K 2 S 2 O 8-Mediated Arylmethylation of Indoles with Tertiary Amines via sp 3 C-H Oxidation in Water

Article abstract of DOI:10.1055/s-0037-1610264

A transition-metal- A nd catalyst-free, highly efficient synthesis of 3-arylmethylindoles has been achieved using tertiary amines as both methylene (-CH ₂-) transfer and arylmethylation agents and K ₂ S ₂ O ₈ as a convenient oxidant. The key feature of this protocol is the utilisation of K ₂ S ₂ O ₈ as an inexpensive and easy to handle radical surrogate that can effectively promote the reaction, leading to the formation of C(sp ²)-C(sp ³)-C(sp ²) bonds via sp ³ C-H bond oxidation in water at room temperature in a one-pot procedure.

Full text of DOI:10.1055/s-0037-1610264

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
M. Singh et al.
Letter
Synlett
K2S2O8-Mediated Arylmethylation of Indoles with Tertiary Amines
via sp3 C–H Oxidation in Water
Manjula Singha
Arvind K. Yadavb
Lal Dhar S. Yadav*b
Rana Krishna Pal Singh*a
R1
R4
N
R4
N
R3
K2S2O8, H2O
R1
R3
rt, 2–4 h
transition-metal- and
catalyst-free
N
N
R2
R2
R1 = H, CH3, OCH3, Ph, F, Cl, Br, I
2 = CH3, PhCH2; R3 = Br; R4 = CH3
a Green Synthesis Electrochemical laboratory, Department of
Chemistry, University of Allahabad, Allahabad 211002, India
b Green Synthesis Lab, Department of Chemistry, University of
Allahabad, Allahabad 211002, India
18 examples
up to 94% yield
R
ldsyadav@hotmail.com
Received: 13.07.2018
Accepted after revision: 12.08.2018
Published online: 30.08.2018
dole derivatives are available.4a,4b,5 The importance of 3-al-
kylindole derivatives is captivating, and consequently they
have been target molecules in several organic syntheses.5–8
Kumar and co-workers have reported the synthesis of 3-
arylmethylindoles from indoles, formaldehyde, and tertiary
amines using silica-supported perchloric acid (HClO4–SiO2)
as a catalyst (Scheme 1a).6 Che et al. reported the direct 3-
arylmethylation of indoles by employing tertiary amines as
both methylene (-CH2-) transfer and arylmethylation
agents using a ruthenium catalyst and tert-butyl hydroper-
oxide as an oxidant at 110 °C (Scheme 1b).7 Very recently,
the research groups of He8a and Weng8b have performed the
same reaction under visible light irradiation using Rose
Bengal as a photosensitiser (Scheme 1c). These reactions
producing 3-arylmethylindoles proceed via an iminium ion
intermediate generated from a tertiary amine by the oxida-
tion of its sp3 C–H bond α to the nitrogen atom. Generally,
metals,9 peroxides,10 or inorganic oxidants11 are required to
generate an iminium ion by the oxidation of tertiary
amines.
Recently, K2S2O8 has been found to be a convenient and
efficient radical surrogate to bring about synthetically use-
ful chemical transformations under mild conditions.12 It is a
good oxidant to be employed in aqueous media. Moreover,
owing to its low cost, easy handling and workability at
room temperature, K2S2O8 is advantageous over organic
peroxides. Economical, environmental, and safety concerns
have established water as the cleanest solvent. Only a few
reports are available on the oxidation of sp3 C–H bonds em-
ploying K2S2O8 as a radical source.13 In view of the above
facts and in continuation of our studies on K2S2O8-mediated
organic synthesis,13a,14 we envisaged the present convenient
and highly efficient protocol for 3-arylmethylation of in-
doles in water (Scheme 1d). Although the previous metal-
free works (Scheme 1c)8 are elegant, they require Rose
Bengal as a photosensitiser and tend to give somewhat low-
DOI: 10.1055/s-0037-1610264; Art ID: st-2018-k0441-l
Abstract A transition-metal- and catalyst-free, highly efficient synthe-
sis of 3-arylmethylindoles has been achieved using tertiary amines as
both methylene (-CH2-) transfer and arylmethylation agents and K2S2O8
as a convenient oxidant. The key feature of this protocol is the utilisa-
tion of K2S2O8 as an inexpensive and easy to handle radical surrogate
that can effectively promote the reaction, leading to the formation of
C(sp2)–C(sp3)–C(sp2) bonds via sp3 C–H bond oxidation in water at
room temperature in a one-pot procedure.
