Peroxy mediated Csp2-Csp3 dehydrogenative coupling: Regioselective functionalization of coumarins and coumarin-3-carboxylic acids

Article abstract of DOI:10.1039/c7ob02771k

A regioselective direct alkylation of coumarins at C-3 via cross-dehydrogenative coupling of unactivated Csp²-Csp³ bonds is developed. This protocol employs tert-butyl hydroperoxide as the sole reagent of the reaction to combine coumarins and ethers in reasonable yields under metal- and solvent-free reaction conditions. This protocol also worked well with coumarin-3-carboxylic acids to unveil a rare instance of a catalyst-free tandem alkylation/decarboxylation reaction with conservation of the double bond.

Full text of DOI:10.1039/c7ob02771k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Peroxy Mediated Csp2-Csp3 Dehydrogenative Coupling:
Regioselective Functionalization of Coumarins and Coumarin-3-
carboxylic acids
Received 00th January 20xx,
Accepted 00th January 20xx
Farnaz Jafarpour*a and Masoumeh Darvishmolla a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A regioselective direct alkylation of coumarins at C-3 via cross-dehydrogenative coupling of unactivated Csp2-Csp3 bonds
is developed. The protocol employs tert-butyl hydroperoxide as the sole reagent of the reaction to combine coumarins and
ethers in reasonable yields under metal- and solvent-free reaction conditions. The protocol also worked well with
coumarin-3-carboxylic acids to unveil a rare instance of catalyst-free tandem alkylation/decarboxylation reaction with
conservation
of
the
double
bond.
their importance, regioselective functionalization of coumarins
has
Introduction
previous works:
H
The formation of C−C bonds is fundamentally important due to
the ubiquitous nature of these bonds in naturally occurring
products and biologically and pharmaceutically active
compounds. Direct coupling of two different C−H centers,
known as cross-dehydrogenative coupling (CDC) has become
the central focus in C−C bond forming reacꢀons in terms of
efficiency and atom economy.1 Pioneered by Li et. al.,
extensive progress has been made in transition metal
catalyzed CDC reactions in the past decade.2 The current trend
in organic synthesis and especially in the pharmaceutical
industry however, is to avoid any poisonous and costly
transition-metal catalysts or metal oxidants in CDC reactions as
a highly desirable and challenging synthetic procedure for the
next generation’s C–C bond formations. This protocol may find
great applications especially in highly appreciable pasting of
functionalities containing oxygen on heteroarenes, via radical
activation of inactive Csp3-H bonds of ethers and alcohols,
converting these compounds to high-value pharmacophore
adducts.3 Although the metal-catalyzed strategy for the direct
alkylation of electron-deficient heteroarenes, pioneered by
Minisci,4 is well documented, the more challenging metal-free
approach has been scarcely investigated.
(I) Metal-catalyzed
alkyl
Fe, Cu, Co
DTBP or TBHP
H
O
O
O
R = EWG, H
R
O
EWG
alkyl
H
(II) Metal-free
TBHP
AcOH (2 eq)
PhCl
EWG
OOt-Bu
O
O
H
R = EWG
this work:
H
O
(III) Metal-free
TBHP
no base,
alkyl
O
R
O
O
no solvent
CO2
R = CO2H, H
Regioselective C-3 alkylation
no Metal, no Base, no Solvent
Two-fold dehydrogenative
coupling
Decarboxylative coupling
Scheme 1. Direct alkylation of coumarins
become an attractive research topic and is being actively
pursued by several research groups.7 Direct installation of
olefins and arenes at C-3 position of these privileged motifs
has already been achieved employing precious Pd-metal
catalysts8 resulting in π-extended biologically active adducts.
Since 2014 however, a great deal of attention has been
devoted to C-3 alkylation of coumarins with alkanes and ethers
by cost effective metals including Cu9, Fe10 and Co11 (Scheme
Coumarins, well-known as key scaffolds in many naturally-
occurring and synthetic compounds, represent notable
activities such as antimicrobial, antibacterial, anti-
inflammatory, antioxidant and anti-HIV activities.5 In addition
they are prevalent in numerous compounds that are of
material interest because of their optical activities.6 Due to
1, I).
