Iodine-Mediated Intramolecular Dehydrogenative Coupling: Synthesis of N-Alkylindolo[3,2-c]- and -[2,3-c]quinoline Iodides

Article abstract of DOI:10.1021/acs.orglett.5b03392

An I₂/TBHP-mediated intramolecular dehydrogenative coupling reaction is developed for the synthesis of a library of medicinally important 5,11-dialkylindolo[3,2-c]quinoline salts and 5,7-dimethylindolo[2,3-c]quinoline salts. The annulation reaction is followed by aromatization to yield tetracycles in good yield. This protocol is also demonstrated for the synthesis of the naturally occurring isocryptolepine in salt form.

Full text of DOI:10.1021/acs.orglett.5b03392

Letter
pubs.acs.org/OrgLett
Iodine-Mediated Intramolecular Dehydrogenative Coupling:
Synthesis of N‑Alkylindolo[3,2‑c]- and -[2,3‑c]quinoline Iodides
Prajesh S. Volvoikar and Santosh G. Tilve*
Department of Chemistry, Goa University, Goa 403 206, India
S
* Supporting Information
ABSTRACT: An I2/TBHP-mediated intramolecular dehydrogen-
ative coupling reaction is developed for the synthesis of a library of
medicinally important 5,11-dialkylindolo[3,2-c]quinoline salts and
5,7-dimethylindolo[2,3-c]quinoline salts. The annulation reaction is
followed by aromatization to yield tetracycles in good yield. This
protocol is also demonstrated for the synthesis of the naturally
occurring isocryptolepine in salt form.
he cross-dehydrogenative coupling (CDC) reaction has
Tgained tremendous importance in organic synthesis as it
allows creation of a new C−C bond without any substrate
prefunctionalization.1 Pioneering studies in the oxidative C−H
functionalization of amines have been performed by the
Murahashi2 and Li3 groups. The oxidative reaction of the sp3
Figure 1. Isocyptolepine and its isomeric salts.
carbon adjacent to the nitrogen atom involving C−C bond
formation has been recently extensively studied by employing
Our retrosynthetic plan for the synthesis of 5,11-dialkylindolo-
[3,2-c]quinolines 4 employing an IMDC reaction is depicted in
Scheme 1. It was envisaged that the key intermediate N,N-
different metal catalysts, organocataysts, photocatalysts, etc., with
a range of nucleophiles to make diverse organic molecules.4
Nitrogen-containing heterocycles are found in abundance in
nature.5 The use of the CDC reaction for the synthesis of
Scheme 1. Retrosynthetic Analysis
tetracycles leading to the synthesis of naturally occurring
compounds or their scaffolds is a challenging task and is less
explored.6 The importance of a isocryptolepine framework in
medicinal chemistry has encouraged synthetic organic chemists
to devise efficient synthetic methods for their construction.7 In
continuation of our interest in iodine chemistry8 and
indoloquinoline alkaloids,9 herein we report I2/TBHP-medi-
ated10 intramolecular dehydrogenative coupling (IMDC) to give
N-alkylindolo[3,2-c]- and -[2,3-c]quinoline iodides under mild
reaction conditions.
dimethyl-2-(1-methyl-1H-indol-2-yl)aniline 6a via IMDC would
yield tetracycle 5a, which could be oxidized to 4 or in situ may be
directly obtained from 6a. Metal-catalyzed reactions suffer from
One of the strategies to find new lead compounds is the
isolation of active components from plant extracts used in
traditional medicine. The roots of the plant Cryptolpis
sangunoleta11 used in traditional medicine in West and Central
Africa have yielded several isomeric indoloquinoline alkaloids
with antimalarial properties.12 Isocryptolepine 1 and its synthetic
compound isocryptolepine hydroiodide 2 show promising DNA
binding activity accounting for anticancer and cytotoxic
properties. Neoisocryptolepine salt 3 and 5,11-dimethylindolo-
[3,2-c]quinoline salt 4 are synthetically derived alkaloids with the
latter showing excellent antiplasmodial activity in the nanomolar
range on L6 cells13 (Figure 1). This activity prompted us to
devise a new synthetic protocol to make a library of such
compounds for biological evaluation.
toxicity of catalyst, high cost of catalyst, ligand, and metal waste as
byproduct; sometimes these reactions are associated with high
temperature. Iodine-mediated reactions overcome some of the
drawbacks of metal-catalyzed reactions as they are inexpensive,
nontoxic, and environmentally benign.8d Hence, we chose iodine
for this coupling reaction.