Key words alkylation, indoles, tertiary amines, heterocycles, K2S2O8,
radical oxidation
A plethora of sp3 C–H bonds are present in organic com-
pounds but they are extremely unreactive bonds. Thus, the
direct functionalisation of sp3 C–H bonds is a challenging
task for synthetic organic chemists that has attracted con-
siderable attention1 because it does not require pre-func-
tionalisation steps such as stoichiometric metalation and
halogenation of the substrates. Particularly, a lot of effort
has been devoted to the direct functionalisation of sp3 C–H
bonds α to a nitrogen, oxygen, or sulfur atom.2 The process
generally involves single electron transfer (SET) reaction
and utilises organic peroxides such as benzoyl peroxide
(BPO), tert-butyl hydroperoxide (TBHP), di-tert butyl perox-
ide (DTBP), and tert-butyl peroxybenzoate (TBPB) as oxi-
dants to achieve couplings at sp3 C–H centre.3 However,
these peroxides are required in an excess amount and work
at only elevated temperatures, which limit their practicali-
ty.
3-Alkylindoles feature as key structural units in many
natural products and pharmaceuticals exhibiting various
biological properties such as antibacterial, antitumour, an-
tioxidative, insecticidal, and antihelmintic activities.4 Excel-
lent reviews covering the synthesis and applications of in-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
M. Singh et al.
Letter
Synlett
Previous work
R1
R4
N
(a) 6
R4
N
R5
R1
R5
HClO4, SiO2
CH3OH
CH2O
N
N
R2
R2
R3
R3
R2
N
R2
N
R2
(b) 7
N
Ru catalyst
N
R1
TBHP, toluene
110 °C , 6 h
N
R1
N
R1
R1
R4
N
(c) 8
R4
R3
20 or 15 W CFL
Rose Bengal
R1
N
R3
N
R2
CH3CN/H2O, 24–48 h
50 °C, air
N
R2
Present work
R1
R4
N
R4
(d)
K2S2O8, H2O
R3
N
R1
R3
rt, 2–4 h
transition-metal- and
catalyst-free
N
R2
N
R2
Scheme 1 Synthesis of 3-arylmethylindoles
er yields in a longer reaction time (24–48 h). The present
work is catalyst-free, uses water as the solvent without ad-
dition of any co-solvent, and gives higher yields in a shorter
reaction time (2–4 h) using a very simple procedure. Thus,
this method is complementary and rather easier to execute
than the previous works.8
Table 1 Optimization of Reaction Conditionsa
N
oxidant (equiv)
N
solvent, rt, time (h)
N
N
H
H
1a
2a
3a
To realise the envisaged protocol, a model reaction was
performed with N,N-dimethylaniline (2a), indole (1a), and
K2S2O8 in CH3CN at r.t., which delivered 87% yield of the de-
sired product 3a after 2 h (Table 1, entry 1). Encouraged by
this result and from economical and environmental points
of view, the same reaction was conducted in water; fortu-
nately, it proceeded more efficiently to afford the product
3a in 89% yield (entry 2). Other screened solvents such as
DCE, DCM and DMSO were found to be far less effective
than water (entry 2 vs. 3–5).
The optimum amount of K2S2O8 was 1.5 equiv; the yield
was significantly reduced on decreasing its amount from
1.5 to 1.0 equiv (Table 1, entry 2 vs. 6), whereas, the yield
remained unchanged on using 2 equiv of the oxidant (entry
2 vs. 7). Other oxidants such as cerium(IV) ammonium ni-
trate (CAN), oxone, TBHP and DTBP were not as effective as
K2S2O8 (entry 2 vs. 8–11). To obtain the optimum yield, all
the reactions were conducted with 1a and 2a in a 1:2 molar
ratio, because the yield was considerably decreased on us-
ing an equimolar amount (entry 2 vs. 12), whereas the yield
was unaffected when 1a and 2a were used in 1:2.5 ratio
(entry 2 vs. 13). The reaction was quenched on addition of a
radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) as the desired product 3a was detected only in
traces, which indicates that a radical intermediate is in-
volved in the reaction (entry 14).