Recently, the groups of Zhou and Ge reported an iron
catalyzed cross-coupling of ethers and coumarins to construct
ether substituted coumarins at α–position.10b Later, Du et. al.
developed a cobalt-catalyzed regioselective C-3 alkylation of
coumarins with a series of (cyclo)alkyl ethers.11 Despite the
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importance of these contributions, the high amount of toxic employed. The inefficiency of the reaction may be rationalized
benzene co-solvent together with the need of an amidine base to an increase in steric encumbrance (3g).
limits severely the application of these methodologies in Interestingly, bromo- and chloro- substituted coumarins which
organic synthesis. Besides, the more desirable metal-free facilitate further functionalization of the scaffold via cross-
Table 1 Optimization of reaction conditions for alkylation of coumarin 1aa
strategy as an alternative synthetic approach for direct
instalment of functionalities on this scaffold is rarely covered.
The only contribution to the field of metal-free alkylation of
coumarins was recently made by Patel and involved C4-
cycloalkylation C3-peroxidation of 3-substitued coumarins
(scheme 1, II).10a Very recently, we have unveiled successive
metal-free regioselective C-H functionalizations of coumarins
towards expedient synthesis of 3-aroyl12a and 3-
arylcoumarins.12b Inspired by radical reactions as a more
natural strategy with good scope and practicality for synthesis
of complicated pharmaceuticals herein, we uncover a versatile
metal-free assembly of the Csp2-Csp3 bonds from coumarins
and (cyclo)alkyl ethers via a two-fold C-H activation reaction.
This protocol features good yields and high regioselectivities,
without the need for excessive pre-activation reactions and
toxic metals and could serve as an alternative approach for
regioselective functionalization of coumarins under mild
reaction conditions.
Entry Oxidant
Additive
—
Solvent
DMSO
DMF
ACN
Toluene
H2O
—
Yield (%)b
25
23
35
0
TBHP
1
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
AIBN
K2S2O8
DTBP
BPO
—
2
—
3
—
4
—
33
0
5
TBAI
KI
6
—
0
7
K2CO3
Cs2CO3
DBU
DABCO
—
—
42
22
56
60
70
40
<5
0
8
—
9
—
10
11
12
13c
14
15
16
17
18d
19d
20d
—
—
—
—
Results & discussion
—
—
—
—
We conducted our initial investigation on the reaction of
coumarin (1a) and 1,4-dioxane (2a) in presence of tert-butyl
hydroperoxide (TBHP) (4.0 eq.) and various solvents (Table 1,
entries 1-5). Satisfyingly, TBHP in acetonitrile gave the desired
product 3a in 35% yield (entry 3). While consumption of iodide
salt additives exhibited inferior results, addition of some
organic tertiary amine bases like DBU and DABCO, promoted
the radical-based CDC reaction (entries 6-11). To our delight, a
70% yield of the product was obtained even in absence of any
bases and solvents (entry 12). Unfortunately, a decrease in
loading of TBHP to 2.0 eq., led to a severe drop in the yield
(entry 13). Although a comparable yield was obtained with di-
tert-butyl peroxide (DTBP), utilization of other oxidants even in
presence of different acids suppressed the reaction drastically
(entries 14-20). The control experiment in the absence of the
oxidant resulted in recovery of starting materials. Gratifyingly,
employing TBHP (4.0 eq.) at 120 °C under metal-free
conditions, led to alkylated coumarin exclusively at C-3
position in 70% isolated yield. This approach offers a practical
and facile functionalization of coumarins with ethers without
any requisite of toxic metals, additives and solvents and could
find numerous applications in pharmaceutics and industry.
