Oxidation of Tetrahydro-β-carbolines by Persulfate

Article abstract of DOI:10.1021/acs.orglett.9b02772

The development of persulfate-mediated oxidation of tetrahydro-β-carbolines is reported. This mild reaction facilitates the formation of a variety of 2-formyl N-substituted tryptamines and the related derivatives as key intermediates in moderate to excell

Full text of DOI:10.1021/acs.orglett.9b02772

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxidation of Tetrahydro-β-carbolines by Persulfate
Haijun Chen,* Fu Ye, Jing Luo, and Yu Gao
Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou
University, Fuzhou, Fujian 350116, China
S
* Supporting Information
ABSTRACT: The development of persulfate-mediated oxidation of
tetrahydro-β-carbolines is reported. This mild reaction facilitates the
formation of a variety of 2-formyl N-substituted tryptamines and the related
derivatives as key intermediates in moderate to excellent yields. The
method is applicable to direct last-stage oxidation of two interesting
pharmaceuticals, Cialis and evodiamine.
THβCs,9 herein we report an efficient persulfate-mediated
xidation as one class of important reactions enables a
1
Orange of powerful transformations. Traditional oxida- oxidation of THβCs for the synthesis of 2-formyl N-substituted
tryptamines and the related derivatives under mild conditions.
Persulfate has been demonstrated to be a useful and versatile
oxidant in organic chemistry because of its characteristics of
easy availability, good stability, and low toxicity.10 We
envisioned that careful consideration of the following points
might be beneficial for oxidation of THβCs: (a) a judicious
choice of the solvent and (b) the choice of an additive that
could enable the transformation under metal-free and mild
conditions.11
tion reactions often use expensive or toxic oxidants such as
chromium/manganese/lead salts. Recently, more and more
researchers are trying to utilize inexpensive and nontoxic
reagents for oxidation.2
Selenium dioxide is a useful and versatile oxidizing reagent
in organic synthesis.3 It participates in various types of
oxidation reactions, including allylic hydroxylation, benzylic
oxidation, oxidative rearrangement, oxidative demethylation,
and oxidative cleavage.4 Because of the toxicity of this reagent,
many reactions have been gradually replaced by other better
reagents in recent years.5 However, the selenium dioxide
oxidation with active methyl or methylene still plays an
important role in the transformation of organic chemical
functional groups.6 For example, in order to obtain 2-formyl N-
substituted tryptamines as key intermediates for further
transformation,7 SeO2-mediated oxidation of tetrahydro-β-
carboline derivatives (THβCs) is the most commonly used
method (Figure 1).8 Therefore, from environmentally friendly
and economic viewpoints, the utilization of other alternative
oxidants instead of SeO2 would be more appealing. In
continuation of our research on the functionalization of
We commenced our evaluation of the reaction parameters
employing THβC 1 as the model substrate (Table 1). An
extensive screening of solvents, oxidants, and additives revealed
that the use of K2S2O8 as the oxidant, additive Me4NCl as the
phase-transfer catalyst, and DMSO/H2O as the mixed solvent
provided Boc-2-formyl-Trp-OH 2 in 90% yield (entry 1).
DMSO/H2O as the mixed solvent was found to have an
important influence on this transformation (entries 2−5). The
use of less water slightly decreased the yield of the oxidation
(entries 6 and 7). No reaction occurred without oxidant (entry
8). Among various oxidants tested, Na2S2O8 and (NH4)2S2O8
were found to be less effective than K2S2O8 (entries 9 and 10).
A slight decrease in the yield was obtained without Me4NCl,
while larger amounts of Me4NCl or other additives did not
improve the yield (entries 11−13). Notably, using an
equivalent amount of K2S2O8 also gave a comparable yield
(entry 14).
With the optimal conditions in hand, we explored the scope
of this new oxidative ring-opening reaction. As shown in Figure
2, a series of THβCs were smoothly transformed into the
corresponding aldehydes in moderate to excellent yields. For
example, N-substituted 2-formyl-Trp-OH(Me) 2−4 were
obtained in good yields. Different N-substituted derivatives
were tolerated, and the desired products 5−11 were isolated in
65%−92% yield. A THβC bearing an N-methyl substituent on
the indole ring also reacted smoothly to provide 12 in 54%
Figure 1. 2-Formyl N-substituted tryptamines and the related
derivatives as key intermediates for the synthesis of representative
natural products and pharmaceuticals.
Received: August 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02772
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
respectively. Notably, in comparison with the traditional
multistep reaction or the direct formylation reaction,7e,f this
oxidation is more general and has milder operational
conditions.