Entry Solvent
Oxidant (1.5 equiv) Temp. (°C) Time (h) Yield (%)b
1
2
CH3CN
H2O
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.0)
K2S2O8 (2.0)
CAN (1.5)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
80
r.t.
r.t.
r.t.
r.t.
2
2
4
4
4
2
2
4
4
4
4
2
2
2
87
89
3
DCE
78
4
CH2Cl2
DMSO
H2O
71
5
62
6
72
7
H2O
89
8
H2O
76
9
H2O
Oxone (1.5)
TBHP (1.5)
DTBP (1.5)
62
10
11
12
13
14
H2O
55
H2O
67
H2O
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
44c
89d
tracese
H2O
H2O
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), oxidant (1–2 equiv),
solvent (3 mL), stirred at r.t. for 2–4 h.
b Isolated yield of the pure product 3a.
c Reaction was carried out with 1a (1.0 mmol) and 2a (1.0 mmol).
d Reaction was carried out 1a (1.0 mmol) and 2a (2.5 mmol).
e Reaction was quenched with TEMPO (4 equiv).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
M. Singh et al.
Letter
Synlett
Employing the optimised reaction conditions (Table 1,
entry 2), we examined the generality and scope of the pres-
ent K2S2O8-mediated synthesis of 3-arylmethylindoles 3
across a wide range of indoles 1 and tertiary amines 2, in-
corporating various substituents such as CH3, OCH3, F, Cl, Br,
I, and Et.15 All of these smoothly reacted to afford 21–94%
yields of the corresponding product 3 (Scheme 2), showing
that the protocol is very mild and that considerable struc-
tural and functional group variations in the substrates 1
and 2 are well tolerated. The electronic and steric effects of
the substituents present in 1 and 2 affect the efficiency of
the reaction. The substrates bearing an electron-donating
group on the aromatic ring appear to react faster and give
slightly higher yields as compared to those having an elec-
tron-withdrawing group (Scheme 2, products 3b–d and 3p
vs. 3e–i and 3q). N-Methylylindole has marginally higher
yield than the corresponding unmethylated indole (Scheme
2, product 3k vs. 3a), whereas N-arylindoles have very low
yields in comparison to N-alkylindoles (Scheme 2, products
3n and 3o vs. 3k–m).
tions. After completion of the reaction (2 h), the desired
product 3a was isolated in an excellent yield of 91% (2.27 g)
without any decrease in efficiency as compared to that of
the 1.0 mmol scale reaction.
In accordance with our observations and on literature
precedent,8a,13a a plausible mechanistic pathway is pro-
posed in Scheme 3. The KHSO4· radical, formed by homoly-
sis of K2S2O8, abstracts a hydrogen atom from N,N-dimeth-
ylaniline (2a) to generate an N,N-dimethylaniline radical A.
·
A SET from radical A to KSO4 radical forms a highly reactive
intermediate B, which undergoes nucleophilic attack by in-
dole (1a) to give the corresponding aminomethylated in-
dole C, and subsequently azafulvalene intermediate D with
the loss of N-methylaniline (E).16 The intermediate D, reacts
with N,N-dimethylaniline (2a) to afford the final product
3a.17 The HRMS (EI) of the reaction mixture confirmed the
formation of the intermediate C [HRMS (EI): m/z calcd for
C6H16N2: 236.1313; found: 236.1316]. This also supports
the proposed mechanism.
