One-Pot Synthesis of N-(α-Peroxy)Indole/Carbazole via Chemoselective Three-Component Condensation Reaction in Open Atmosphere

Article abstract of DOI:10.1021/acs.orglett.5b02881

A facile one-pot synthesis of N-(α-peroxy)indole and N-(α-peroxy)carbazole has been developed using metal-free, organo-acid-catalyzed three-component condensation reactions of indole/carbazole, aldehyde, and peroxide. Based on the reaction discovered, a new synthetic proposal for Fumitremorgin A and Verruculogen is introduced. Such a protocol could be easily handled and scaled up in an open atmosphere with a wide substrate scope, enabling the construction of a new molecule library.

Full text of DOI:10.1021/acs.orglett.5b02881

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of N‑(α-Peroxy)Indole/Carbazole via
Chemoselective Three-Component Condensation Reaction in Open
Atmosphere
,
†,‡
†
†
,†
Xinbo Wang,* Yupeng Pan, Kuo-Wei Huang, and Zhiping Lai*
†Division of Physical Science and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900,
Kingdom of Saudi Arabia
‡
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen 518055, China
*
S Supporting Information
ABSTRACT: A facile one-pot synthesis of N-(α-peroxy)-
indole and N-(α-peroxy)carbazole has been developed using
metal-free, organo-acid-catalyzed three-component condensa-
tion reactions of indole/carbazole, aldehyde, and peroxide.
Based on the reaction discovered, a new synthetic proposal for
Fumitremorgin A and Verruculogen is introduced. Such a protocol could be easily handled and scaled up in an open atmosphere
with a wide substrate scope, enabling the construction of a new molecule library.
any indole-, carbazole-, and peroxide-containing com-
M
pounds possess antimalarial, antibacterial, and antitumor
1
activities. For example, the indoloquinoline alkaloid, cryptole-
pine, has been used as an antimalarial drug especially in central
and western Africa and also as an anticancer drug to intercalate
2
into DNA at cytosine−cytosine sites. Artemisinin (qinghaosu),
a peroxide-containing natural product, has long been used as a
3
highly effective antimalarial drug. As parasites evolve to be more
resistant to existing drugs, continuous design and synthesis of
4
new antimalarial compounds are desirable.
The α-amino peroxide pharmacophore is one of the salient
structural features that has been found to be effective in
5
antimalarial activities. Landmark accomplishments have been
achieved for the synthesis of α-amino peroxides, such as metal/
iodine/Brønsted acid-catalyzed benzylic N-adjacent C−H
6
peroxidation, radical oxidation of amino acid derivatives under
7
3
50 nm light irradiation, peroxide nucleophilic addition to
5
,8
imines,
and FeCl -catalyzed condensation of carbonyl,
3
t
9
BuOOH, and TMS-azide. These methods provided tools to
synthesize α-N-peroxy compounds, some of which have been
found to possess in vitro antimalarial activities. Unfortunately,
5
Figure 1. Literature-reported and our proposal for the late-stage
peroxide bridge formation and the key N-(α-peroxy)indole motif (in the
dashed box).
all of these protocols require either a special substrate (e.g.,
benzylic amine with N protected) or special conditions (e.g.,
heavy metal or hν). Moreover, none of them can be integrated
with the readily oxidizable indole residue and the classic oxidant
of peroxide to give N-(α-peroxy)indole, a somewhat rare
structure that is present in active natural products. For example,
12
14
cally, while no practical applicable method has been developed
over 40 years since its discovery. We have proposed a
nucleophilic annulation strategy to construct the α-indole
peroxide bridge (Figure 1) through an intermolecular three-
component condensation reaction of indole, aldehyde, and
10
11
Fumitremorgin A, Verruculogen, and its acetoxy derivative
Figure 1), three of the top-end products of the Fumitremorgin
(
15
16
peroxide. Baran et al. have used a similar strategy in their
recent total synthesis of Verruculogen and Fumitremorgin A.
family, contain an astounding α-indole amino endoperoxide
bridge. It was found that Fumitremorgin A affects the brain
stem, while Verruculogen decreases the GABA level and
inhibits the mammalian cell cycles. A non-heme Fe(II)-
catalyzed oxygen insertion pathway was proposed biosyntheti-
1
3
1c
Received: October 5, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02881
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Herein, we present our study of this condensation reaction to
build a new molecule library for new drug discoveries.
