Metal-free regioselective C-H chalcogenylation of coumarins/(hetero)arenes at ambient temperature

Article abstract of DOI:10.1039/c9cc09001k

A novel, practical and metal-free approach for the regioselective selenation of coumarins employing (bis(trifluoroacetoxy)iodo)benzene (PIFA) at room temperature is presented. The developed method is suitable for a wide substrate scope and affords 3-selen

Full text of DOI:10.1039/c9cc09001k

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DOI: 10.1039/C9CC09001K
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Metal-Free Regioselective C–H Chalcogenylation of Coumarins/
(Hetero)Arenes at Ambient Temperature
Received 00th January 20xx,
Accepted 00th January 20xx
Zengqiang Song,‡,* Chaochao Ding,‡ Shaoli Wang,‡ Qian Dai, Yaoguang Sheng, Zhilong Zheng and
Guang Liang*
DOI: 10.1039/x0xx00000x
A novel, practical and metal-free approach for the regioselective
selenation of coumarins employing
previous work:
metal catalyst
H
O
R
O
excessive oxidant
+
RH
(bis(trifluoroacetoxy)iodo)benzene (PIFA) at room temperature is
presented. The developed method is suitable for a wide substrate
scope and affords 3-selenyl coumarins in good to excellent yields
with high selectivity. A radical mechanism is proposed for this new
transformation. Furthermore, the application of sulfenylation with
coumarines and selenation with other (hetero)arenes in this
transformation is successful.
(a)
high temperature
O
O
R = aryl, alkenyl,
phosphoryl, alkyl,
benzyl, aroyl group
H
O
H
O
CF2H
Eosin Y, blue LED
air, rt
+
+
NaSO2CF2H
O
(b)
(c)
O
O
O
R
O
Ir(ppy)3, white LEDs,
CF3COOH, nitrogen, rt
O
O
N
Coumarin and its derivatives are largely distributed in naturally
occurring products and pharmaceuticals as key scaffolds, and
they also play an important role in organic materials due to their
optical activities.1 Among a broad range of coumarin derivatives
known, 3-substituted coumarins are recently drawing
considerable attention since they exhibit a wide spectrum of
biological activities, such as anti-inflammatory, antioxidant, anti-
HIV, anticancer and antimicrobial.2 On account of the important
applications of 3-substituted coumarins in various fields,
methods for synthesizing this type of compounds have been
widely explored.
O
this work:
O
R
O
O
R = alkyl group
H
O
SeR
PIFA (1.0 equiv.)
air, rt
+
RSeSeR
(d)
O
O
R = (hetero)aryl or alkyl group
Scheme 1. Direct regioselective functionalization of coumarins at the C3-postion.
phosphoryl coumarins. The other one involves electrophilic
attack of radicals to the C3-position of coumarins.5 Metal
catalysts (such as cobalt, copper, iron), excessive oxidants and
high temperature are needed for this type of reaction to generate
radicals. Different 3-alkyl coumarins, 3-benzyl coumarins and 3-
aroyl coumarins were constructed by using these methods. Very
recently, two elegant methods for the installment of
difluoromethyl and alkyl groups to the C3-position of coumarins
were achieved under photocatalysis at room temperature by
Deng’s group6a and Yang’s group6b, respectively (scheme 1b, 1c).
Obviously, novel approaches for the regioselective formation of
new bond, especially C–X bond at the C3-postion of coumarins
under environmentally friendly reaction conditions are in high
demand.
Coupling reactions with pre-functionalized reactants
(coumarins or partners) are regarded as conventional procedures
for the preparation of 3-substituted courmarins.3 In recent years,
direct C–H functionalization has emerged as a straightforward
and atom-economical route in modern synthetic chemistry. On
the basis of this strategy, a number of methods have been
established for regioselective introduction of groups to the C3-
position of coumarin skeleton via cross-dehydrogenative
coupling (CDC). According to the mechanism, the reported
protocols can be generally classified into two categories. One
involves electrophilic attack of palladium species to the C3-
position of coumarins (scheme 1a).4 Normally, this type of
reaction requires extra additives and ligands, and is used to
synthesize 3-aryl coumarins, 3-alkenyl coumarins and 3-
Selenium is a very important element in our body, selenium-
containing compounds are widely distributed in bioactive
compounds and natural products.7 So far, a series of routes have
been developed for the construction of C–Se bond using
elemental selenium or non-elemental selenium as selenating
reagents.8,9 However, methods for the selenation of coumarins at
the C3-position are rare. Only three protocols were reported, but
they were limited to 4-substituted coumarins.9 To the best of our
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou325035, Zhejiang, China
E-mail: songzengqiang09@163.com; wzmcliangguang@163.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
‡ These authors contributed equally to this work.
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Table 2 Selenation of coumarins and diselenidesa
knowledge, direct regioselective selenation of coumarin skeleton
at the C3-position has never been reported.
View Article Online
DOI: 10.1039/C9CC09001K
SeR2
PIFA (1 equiv.)
R1
+
R2SeSeR2
As part of our ongoing studies on the development of new
approaches for the chalcogenylation of heterocyclic
compounds,8h,10 we are interested in the exploration of novel