In conclusion, we have developed an operationally sim-
ple, transition-metal- and catalyst-free highly efficient syn-
thesis of 3-arylmethylindoles from indoles and tertiary
amines using K2S2O8 as a convenient oxidising agent in wa-
ter. The reaction utilises tertiary amines as both methylene
(-CH2-) transfer and arylmethylation agents, K2S2O8 as a
To evaluate the application of the present protocol in or-
ganic synthesis, a gram-scale synthesis of 3a was conduct-
ed. Thus, the reaction of indole 1a (10 mmol, 1.17 g) was
performed with N,N-dimethylaniline 2a (20 mmol, 2.42 g)
in water (30 mL) at r.t. under the optimised reaction condi-
R4
R4
R1
R3
N
N
K2S2O8 (1.5 equiv)
H2O, rt, 2–4 h
R1
R3
N
N
R2
R2
3a
2
1
(21–94% )b
CH3
F
Cl
CH3
N
N
N
N
N
CH3
N
N
N
N
N
N
N
H
H
H
H
H
H
3a, 89%, 2 h
3b, 92%, 2 h
3d, 94%, 4 h
3e, 62%, 4 h
3f, 66%, 4 h
3c, 91%, 2 h
I
Br
CH3
N
N
N
N
N
N
N
N
N
H
H
H
N
N
N
Br
H
H3C
H3C
CH3
3g, 69%, 4 h
3h, 76%, 4 h
3i, 67%, 4 h
3j, 41%, 4 h
3k, 91%, 2 h
Ph 3l, 43%, 4 h
CH3
H3C
Br
N
N
N
N
N
N
Ph
N
N
N
N
N
N
H
H
H
H3C
H3CO
3m, 86%, 2 h
3n, 32%, 2 h
3o, 21%, 4 h
3p, 93%, 2 h
3q, 68%, 2 h
3r, 90%, 2 h
CH3
Scheme 2 Substrate scope for the synthesis of 3-arylmethylindoles. For experimental procedure, see ref.15 a All compounds are known and were char-
acterized by comparison of their spectral data with those reported in the literature7,8 (see the Supporting information). b Yields of isolated pure com-
pounds 3.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
M. Singh et al.
Letter
Synlett
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N
N
N
KSO4
B
O
O
A
KSO4
2a
KHSO4
KSO4
KO-S-O-O-S-OK
1a K2S2O8
O
O
N
H2O, rt
2–4 h
1a
H
N
H
N
H
E
2a
H
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N
H
N
N
N
H
C
H
3a
H
D
Scheme 3 A plausible mechanism for the formation of 3-arylmethylin-
doles 3
readily available, inexpensive, and easy to handle radical
surrogate, and water as the greenest solvent. The protocol
involves sequential formation of C(sp2)–C(sp3)–C(sp2)
bonds via sp3 C–H bond activation in a one-pot operation at
room temperature.
Funding Information
M.S. is grateful to the UGC, New Delhi, for a research fellowship.
)(
Acknowledgment
We sincerely thank the SAIF, Punjab University, Chandigarh, for pro-
viding spectra.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610264.
S
u
p
p
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S
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Yadav, L. D. S. Org. Biomol. Chem. 2014, 12, 8550. (c) Chawla, R.;
Singh, A. K.; Yadav, L. D .S. Eur. J. Org. Chem. 2014, 2032.
(d) Singh, A. K.; Chawla, R.; Yadav, L. D. S. Tetrahedron Lett. 2014,
55, 2845.
(15) General procedure for the synthesis of 3-arylmethylindoles
3: A mixture of N,N-dimethylaniline 1 (2.0 mmol), indole 2 (1.0
mmol), K2S2O8 (1.5 equiv), and CH3CN (3 mL) was taken in a
flask and stirred at r.t. for 2–4 h (Scheme 2). After completion of
the reaction (monitored by TLC), water (5 mL) was added and
the mixture was extracted with ethyl acetate (3 × 5 mL). The
combined organic phase was dried over anhydrous Na2SO4, fil-
tered, and evaporated under reduced pressure. The resulting
crude product was purified by silica gel chromatography using a
mixture of hexane/ethyl acetate (4:1) as eluent to afford an ana-
lytically pure sample of product 3.
Compound 3a [see ref. 8]: 1H NMR (400 MHz, CDCl3): δ = 7.93 (s,
1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.14 (m,
3 H), 7.06 (m, 1 H), 6.85 (s, 1 H), 6.71 (d, J = 8.4 Hz, 2 H), 4.04 (s,
2 H), 2.93 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 149.1, 136.6,
129.7, 129.3, 127.6, 122.1, 121.9, 120.0, 119.3, 116.7, 113.1,
111.0, 41.1, 30.6. HRMS (EI): m/z calcd for C17H18N2: 250.1470;
found: 250.1473.
(16) Pu, F.; Li, Y.; Song, Y.-H.; Xiao, J.; Liu, Z.-W.; Wang, C.; Liu, Z.-T.;
Chen, J.-G.; Lu, J. Adv. Synth. Catal. 2016, 358, 539.
(17) Niu, H. L. T.; Wu, J.; Zhang, Y. J. Org. Chem. 2011, 76, 1759.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E