Biomimetic Oxidative Coupling Cyclization Enabling Rapid Construction of Isochromanoindolenines

Article abstract of DOI:10.1021/acs.orglett.8b02377

Herein, we report a biomimetic oxidative coupling cyclization strategy for the highly efficient functionalization of tetrahydrocarbolines (THCs). This process enables rapid access to complex isochromanoindolenine scaffolds in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.8b02377

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Biomimetic Oxidative Coupling Cyclization Enabling Rapid
Construction of Isochromanoindolenines
Jinxiang Ye,† Yuqi Lin,† Qing Liu, Dekang Xu, Fan Wu, Bin Liu, Yu Gao, and Haijun Chen*
College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
S
* Supporting Information
ABSTRACT: Herein, we report a biomimetic oxidative coupling
cyclization strategy for the highly efficient functionalization of
tetrahydrocarbolines (THCs). This process enables rapid access
to complex isochromanoindolenine scaffolds in moderate to
excellent yields. The reaction proceeds smoothly and rapidly
(complete within minutes) in an open flask. This operationally
simple protocol is scalable and compatible with a wide range of
functional groups. Late-stage functionalization of a pharmacologically relevant molecule is also demonstrated.
he development of concise and efficient approaches for
the rapid construction of diverse intricate molecular
T
architectures is of crucial importance. Therefore, this endeavor
still remains a preeminent goal in current synthetic method-
ology.1 Oxidative coupling reactions enable the direct
formation of new bonds in a sustainable and efficient manner2
and are extensively applied to synthesize complex molecules.3
Tetrahydrocarbolines (THCs) are a commonly occurring
core motif in several ubiquitous biologically active natural
alkaloids and pharmaceuticals.4 Among THCs, tetrahydro-β-
carbolines (THβCs) and tetrahydro-γ-carbolines (THγCs)
possess interesting pharmacological profiles,4a,5 indicating that
they are promising building blocks for the rapid synthesis of
complex scaffolds in drug discovery and development.4b,6
Therefore, functionalization of THCs has become an intense
subject in chemical research.7 For example, Liu et al. reported a
practical metal-free oxidative C−H functionalization of N-
carbamoyl THCs in the α-position.8 Kozmin and co-workers
demonstrated an efficient synthetic strategy to a skeletally
diverse chemical library of indoloquinolizidines.9 Roussi et al.
reported a direct functionalization of THβCs at the C4
position with various nucleophiles.10 We recently reported a
new oxidative rearrangement coupling reaction for the
synthesis of pyrrolo[3,4-b]quinolin-9-amines via efficient
functionalization of THβCs.11
Figure 1. Recent work for the construction of isochromanoindolenine
scaffolds.
oxidation reaction (Figure 1c),16 allowing for rapid access to a
library of isochromanoindolenines in a highly efficient and
selective manner.
We began our investigation by using THβC as the substrate.
After considerable efforts, the optimized reaction conditions
were found to furnish the desired product efficiently (Table 1).
FePc was crucial for the conversion (entry 1, Figures S1 and
S2),17 and other transition-metal catalysts did not lead to the
expected conversion (entry 2, Table S1).17 Using hydrogen
peroxide in lieu of TBHP (tert-butyl hydroperoxide) did not
afford the desired product (entry 3). Replacing CH3CN with
other solvents gave the desired product in low to modest yield
(entry 4, Table S2),17 while dichloromethane as the solvent
gave a similar yield. Accumulating evidence has suggested that
acetic acid can accelerate some catalytic oxidation reactions.18
Isochromanoindolenines are the central core of some natural
products such as voacalgine A and bipleiophylline (Figure
1a).12 However, the synthesis of isochromanoindolenine
scaffold had been scarcely explored before. Recently, Vincent
et al. developed an oxidative coupling strategy to access
isochromanoindolenines by using excess silver oxide as the
oxidant (Figure 1b).12c,13 In a continuing effort on late-stage
functionalization of complex molecules,14 we hypothesized that
direct functionalization of THCs for the synthesis of
isochromanoindolenines could be achieved via a catalytic
synthesis process.15 Herein, we present the oxidative coupling
between THCs and 2,3-bishydroxybenzoic acid using iron(II)
phthalocyanine (FePc) as a catalyst via biomimetic catalytic
Received: July 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02377
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
utility of MsOH was also beneficial to this reaction (entry 6),
despite other acids instead of MsOH also leading to a
comparable yield (entry 7, Table S3).17
Table 1. Optimized Reaction Conditions
Having established the optimal reaction conditions, the
substrate scope was then investigated to examine the generality
of this protocol. As shown in Figure 2, the reaction conditions
could be applied to a wide range of THβCs and THγCs, to
provide the corresponding products in moderate to excellent
