Directed C3-alkoxymethylation of indole via three-component cascade reaction

Article abstract of DOI:10.1021/acs.orglett.9b00357

An efficient and regioselective C3-alkoxymethylation of indoles has been developed with aldehydes and alcohols via three-component cascade reaction under transition-metal free conditions. This method allows for rapid access to a variety of C3-alkoxymethyl

Full text of DOI:10.1021/acs.orglett.9b00357

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Directed C3-Alkoxymethylation of Indole via Three-Component
Cascade Reaction
Chao Pi,†,# Xiaohang Yin,†,# Xiuling Cui,*,† Yuwen Ma,‡ and Yangjie Wu*,†
†College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key
Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China
‡Zhengzhou Railway Vocational and Technical College, Zhengzhou 450052, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and regioselective C3-alkoxyme-
thylation of indoles has been developed with aldehydes and
alcohols via three-component cascade reaction under tran-
sition-metal free conditions. This method allows for rapid
access to a variety of C3-alkoxymethylaed free (N−H) indole
in up to 98% yield with excellent regioselectivity. The titled
products are useful building blocks in organic synthesis.
ndole is a privileged scaffold, acting as an important
Ibuilding block in the synthesis of natural products,
pharmaceuticals, and functional materias.1 Especially, the 3-
substituted indole is widely found in biologically active
molecules,2 such as anticancer, anti-inflammatory, antidepres-
sant, anti-Alzheimer, and antihypertensive, as exemplified in
Figure 1. Consequently, developing simple and efficient access
to build such a motif is of great significance.
egies have been developed,5 some problems still exist, such as
requirement of transition metals as catalysts, which may cause
potential contamination of the products, particularly significant
in the pharmaceutical industry and advanced functional
materials. Moreover, functionalization at the C3 of free (N−
H) indoles is still challenging because competing reactions
exist at N1 and C2 due to the inherent reactivity of the
aromatic system.5a−d,6 Furthermore, the side reactions such as
polymerization and dimerization are difficult to avoid for the
electron-rich indoles.7 Therefore, a general, straightforward,
and metal-free strategy to highly regioselective access C3-
functionlization starting from free (N−H) indoles remains
highly desirable.8
The reactions at indole C3 position have been successfully
performed employing aldehydes or ketones in the presence of
catalyst, and the final products obtained are generally
diindolylmethane derivatives (Scheme 1a).9 However, to the
best of our knowledge, highly regioselective C3 alkoxymethy-
lation of indoles with aldehydes has not been developed. Based
Scheme 1. C3-Functional Alkylation Strategies of Indoles
Figure 1. Examples illustrating the importance of 3-substituted
indoles of interest.
Traditional methods based on the cyclization are the choice
for the synthesis of 3-substituted indoles.3 However, these
protocols suffer from tedious procedures, low atom economy,
and relatively harsh reaction conditions. In contrast, the direct
C3−H functionalization of commercially available indoles has
emerged as an increasingly viable strategy due to its
convenience, atomic economy, step economy, and high
efficiency.4 Although various transition-metal catalyzed strat-
Received: January 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00357
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
on these important precedents and our continuing effort to
develop green C−H functionalization,10 we have developed a
base-promoted direct C3-alkoxymethylation of indoles under
transition-metal free conditions via electrophilic aromatic
substitution reaction (SArE) (Scheme 1b). This protocol
features rapid access to a variety of useful building blocks
with excellent yields and regioselectivity.
Scheme 2. Isotope Tracer Experiments
We initiated our investigation on the model reaction of
indole (1a) and methanol to optimize various reaction
parameters (Table 1). Initially, a 54% yield of the desired
a
Table 1. Optimization of the Reaction Conditions
proceed, but slowly without base (Table 2, entry 8). After
screening various bases and loading of starting materials (Table
a
b
Table 2. Optimization of the Reaction Conditions
entry
cat (10% mol)
TBHP (equiv)
time (h)
yield
1
2
3
4
5
6
7
8
9
10
CuCl
Cu(OAc)2
CuCl2
CuBr
CuBr2
CuI
CuCl
CuCl
CuCl
CuCl
1
1
1
1
1
1
2
2
2
1
18
18
18
18
18
18
18
18
54
32
47
42
45
53
59
b
entry
2a (equiv)
bases
time (h)
yield
c
21
89
1
2
3
4
5
6
7
8
1
1
1
1
1
2
2
2
NaOH
KOH
K2CO3
Et3N
pyridine
NaOH
NaOH
--
18
18
18
18
18
2
85
80
82
81
76
62
d
9 + 9
1*10
e
89
a
Reaction conditions: 1a (0.10 mmol), methanol (1 mL), NaOH (1
equiv) under air and sealed, 120 °C. Isolated yield. Open in the air.