Table 1. Optimization of the Reaction Conditions
To prove both the practicality and effectiveness of this
approach for large-scale synthesis, we prepared N-Boc-2-
formyl-Trp-OH 2 on a gram scale under the optimized
reaction conditions without a significant decrease in efficiency
(87% vs 90%, Figure 3; also see the detailed graphical
procedure in the Supporting Information).
b
entry
solvent
oxidant
K2S2O8
additive equiv of H2O yield (%)
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMSO
DMF
DMA
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0
20
20
20
0
0
5
10
20
20
20
20
20
20
20
93 (90 )
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
−
trace
46
trace
0
75
84
0
82
38
66
H2O
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Na2S2O8
(NH4)2S2O8
K2S2O8
K2S2O8
K2S2O8
0.2
0.1
0.1
89
<80
82
d
e
K2S2O8
Figure 3. Gram-scale reaction and last-stage oxidation.
a
Reactions were carried out by adding the oxidant (2.0 equiv) to a
stirred solution of 1 (0.1 mmol), H2O (0−20 equiv), and the additive
To further exemplify the synthetic utility of this oxidation,
two important pharmaceutical drugs were selected for last-
stage oxidation (Figure 3). Compound 24 was readily prepared
from the marketed small-molecule drug Cialis in a satisfactory
yield by our convenient oxidation. Rhetsinine (25)12 was
obtained in high yield through last-stage oxidation of
evodiamine without purification by column chromatography.
Further transformation of rhetsinine afforded one interesting
lead compound 26 with antibacterial activity.13
b
(Me4NCl, 0.1 equiv) in 1.0 mL of the solvent at 40 °C. Determined
by 1H NMR analysis of the crude products using 1,3,5-
c
d
trimethoxybenzene as an internal standard. Isolated yield. Other
additives instead of Me4NCl; see the Supporting Information for
e
details. K2S2O8 (1.0 equiv).
Several control experiments were carried out to investigate
the mechanism of this reaction. First, the oxidation of THβCs
is completely inhibited in the presence of TEMPO or ascorbic
acid, indicating that a free radical is involved in this reaction.
Second, this reaction afforded [18O]2 when H218O was used,
indicating that the oxygen atom comes from H2O (Figure 4A).
On the basis of the above results and literature reports, a
Figure 2. Reaction scope of persulfate-mediated oxidation.
yield. THβCs with a substituent on ring A were compatible
with this reaction, and the corresponding aldehydes 13−21
were obtained in good to high yields. The efficiency and
usefulness of this transformation was further demonstrated by
the synthesis of N-substituted 2-ketone derivatives. Com-
pounds 22 and 23 were obtained in 70% and 75% yield,
Figure 4. Mechanistic investigations and the proposed mechanism.
B
DOI: 10.1021/acs.orglett.9b02772
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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proposed mechanism for this mild oxidation is shown in Figure
4B.14 Decomposition of S2O8 leads to the formation of
2−
−•
sulfate radical anion SO4 under thermolysis in the DMSO
solvent.11 The carbon-centered radical A is generated from
THβC 1 by single electron transfer (SET) to SO4−•, followed
by further oxidation to afford B.15 Intermolecular nucleophilic
addition to B finally delivers N-Boc-2-formyl-Trp-OH 2.
In summary, a novel persulfate-mediated oxidation of
THβCs has been developed for the synthesis of a broad
range of 2-formyl N-substituted tryptamines and the related
derivatives under mild conditions. It was found that both the
oxidant and the cosolvents (DMSO/H2O) were critical factors
for this oxidation. The synthetic utility of this approach was
further demonstrated by last-stage oxidation of the marketed
small-molecule drug Cialis and the natural product evodi-
amine.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02772.
(12) (a) Miyazawa, M.; Fujioka, J.; Ishikawa, Y. J. Sci. Food Agric.
2002, 82, 1574. (b) Kato, A.; Yasuko, H.; Goto, H.; Hollinshead, J.;
Nash, R. J.; Adachi, I. Phytomedicine 2009, 16, 258. (c) Wehle, S.;
Espargaro, A.; Sabate, R.; Decker, M. Tetrahedron 2016, 72, 2535.
(13) Wang, Q.; Feng, X.; Wang, M.; Chen, Y.; Guan, F.; Shan, Y.;
Yin, M.; Zhao, X.; Sun, H.; Zhao, Y. CN 102093357 A, 2011.
(14) (a) Laha, J. K.; Satyanarayana Tummalapalli, K. S.; Jethava, K.
P. Org. Biomol. Chem. 2016, 14, 2473. (b) Xie, L.; Lu, C.; Jing, D.; Ou,
X.; Zheng, K. Eur. J. Org. Chem. 2019, 2019, 3649.
Optimization studies, mechanistic studies, synthesis
procedures, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chenhaij@gmail.com.
ORCID
(15) (a) Li, C. Acc. Chem. Res. 2009, 42, 335. (b) Liu, X.; Meng, Z.;
Li, C.; Lou, H.; Liu, L. Angew. Chem., Int. Ed. 2015, 54, 6012.
Haijun Chen: 0000-0001-7945-2461
Yu Gao: 0000-0002-1137-7669
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the Natural Science
Foundation of Fujian Province (2019J01202).
■
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DOI: 10.1021/acs.orglett.9b02772
Org. Lett. XXXX, XXX, XXX−XXX