yields. The reaction was suitable for different N-substituted
THCs, such as 2, 5, 7, 9, and 11. THCs bearing electron-
donating groups, such as tert-butyl, methyl, and methoxy, were
suitable substrates affording the corresponding products (16−
18, 22, 29) in satisfactory yields. Electron-withdrawing groups,
such as F, Cl, and CF3, were well tolerated in this
transformation (1, 6, 8, 10, 13−15, 19−21, 23−25, 28, 31,
and 33).
b
entry
1
2
variation of reaction conditions
yield (%)
c
as shown
85 (82)
<50
trace
0−80
25
36
50−81
d
other catalyst instead of FePc
H2O2 instead of t-BuOOH
other solvents
without AcOH
without MsOH
3
4
d
5
6
7
d
other acids instead of MsOH
a
Reaction conditions: THβC (0.1 mmol), 2,3-dihydroxybenzoic acid
Notably, polyhalogenated THγC was also compatible with
the reaction leading to the desired product 26 in good yield.
The chemical structures of 2 and 19 were further established
by the X-ray crystallographic analysis.
Evodiamine, an important class of THβC, exhibits diverse
pharmacological properties.19 Under slightly optimized reac-
tion conditions, evodiamine could be submitted to this method
to afford the desired product 35 in 65% yield (Figure 3a). To
investigate the practical application of this transformation in
(0.2 mmol), cat. FePc (2.5 mol %), AcOH (0.2 mmol), MsOH (0.1
equiv), CH3CN (1 mL), and then t-BuOOH (aq, 65%, 0.3 mmol), 5
b
1
°C, 10 min. The yield was determined by H NMR analysis of the
crude products with dibromomethane as the internal standard.
Isolated yield. See Supporting Information Tables S1−S3.
c
d
We were thus delighted to find that the addition of acetic acid
did significantly improve the solubility of FePc (Figures S3 and
S4), and it was crucial for a full conversion (entry 5). The
Figure 2. Scope of the oxidative coupling cyclization.
B
DOI: 10.1021/acs.orglett.8b02377
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Organic Letters
Letter
investigation21 and our experimental observations, a plausible
mechanism is proposed (Figure 4c). The generation of a tert-
butyloxy radical from TBHP is catalyzed by FePc. This tert-
butyloxy radical can abstract a hydrogen atom from SM2,
forming the radical species 40 and tert-butanol.22 FePc-
catalyzed oxidation of 2,3-dihydroxybenzoic acid delivers the
unstable ortho-quinone intermediate (detected by HRMS, see
Figure S5), which combined with radical 40 to form 41.17,23
Then 41 is transformed into the desired product by Bronsted
acid.
In conclusion, we have developed the first catalytic method
for the functionalization of THCs under mild conditions via an
efficient FePc-catalyzed oxidative coupling cyclization. This
scalable reaction proceeds readily in an open flask using
inexpensive reagents and enables rapid access to complex
isochromanoindolenines in an atom-economic manner. Nota-
bly, the suitable calculated physicochemical properties of all
final compounds (Table S5) suggest that these isochroma-
noindolenines will be worthwhile for future biological
evaluation.17 Further pharmacological characterizations are
underway, and findings will be reported in due course.
Figure 3. Application of oxidative cyclization coupling reaction.
organic synthesis, we conducted a gram-scale reaction (Figure
3b). The desired product 33 was obtained without a significant
decrease in efficiency (81% versus 82%, see detailed graphical
procedure in the Supporting Information).
To gain an insight into the mechanism of this biomimetic
oxidative coupling cyclization, several controlled experiments
were conducted. We found that THCs with N-substituents on
the indole ring failed to react with 2,3-dihydroxybenzoic acid
(Figure 4a). We next investigated the occurrence of potential
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.8b02377.
1
Details of the experiments and H and 13C NMR of all
new compounds (PDF)
Accession Codes
CCDC 1813585, 1813868, 1816179, and 1841119 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chenhaij@gmail.com.
ORCID
Yu Gao: 0000-0002-1137-7669
Haijun Chen: 0000-0001-7945-2461
Author Contributions
†These authors contributed equally.
Notes
Figure 4. Mechanistic investigation of FePc-catalyzed oxidative
coupling cyclization.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
intermediates in FePc/TBHP system. Treatment of THβC or
THγC with 2.5 mol % of FePc in the presence of TBHP
without adding 2,3-dihydroxybenzoic acid provided peroxides
38 and 39, respectively.20 However, these intermediates 38 or
39 did not provide any desired products under our standard
conditions (Figure 4b). To gain preliminary mechanistic
information about this transformation, radical trapping experi-
ments were performed. In the presence of various radical
inhibitors, no product was obtained under the optimized
conditions (Table S4).17 Based on previous mechanistic
This work was supported by Joint research project of health
and education of Fujian Province (No. WKJ2016-2-06) and
the National Natural Science Foundation of China (No.
81571802).
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