Indole derivative C, 3-methylbutanal, and BuOOH were
Scheme 1. Synthesis of N-(α-Peroxy)indole from the Three-
Component Condensation Reaction of Various Indoles,
t
a
Aldehydes, and Peroxides
chosen first as the model substrates to screen the reaction
conditions. As demonstrated in Table 1, p-toluenesulfonic acid
a
Table 1. Reaction Condition Screening
yield
yield
,
bc
b
,
c
entry solvent
time
(%)
entry solvent
time
(%)
d
1
DCM
DCM
DCM
DCM
DCE
1 h
5 s
20
8
DMF
THF
1 h
NR
NR
NR
40
e
2
85 (84 )
complex
complex
84
9
1 h
f
3
5 s
10
11
12
13
14
DMSO
MeCN
EA
1 h
g
4
0.5 h
5 s
0.5 h
1 h
5
17
6
7
CHCl3
acetone
5 s
86
toluene
EtOH
1 h
NR
35
1 h
NR
0.5 h
a
Reaction conditions: C (0.1 mmol), aldehyde (0.2 mmol), and
t
BuOOH (0.6 mmol) in 2 mL of solvent, rt, air. Then PTSA (ca. 3
b
1
mg) was added. Yield determined by H NMR data of reaction
mixture. The dr value was found to be 1:1 in all cases. Acetic acid
c
d
e
f
t
(
0.1 mmol) was used instead of PTSA. Isolated yield. BuOOH was
g
used as 75% solution in water. H O (30% solution in water) was
used instead of BuOOH.
2
2
t
(
PTSA), a readily available organic acid, catalyzed the reaction
with a much higher efficiency than other acids, such as acetic acid
entry 1, Table 1). Solvent or reagents with a large amount of
(
water may generate a lot of byproducts (entries 3 and 4), but
exposure to moisture is tolerated. This reaction can thus be
performed in open air, and the PTSA can be used without further
dehydration treatment. The choice of solvent was found to be
crucial for the condensation. No product was obtained when high
polar solvents, such like acetone, DMF, and DMSO, were used as
the reaction medium. When acetonitrile, ethyl acetate, and
ethanol were applied as the reaction solvent, the reaction only
gave the desired product in relatively low yields. Nonpolar
solvents such as toluene were not good for the reaction,
presumably due to poor solubility. To our delight, chlorinated
a
Reaction conditions: indole (1 mmol), aldehyde (2 mmol), peroxide
t
(6 mmol for BuOOH and 4 mmol for the others), PTSA (0.1 mmol,
b
1
0 mol %) in CH Cl , at rt, air. Isolated yield. The reaction was
2 2
carried out for 2 h.
corresponding N-(α-peroxy)indole compounds were prepared
in good to excellent yields. Moreover, indoles with or without the
electron-donating substituent of a methoxy group on the aryl ring
gave no apparent difference in activity, and no oxidized product
of the readily oxidizable methoxyindole was observed.
Substituents on the side chain of indole with various functional
groups are well-compatible with the reaction conditions. The
structure of the peroxide counterpart can also be easily extended
(1e−1i, Scheme 1), providing more diversities to the molecular
library, which demonstrated the broad substrate scope of this
method. It is noteworthy that the pentacyclic indole derivative
with the core structure of Verruculogen and Fumitremorgin A
can produce the desired peroxide product with 75% yield (1j,
Scheme 1), indicating the possibility of using this protocol in
natural product synthesis. C-3 unsubstituted indole produced
other products instead of the desired N-(α-peroxy)indole under
the standard conditions (see details in Supporting Information).
Similar results were observed in the α-azide peroxide
solvents, such as DCM, DCE, and CHCl , could significantly
3
improve both the reaction rate and the product yield (entries 2, 5,
and 6). With DCM as the solvent, the solution color changed
immediately after the addition of a catalytic amount of PTSA into
the mixture of aldehyde, indole, and peroxide, at which point the
TLC and in situ NMR analysis showed a complete conversion
and high yield of the desired N-(α-peroxy)indole product (entry
2
).