Thus, the required starting 6a was prepared by Stille coupling
(SI). Once compound 6a was in hand, the first experiment was
attempted with substrate (0.1 mmol) and iodine (0.1 mmol) in
excess TBHP in decane at room temperature (Table 1).
Pleasingly, it gave the aromatized product 4a directly as
Received: November 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
relatively lower yields (entries 14 and 15). The absence of an
oxidizing agent or the halogen source failed to show any change
in starting material. Similarly, when the oxidizing agent was
replaced with oxygen atmosphere no reaction took place. Iodine
concentration was optimized, and 1.1 equiv was found to give the
best results (entries 19−23). Metal-mediated reaction resulted in
a complex mixture of products (entries 24 and 25).
Table 1. Optimization Studies for Synthesis of N-
Methylisocryptolepinium Salt
a
Having established the optimum conditions (I2 (1.1 equiv),
TBHP (2.0 equiv), CHCl3, rt; entry 20) for this transformation,
we then examined the scope of the reaction with different
substituents on the indole ring such as methoxy and methyl at the
5 position of indole (Scheme 2). Both substrates gave good yield,
f
halide source
(equiv)
temp (°C),
yield
(%)
entry
oxidant
TBHP
solvent
EtOH
time (h)
b
1
I2
rt, 14
60, 10
60, 10
60, 10
60, 10
rt, 14
rt, 14
60, 10
rt, 3
24
46
62
67
62
67
70
48
2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
3
I2
EtOAc
CH3CN
acetone
CH2Cl2
CHCl3
toluene
CHCl3
CHCl3
Scheme 2. Scope of IMDC for N-Methylisocryptolepinium
4
I2
a,b
Iodide Derivative
5
I2
6
I2
7
I2
8
I2
c
9
KI
NaI
KI
nd
c
10
11
rt, 14
rt, 3
nd
c
CHCl3,
Pivalic acid
nd
12
13
14
NIS
TBAI
I2
TBHP
TBHP
CHCl3
CHCl3
rt, 14
36
H2O2 (30%) CH3CN
(aq)
60, 10
40
45
15
16
17
18
19
20
21
22
23
I2
TBHP (aq) CH3CN
60, 10
80, 16
60, 10
80, 16
rt, 14
rt, 14
rt, 14
rt, 14
rt, 14
rt, 1
d
I2
O2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
nr
d
−
I2
TBHP
air
nr
d
nr
I2(0.5)
I2(1.1)
I2(1.2)
I2(1.5)
I2(2)
CuBr
RuCl3
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
16
74
73
72
74
e
c
24
e
nd
a
c
Reaction conditions: substrate (0.1 mmol), chloroform (1 mL),
25
rt, 1
nd
TBHP−decane (0.2 mmol), and iodine (0.11 mmol) at rt for 14 h.
a
Reaction conditions: substrate (0.1 mmol), solvent (1 mL), oxidant
(0.2 mmol), and halide source (0.1 mmol), TBHP (5.5 M in decane)
b
Isolated yield.
b
c
is used unless noted. Oxidant is used as solvent. Not determined.
d
e
f
indicating a negligible effect of electron-donating groups like
methoxy and methyl at the 5 position of indole. Similarly
presence of a substituent at the para position of the aniline ring
did not have any pronounced effect on the yield of the products.
When the N,N-dimethyl group was replaced with N,N-diethyl,
pyrrolidine, or piperidine it gave 4j and pentacyclic hetrocycles
4k and 4l, respectively. If the nucleophilicity of the indole ring
was reduced by placing an electron-withdrawing group such as
carbethoxy on the nitrogen, no reaction was observed in 24 h and
a complex mixture was obtained at higher temperature.
To evaluate the protocol for the synthesis of the naturally
occurring isocryptolepine 1, a free NH group on indole nucleus
was required. The required substrate 8 was prepared from 7 and
subjected to the same reaction conditions (Scheme 3).
No reaction. 0.1 equiv of halide source. Isolated yield.
envisaged in 24% yield after 14 h (entry 1). The product was
precipitated out by adding 20% ethyl acetate−petroleum ether
followed by filtration.