With the optimized reaction conditions in hand, we assessed
the scope and generality of the approach utilizing a variety of
coumarin derivatives (Table 2). Methyl substituted coumarins
resulted the desired products 3b and 3c even more practically
in 78% and 82% yields, respectively. 7- And 8-alkoxy
substituted substrates also went through the reaction
—
—
68
<5
<5
<5
15
—
—
BPO
TFA
TsOH
TFA
—
BPO
—
K2S2O8
H2O
aReaction conditions: Coumarin 1a (0.2 mmol), 1,4-dioxane (0.4 mL), oxidant (4
eq.), additive (20 mol%), solvent (0.4 mL), 120 °C, 24 h; bIsolated yield; cTBHP (2
eq.) was used; dOxidant (1.3 eq.) and additive (1.3 eq.) were used. AIBN =
Azobisisobutyronitrile, BPO = benzoyl peroxide, DTBP = di-tert-butyl peroxide,
TBHP = tert-Butyl hydroperoxide, TFA = trifluoroacetic acid.
coupling techniques, were also tolerant to reaction conditions,
affording alkylated coumarins 3h and 3i in good yields.
Gratifyingly, benzochromenone likewise participated well in
this transformation and resulted the desired product 3j in 78%
yield.
Afterward, the tolerance of this reaction to a range of cyclic as
well as linear ethers was examined (Table 2). Ethereal entities
such as tetrahydrofuran, tetrahydropyran and 1,3-dioxolane
were utilized and the CDC reactions proceeded smoothly to
functionalize Csp3-H bonds in moderate to good yields (3k-3q).
Notably, when coumarin was reacted with 1,3-dioxolane, a 1:1
regioisomeric mixture of both 2- and 4-substituted dioxolane
adducts were composed
(
3n and 3nˈ
,
respectively).
Unfortunately, electron deficient coumarin bearing a nitro
group was not tolerated under the reaction condition (3r).
Further investigation revealed that the two-fold regioselective
alkylation protocol was also compatible to acyclic ethers such
as diethyl ether, di-n-butyl ether and dimethoxy ethane, and
smoothly and afforded the corresponding products 3d, 3e and
generated alkyl coumarins 3s
Furthermore, under the transition-metal-free reaction
coumarin reacted well with simple alkane such as
-3v in satisfactory yields.
3f in moderate to good yields. Unfortunately, no satisfactory
result was observed when 4-substituted coumarin was
a
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cyclohexane and furnished 3w in 60% isolated yield. Finally,
the reaction could be scaled up to 2.0 mmol without significant
loss of efficiency (3a, Table 2).
Table 2 Scope of the two-fold C-H functionalization of coumarins with ethersa,b
Scheme 2. Metal-free CDC benzoylation of coumarin with benzyl ether.
Scheme 3. Decarboxylation versus Esterification in the presence and absence of
metals.
On the other hand, typical procedures for construction of
coumarins, leave behind a surplus carboxyl group at C-3
position of coumarins which should be removed prior to
functionalizations.14 Although metal-catalyzed decarboxylative
functionalization of coumarin-3-carboxylic acids is well
documented15 however, there is no precedence for metal-free
decarboxylation of this scaffold. Recently, Wan et. al.16 as well
as Mao and Xu et. al.17 reported on metal-free reactions of
ethers and some similar carboxylic acids which both
accompanied with conservation of carboxyl group generating
esterification products (Scheme 3).
Furthermore, Xiao et. al.18 has recently communicated
catalyst-free functionalizations of coumarin-3-carboxylic acids
which led to regioselective alkylation/heteroarylation of
coumarins at C-4 with subsequent reduction of the double
bond to build up 3,4-dihydrocoumarins. Consequently, we
hypothesized that a metal-free one-pot cascade reaction
combining direct alkylation and decarboxylation process would
find great application in synthetic organic chemistry. To our
delight, the optimum conditions used for coupling of
coumarins and ethers also worked well for functionalization of
coumarin-3- carboxylic acids so that when coumarin-3-
carboxylic acid and dioxane
aAll reactions were run under the optimized reaction conditions. bIsolated yield.
c2.0 mmol scale.