A wide substrate scope with good functional group tolerance
and easy scalability are important characteristics for practical
applications (e.g., building a library and high-throughput
biological screening). The metal-free condition is also highly
desired, especially in the pharmaceutical industry. Encouraged by
the mild reaction conditions described above, we then examined
the general applicability of this method to build a small-molecule
library by changing the condensation partners, as summarized in
Scheme 1. All condensation of indoles, aldehydes, and peroxides
with various substituents and complexity were tolerated, and the
9
construction reaction, where aromatic aldehydes with elec-
tron-withdrawing substituents gave acceptable reactivity and
B
DOI: 10.1021/acs.orglett.5b02881
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield of the desired product (1k, Scheme 1). However, arene with
a strong electron-donating substituent resulted in compromised
reactivity and yield of the desired product (1l, Scheme 1),
presumably due to the competition of the Baeyer−Villiger
ered, the intriguing importance of both peroxide and carbazole,
as well as the already established indole peroxide alkaloids of
Fumitremorgin A and Verruculogen, prompted us to further
extend the protocol to combine the two moieties of carbazole
and peroxide in one N-(α-peroxy)carbazole molecule. On the
other hand, while the N-(α-alkoxyalkyl)amines, including N-(α-
alkoxyalkyl)carbazoles, have been synthesized and found to have
good bactericidal and fungicidal activity, to our best knowledge,
the N-(α-peroxy)carbazole has not been mentioned yet. As
shown in Scheme 4, the condensation processed smoothly under
9
rearrangement.
To understand the reaction mechanism of the condensation
process, we performed control experiments, as shown in Scheme
19
2. The formation of peroxide hemiacetal 2a and acetal 2d was
Scheme 2. Control Experimentsa,b
Scheme 4. Synthesis of N-(α-Peroxy)carbazole from the
a
Three-Component Condensation Reaction
a
a
b
1
Reaction conditions: carbazole (1 equiv), aldehyde (2 equiv),
Reaction performed in air. Yields based on H NMR of the crude
peroxide (5.5 M in decane, 6 equiv), PTSA (0.1 mmol, 10 mol %)
in CH Cl , at rt, air. Isolated yield.
reaction mixture.
2
2
observed immediately after the addition of PTSA to the mixture
of aldehyde and peroxide in DCM, both of which were found to
be reactive with indole to give the N-(α-peroxy)indole. On the
other hand, although nucleophilic addition of indole to aldehyde
has been reported, no reaction was observed in the above-
mentioned conditions. Meanwhile, di-tert-butyl peroxide and
tert-butyl peroxybenzoate, without a free nucleophilic hydro-
peroxide group, were found to be unreactive. These observations
clearly indicate that a peroxycarbenium ion intermediate is
involved in the reaction mechanism, similar to that proposed by
standard conditions, and the desired N-(α-peroxy)carbazoles
were obtained in excellent yields within a few minutes. Notably,
all of these reactions were performed in an open flask without any
t
17
inert gas protection, and the pure BuOOH was replaceable with
t
safer BuOOH solution in decane, favorable for future scale-up of
the synthetic process. The N-(α-tert-butylperoxy)heptyl carba-
zole structure (4c, Scheme 4) was further evidenced by crystal X-
ray analysis (Supporting Information). Other nitrogen hetero-
compounds, such as diphenylamine, 10,11-dihydro-5H-dibenzo-
[
b,f ]azepine, 1H-benzo[d]imidazole, and 1H-benzo[d]-
Pramanik and Ghorai for the formation of the α-azide peroxide
9
imidazole, were found to be unreactive under the standard
conditions.
(
Scheme 3). Nucleophilic addition of indole to the
peroxycarbenium ion then produces the N-(α-peroxy)indole.
Since the first report on the isolation and antibiotic properties
of murrayanine from Murraya koenigii Spreng by Chakraborty et
al., carbazole alkaloids have attracted significant interest from
chemists and biologists due to their intriguing structural features
In conclusion, a facile chemoselective methodology for the
synthesis of N-(α-peroxy)indole and N-(α-peroxy)carbazole has
been developed via a one-pot, rapid, three-component reaction
of indole/carbazole, aldehyde, and peroxide using a simple
organic acid (PTSA) as the catalyst, without any inert gas
protection. This approach provides direct access to a new class of
α-amino peroxides and could be easily scaled up. Additional
investigation into the enantioselective synthesis and diversity-
oriented synthesis of a molecular library, with the aim of
developing new antimalarial drugs (novel molecules merging
indole/carbazole and peroxide), is under active consideration,
and the results will be reported in due course.
18
and promising biological activities. Although a naturally
occurring carbazole peroxide compound has not been discov-
Scheme 3. Proposed Mechanism
Caution! Anhydrous or highly concentrated solutions of
TBHP are potentially hazardous and can undergo violent
decomposition upon exposure to certain metal salts. Reactions
and subsequent operations involving peroxides should be run
behind a safety shield. All hazardous materials should be handled
in accordance with the standard procedure described in
C
DOI: 10.1021/acs.orglett.5b02881
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*
*
S. J. Am. Chem. Soc. 2015, 137, 10160−10163.
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E-mail: zhiping.lai@kaust.edu.sa.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the Graduate fellowship of
Peking University Shenzhen Graduate School and KAUST
baseline fund BAS/1/1375.
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