TBHP (2 equiv) was dissolved in 1 mL of methanol and 0.5 mL of
the solution was added every 9 h. TBHP (1 equiv) was dissolved in 1
mL of methanol and 0.1 mL of the solution was added every 1 h.
b
c
d
e
c
2
18
89
54
a
Reaction conditions: 1a (0.10 mmol), methanol (1 mL), NaOH (1
b
c
dehydrogenative coupling product 4aaa was obtained in the
presence of CuCl (10 mol %) and TBHP (tert-butyl
hydroperoxide) in methanol at 120 °C under air for 18 h
(Table 1, entry 1). The molecular structure of product 4aaa
was confirmed by NMR spectra and single crystal X-ray
diffraction analysis (SI, Figure S1). Among the copper salts
examined (CuCl, Cu(OAc)2, CuCl2, CuBr, CuBr2, and CuI),
CuCl was the best (Table 1, entry 1 vs entries 2−6). Slightly
lower yields were obtained when the loading of NaOH was
reduced to 0.5 or 0.3 equiv. The higher yield was obtained by
increasing the amount of TBHP to 2 equiv (Table 1, entry 7 vs
entry 1). The yield decreased significantly under air
atmosphere (Table 1, entry 8). The yield of 89% was obtained
by adding TBHP (2 equiv) two times, or adding TBHP (1
equiv) ten times (Table 1, entries 9−10). In order to verify the
source of the methyl and methylene in product 4aaa, the
isotope labeled experiments were carried out (Scheme 2).
Deuterated methanol was used as the solvent under the
equiv) under air and sealed, 120 °C. Isolated yield. NaOH (2
equiv).
2), the optimal reaction conditions were assigned as follows:
indole (1a), paraformaldehyde (2a), methanol (1 mL), NaOH
(2 equiv) under air and sealed, 120 °C for 2 h (Table 2, entry
7).
With the optimized conditions in hand, the scope of
substrates was investigated (Scheme 3). A range of indoles was
first investigated to react with paraformaldehyde (2a) and
methanol (3a) under the optimized reaction conditions.
Generally, various indoles bearing either electron-donating or
-withdrawing groups were well-tolerated and converted into
the corresponding products in good to excellent yields (4aaa
to 4qaa). Among them, 5-nitro and 6-COOCH3 indoles gave
the corresponding products 4iaa and 4maa in moderate yields.
In addition, 7-nitroindole could give the product 4qaa in 92%
yield prolonging the reaction time to 24 h. In general, the
reaction rate of indoles with electron-donating groups is faster
than those with electron-withdrawing groups, and the reaction
could proceed well for substrates bearing a steric substituent
(4baa, 4eaa, and 4faa). Moreover, the substrates with halogen
groups produced the target products (4caa-4daa, 4jaa-4laa,
4naa-4paa) with high yields, which provide the possibility to
build complicated molecules through further chemical trans-
formations. Then, a range of aldehydes were tested with indole
(1a) and methanol (3a). Aromatic aldehydes gave the desired
products in good to excellent yields (4aba-4ama). Benzalde-
1
condition of entry 9 (Table 1). Based on H NMR (SI, 4aaa-
d5), there is no signal found in the aliphatic area, suggesting
that TBHP as methyl source was ruled out. Then, indole and
formaldehyde were soluble in deuterated methanol. Only the
signal at 4.67 ppm (s, 2H) was observed, and the methyl signal
1
disappeared from the H NMR spectrum (SI, 4aaa-d3), which
implied that the −CH2− is derived from formaldehyde and the
−CH3 is from methanol. On the basis of these results, the
reaction conditions were optimized in the absence of copper
salt and any oxidants. Additionally, the reaction could also
B
DOI: 10.1021/acs.orglett.9b00357
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of Indoles with Aldehydes and
Alcohols
Scheme 4. Gram-Scale Reaction and Transformation of C3-
Alkoxymethylaed Product
a,b
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), 3 (1.0 mL), 120
b
c
d
e
°C, 2 h, air and sealed. Isolated yield. 6 h. 8 h. 24 h.