Interestingly, when dibenzyl ether was used as coupling
partner in this transformation, 3-alkyl coumarin was not
observed and instead, 3-aroyl coumarin
4 was achieved
(Scheme 2). Although benzyl ether is claimed to serve as aroyl
(ArCO−) surrogate both under palladium(II) and copper(I/II)-
catalysed aroylation reactions,13 but to the best of our
knowledge, this process is the first example of converting
benzyl ether to its aroyl equivalent in the absence of any metal
catalyst.
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Table 3 Scope of cascade decarboxylative functionalization of coumarinsa,b
product 3k could not be obtained (see SI). The result indicates
that the reaction may involve a radical process. A putative
mechanism is outlined in Scheme 4. Initially, TBHP
decomposes to tert-butoxy and hydroxyl radicals under
CO2H
H
O
O
TBHP
120 °C, 24 h
+
heating. Next, each of the radicals may abstract Csp3
ether to generate radical intermediate Subsequently,
selective addition of to C-3 position of coumarin(-3-carboxylic
acid) affords the more stable benzyl radical intermediate (II).
−H of
O
O
O
O
R
R
-CO2
I.
I
O
O
O
O
O
Br
Hydrogen abstraction by hydroxyl radical (path
competitive single electron-transfer pathway (path
a
) or a
O
O
b
) are the
O
O
O
O
O
O
proposed tips which result in construction of the coumarin
backbone. More probably, the reaction proceeds via path
3a, 71%
3h, 58%
3f, 60%
OMe
b
where radical intermediate (II) loses an electron to TBHP to
reduce it to tert-butoxy radical and a hydroxide anion.19 Finally
deprotonation/darcarboxylation of intermediate III under the
basic conditions regenerates double bond leading to the
O
O
O
O
O
O
O
O
3k, 66%
3l, 59%
OMe
3p, 75%
Br
O
desired product 3.
O
O
3q, 61%
Conclusions
aAll reactions were run under the optimized reaction conditions. bIsolated yield.
In summary, an efficient cross-dehydrogenative coupling of
coumarins and inactive ethers under ultimate metal-free
circumstances is presented. The protocol provides an
environmentally benign approach to alkylated coumarins
regioselectively at C-3 employing tert-butyl hydroperoxide
exclusively. Moreover, based on this protocol an
unprecedented facile tandem alkylation/decarboxylation of
coumarin-3-carboxylic acids with ethers for construction of
privileged 3-alkyl coumarins is conceived. This practical
innovative approach with a broad substrate scope, may render
this method as a valuable alternative to hitherto transition-
metal-catalyzed cross-coupling methods for broadening the
library of coumarins, which are especially prevalent in
pharmaceutical industry.
O
O
t-BuOOH
t-BuO
OH
+
2
(I)
H (CO2H)
1
O
O
O
O
t-BuO t-BuOOH
H (CO2H)
O
H (CO2H)
O
SET
O
O
(II)
(III)
OH
OH
path b
-CO2
O
HOH
t-BuOOH
t-BuO
HOH
+
-CO2
Conflicts of interest
3
O
O
There are no conflicts to declare.
Scheme 4. Proposed mechanism of TM-free alkylation of coumarins/coumarin
carboxylic acids.
Acknowledgements
were reacted in presence of TBHP, a comparable yield of the
desired product 3a was obtained (Table 3). Similar
achievements were raised in functionalization of coumarin-3-
carboxylic acid derivatives with cyclic ethers. 8-Methoxy
coumarin-3-carboxylic acid afforded even superior results (3f
and 3p). This protocol admits interesting synthetic attributes,
such as regioselective tandem alkylation/decarboxylation
We acknowledge the financial support from University of
Tehran.
Notes and references
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process with
a fruitful conservation of double bond
functionality under mild and environmentally compassionate
reaction conditions without the requisite for addition of any
salts and bases.
To get insight to the mechanism of this reaction, 2,2,6,6-
tetramethylpiperidyl-1-oxyl (TEMPO) as a radical scavenger
was added (2.0 equiv.) into the reaction mixture of coumarin
and THF under the optimized reaction conditions. The reaction
was fully suppressed in presence of TEMPO and the desired
4 | J. Name., 2012, 00, 1-3
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