Encouraged by this result, we screened different solvents such
as ethanol, ethyl acetate, acetonitrile, and acetone with 1 equiv of
iodine and 2 equiv of TBHP in decane (entry 2−8). However,
even after 24 h the reactions failed to reach completion at room
temperature. These reactions were then conducted at 60 °C for
12 h for complete conversion with good isolated yields. Toluene
gave a low yield of product. Chlorinated solvents such as DCM
and chloroform showed complete conversion in 14 h at room
temperature with 67 and 70% yields. We then examined the other
halide sources such as KI, NaI, TBAI, and NIS (entry 9−13).
Reaction with KI was found to be exothermic and resulted in a
complex mixture of products. Similarly, this was observed with
NaI; the only difference was that the reaction was not
exothermic. Considering that the complex mixture of products
could be due to overoxidation of the indole ring, we added pivalic
acid14 in the reaction medium but the same trend continued.
When N-iodosuccinamide was used it gave 36% of desired
product. Changing the oxidant to H2O2 and aq TBHP gave
Scheme 3. Synthesis of Naturally Occurring Isocryptolepine
as Its Salt
B
DOI: 10.1021/acs.orglett.5b03392
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Organic Letters
Letter
Isocryptolepinium hydroiodide 2a was obtained in 56% yield.
This salt 2a has been reported to give isocryptolepine 1 on
basification with NH4OH.7g Interestingly, during this reaction
the free NH group of indole did not interfere.
The scope of IMDC was further extended for the synthesis of
isomeric indolo[2,3-c]quinoline salts (Scheme 4). Thus, 9a−c
under standard conditions provided N-methylneoisocryptolepi-
nium iodide salts 10a−c in moderate yields.
not be following a radical pathway. Compound 6a on treatment
with iodine and KOH gave 4a in 51% yield, and treatment with 2
equiv of iodine monochloride gave 4a in 54% yield. This suggests
that the reaction may be following a (hypo)iodite-mediated
pathway.15
A plausible mechanistic pathway for the transformation is
depicted in Scheme 7 for the formation of product. Iodine must
Scheme 7. Plausible Mechanistic Pathway
Scheme 4. Scope of IMDC for N-
Methylisoneocryptolepinium Iodide Derivative
a,b
a
Reaction conditions: substrate (0.1 mmol), chloroform (1 mL),
TBHP−decane (0.2 mmol), and iodine (0.11 mmol) at rt for 14 h.
b
Isolated yield.
The usefulness of the salt prepared was also tested for
preparing some addition products. Thus, the salt 4a was treated
with a nucleophile such as sodium borohydride or methyl
magnesium bromide to obtain the corresponding addition
adducts in good overall yield (Scheme 5).
be coordinating with 6a through the tertiary amine moiety, which
is then oxidized with TBHP to give tert-butyl alcohol and IO−.
The hypoiodite anion then abstracts the proton from
intermediate ii to give iminium species iii, which then undergoes
intramolecular nucleophilic attack to give iv, which loses the
molecule of HI to give 5a. Further oxidation of 5a via similar a
hypoiodite intermediate provided 4a.
Scheme 5. Nucleophilic Addition Adducts of 4a
In conclusion, we have developed a mild and an efficient metal-
free approach for the activation of an sp3 carbon adjacent to
nitrogen with IMDC followed by aromatization to obtain
hydroiodide salts of indolo[3,2-c]quinolines and indolo[2,3-
c]quinolines. A hypoiodite-mediated mechanism is proposed on
the basis of control experiments. The utility of the protocol was
also demonstrated for the synthesis of naturally occurring
indoloquinoline alkaloid isocryptolepine as its hydroiodide.
Thus, we are able to show the potential of the IMDC reaction for
the synthesis of complex scaffolds.
To elucidate the mechanism, when the reaction was carried
out on 6a in the presence of (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (TEMPO), a known radical inhibitor, 4a, was obtained in
73% yield. When TBHP was replaced with TEMPO, 4a was
obtained in 56% yield (Scheme 6). In both cases, no tempo-
bound adduct 11 was observed, indicating that the reaction may
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03392.
Experimental procedures, characterization data of new
compounds, and 1H and 13C NMR spectra (PDF)
Scheme 6. Control Experiments
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stilve@unigoa.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the CSIR and DST New Delhi for financial
assistance and IISc, Bangalore, and Syngenta Biosciences Pvt.,
■
C
DOI: 10.1021/acs.orglett.5b03392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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