hyde (2b) and donating substituted benzaldehydes result in
relatively low yields (4aga vs 4afa and 4aea). The p-
withdrawing substituted benzaldehydes can give better results
(4aka and 4ala). No reaction was observed for pyrroles,
thiofuran, furan, benzofuran, 3-mehtyl indole, and benzothio-
phene under standard reaction conditions. However, the
trifluoroacetaldehyde and ethyl glyoxalate obtained the
unexpected product in 62% yield (4ana) and 58% yields
(4aoa), respectively. The molecular structure of product 4ana
was confirmed by NMR and single crystal X-ray diffraction
analysis (SI, Figure S2). It might be caused by the presence of
strong electron-withdrawing groups which inhibit the
departure of hydroxyl groups. Other alkylaldehydes, such as
acetaldehyde, pivaldehyde, and valeraldehyde, were not
beneficial for this transformation and no desired products
were detected.
In addition, some alkyl alcohols (such as ethanol,
trifluoroethanol, tert-butanol, n-butanol, tert-amyl alcohol,
isoamyl alchol, 1-amyl alcohol, and benzyl alcohol) had been
examined. Unfortunately, only 2,2,2-trifluoroethanol pro-
ceeded smoothly, giving the target product 4aab in 83% yield.
To demonstrate the synthetic potential application of the
present method, the 3-(methoxymethyl)-1H-indole is an
important molecule. A gram scale reaction of indole (1a)
and paraformaldehyde (2a) was carried out in methanol (3a)
under 120 °C for 12 h. The product (3-(methoxymethyl)-1H-
indole (4aaa) was obtained in 85% yield (eq 1, Scheme 4). In
comparison with traditional methods, the current reaction
provided an easier, more direct, and step-economic method to
various C3-alkoxymethylaed free (N−H) indole derivatives
with important biological.2 Compound 6 that is easy to convert
could be synthesized by N-protection and substitution of C3-
alkoxymethylated indole obtained from our methodology,
providing 83% yield in all (eq 2, Scheme 4).
B reacts with formaldehyde easily and forms intermediate C via
a nucleophilic addition reaction. Then the hydroxide was
removed from C by the electron transport process to form D.
Finally, compound D reacted with CH3O− which comes from
methanol by an addition reaction to give product 4aaa.
In summary, we have developed a novel, simple, and efficient
protocol for the base-promoted direct C3-alkoxymethylation of
indoles with aldehydes and alcohols. In this approach, a broad
range of 3-(alkoxymethyl)-1H-indole were conveniently
obtained in moderate to excellent yields with good functional
group tolerance under air and metal-free conditions, thus
providing an environmentally benign alkoxymethylation
process. The present protocol is anticipated to be an important
approach to indoles, which would be useful to build
multitudinous biologically active molecules.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00357.
Experimental procedures and characterization data for
all new compounds (PDF)
Accession Codes
On the basis of the above discussion and previous
literature,11 a plausible reaction mechanism is illustrated
(Scheme 5). Initially, the hydrogen positive ion was removed
from indole (1a) to form compound A by aid of NaOH. Then
compound A could convert to the indolium intermediate (B)
through charge transfer in the conjugated system. Intermediate
CCDC 1520906 and 1527983 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.
C
DOI: 10.1021/acs.orglett.9b00357
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cuixl@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
ORCID
Chao Pi: 0000-0002-3404-1543
Xiuling Cui: 0000-0001-5759-766X
Yangjie Wu: 0000-0002-0134-0870
Author Contributions
#C. P. and X. Y. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We greatly acknowledge partial financial support from the
MOST of China (2016YFE0132600) and Zhengzhou
University.
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DOI: 10.1021/acs.orglett.9b00357
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