-kolomets, A.; Murphy, M. E.; Winkler, J. D. Bioorg.
Med. Chem. Lett. 2016, 26 (20), 4884–4887.
Cuny, G. D.; Ulyanova, N. P.; Patnaik, D.; Liu, J.; Lin, X.; Auerbach, K.; Ray, S. S.; Xian,
J.; Glicksman, M. A.; Stein, R. L.; Higgins, J. M. G. Bioorg. Med. Chem. Lett. 2015, 22
(5), 2015–2019.
7.
Queiroz, M. M. F.; Queiroz, E. F.; Zeraik, M. L.; Marti, G.; Favre-Godal, Q.; Simoes-Pires,
C.; Marcourt, L.; Carrupt, P. A.; Cuendet, M.; Paulo, M. Q.; Bolzani, V. S.; Woolfender, J.
L. Phytochem. Lett. 2014, 10, 88–93.
8.
9.
Kamal, A.; Tangella, Y.; Manasa, K. L.; Sathish, M.; Srinivasulu, V.; Chetnac, J.;
Abdullah, A. Org. Biomol. Chem. 2015, 13 (32), 8652–8662.
Wu, J.; Zhao, M.; Wang, Y.; Wang, Y.; Zhu, H.; Zhao, S.; Peng, S. Bioorg. Med. Chem.
Lett. 2016, 26 (19), 4631–4636.
10. Liew, L. P. P.; Fleming, J. M.; Longeon, A.; Mouray, E.; Florent, I.; Bourguet-kondracki,
M.; Copp, B. R. Tetrahedron 2014, 70 (33), 4910–4920.
11. Zhang, Y.; Ling, Y.; Xu, C.; Luo, L.; Cao, J.; Feng, J.; Xue, Y.; Zhu, Q.; Ju, C.; Li, F.;
Zhang, Y.; Ling, X. J. Med. Chem. 2015, 58 (23), 9214–9227.
12. Panarese, J. D.; Waters, S. P. Org. Biomol. Chem. 2013, 11, 3428–3431.
13. Panarese, J. D.; Waters, S. P. Org. Lett. 2010, 12 (18), 4086–4089.
14. Shahinas, D.; Macmullin, G.; Benedict, C.; Pillai, D. R.; Shahinas, D.; Macmullin, G.;
Benedict, C.; Crandall, I.; Pillai, D. R. Antimicrob. Agents Chemother. 2012, 56 (8), 4207–
4213.
15. Eagon, S.; Anderson, M. O. Eur. J. Org. Chem. 2014, 1653–1665.
16. Youn, S. W.; Kim, Y. H. Org. Lett. 2016, 18, 6140–6143.
17. Seo, J.; Park, Y.; Jeon, I.; Ryu, T.; Park, S.; Lee, P. H. Org. Lett., 2013, 15, 3358–3361.

•
•
•
A novel oxidation of tetrahydro-β-carbolines using silver carbonate is reported
This methodology tolerates a wide range of reduction sensitive functional groups.
The reaction proceeds in an open flask and is not sensitive to light or moisture.