routes for the regioselective selenation of coumarin skeleton at
the C3-position. In the past decades, several impressive methods
with radical processes were reported for the direct incorporation
of groups onto heterocycles by formation of C–C bond, using
hypervalent iodine reagents as promoters.11 These reactions were
conducted at ambient room temperature, under metal-free
conditions. Combining the applications of hypervalent iodine
reagents in radical reactions and the aforementioned background
of preparation of 3-substituted coumarins, it was envisioned that
regioselective formation of C–Se bond could be accomplished by
promotion of hypervalent iodine reagents via a radical process
under environmentally friendly conditions. Herein, we wish to
unveil a novel protocol for the PIFA mediated regioselective
selenation of coumarins at the C3-position with diselenides at
ambient temperature (scheme 1d).
R1
DCM, rt
O
O
O
O
1
2
3
O
O
R1
Se
O
Se
Se
O
R1
O
O
O
, R1 = Me, 0.5 h, 98%
, R1 = Br, 7 h, 92%
3c
, R1 = OMe, 0.5 h, 97%
, R1 = Cl, 1 h, 97%
, R1 = OAc, 0.5 h, 98%
3g
3h
3i
3d
3e
3b
, 1 h, 92%
Se
, R1 = NO2, 24 h, 83%
1
3f
, R = Ph, 1 h, 95%
AcO
Se
O
Se
O
O
AcO
O
R1
O
O
, R1 = Me, 0.5 h, 98%
3j
, R1 = F, 2.5 h, 94%
3k
3l
3n
3o
, 1 h, 94%
, 0.5 h, 98%
Se
, R1 = Cl, 2.5 h, 92%
, R1 = Br, 3 h, 98%
3m
R2
Se
Se
O
O
O
O
O
O
, R2 = Me, 1.5 h, 98%
3r
We started our investigation focusing on the reaction between
coumarin 1a and diphenyl diselenide 2a. Different solvents,
oxidants, amounts of oxidants, equivalents of diphenyl diselenide
were screened (see the ESI†, table 1). Finally, the optimal
conditions for the regioselective selenation of coumarins at the
C3-position were obtained: diphenyl diselenide (1.2 equiv.),
PIFA (1.0 equiv.), in DCM (2 mL) at room temperature for 1 h
(entry 11). Furthermore, a 10 mmol scale reaction was performed
under the standard reaction conditions, and the desired product
was obtained in 93% yield in 2 h (entry 13). The structure of
product 3a was further confirmed by single-crystal X-ray
analysis (CCDC 1944304, see the ESI†).
, 0.5 h, 91%
Se
, 0.5 h, 98%
Se
, R2 = Br, 1.5 h, 88%
3p
3q
3s
R2
Se
O
O
R2
O
O
O
O
, R2 = Me, 2.5 h, 95%
, R2 = Me, 1 h, 98%
, R2 = F, 6 h, 87%
, R2 = Br, 1.5 h, 97%
3t
3x
, R2 = F, 2 h, 98%
, R2 = Cl, 7 h, 82%
3u
3v
3y
3z
3ab
, 12 h, 60%
, R2 = NO2, 12 h, 89%
, R2 = OMe, 12 h, 64%
3w
3aa
O
R2
Se
Se
O
N
O
O
O
3adb
3aeb
3afb
, R2 = Me, 5 h, 82%
, R2 = Et, 5 h, 83%
, R2 = n-Bu, 3.5 h, 80%
3ac
, 1.5 h, 81%
aReaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), PIFA (1 equiv.), in DCM (2 mL)
at room temperature in air. b3 equiv. of PIFA were used.
Having identified the optimal parameters of the model reaction,
the substrate scope and generality of this transformation were
evaluated. Initially, coumarin derivatives bearing diverse
electron-donating or -withdrawing groups at different positions
of coumarin rings were tested with diphenyl diselenide under the
standard reaction conditions. Generally, most of the reactions
proceeded smoothly, giving the expected products in good to
excellent yields in a short reaction time (table 2, 3b–3q). It is
worth mentioning that coumarin derivatives with halogens or
ester groups were tolerated in this transformation, allowing
the desired product in 81% yield in 1.5 h (3ac). Due to the
reactivity of alkyl selenides, reactions of selenation with dialkyl
diselenides involving radicals are difficult. Interestingly, the
application of dialkyl diselenides in this novel transformation
was also successful, and the corresponding products were
obtained in good yields (3ad–3af).
After successful development of this novel protocol, we
subsequent elaboration of corresponding products at the wondered if this transformation is applicable for the direct
remaining reactive sites (3d, 3h, 3i, 3k–3m, 3o). The electron- regioselective sulfenylation of coumarins at the C3-position.
deficient nitro coumarin also gave the desired product in 83% Although many methods were reported for the direct
yield in 24 h (3e). Furthermore, the reactions of diphenyl regioselective formation of C–S bond at the C3-position of
diselenide with 2H-benzo[h]chromen-2-one or 7,8,9,10- coumarins, all of them are limited to 4-hydroxyl
tetrahydro-2H-benzo[h]chromen-2-one worked well, affording
Table 3 Sulfenylation of coumarins and disulfidesa
the desired products in 91% and 98% yields, respectively (3p,
3q). No reaction was observed when 3-methyl coumarin was
used as a substrate, this result further proved the specific
SR2
PIFA (1 equiv.)
R1
+
R2SSR2
R1
DCM, rt
O
O
O
O
regioselectivity of this transformation. Subsequently, we turned
our attention to investigate the scope of the reaction with respect
to the diselenide reactants8h,10a,12 with coumarin under the
standard reaction conditions. Reactions of dipenyl diselenides
with various substitutents (OMe, Me, F, Cl, Br, NO2) at different
positions of the phenyl ring worked well, and the desired
products were obtained in good to excellent yields (3r–3aa).
Moreover, the reaction proceeded smoothly with dinaphthyl
diselenide, furnishing the desired product in 60% yield in 12 h
(3ab). This protocol was also suitable for heterocyclic diselenide,
the reaction of 1,2-bis(2-methoxypyridin-3-yl)diselane provided
1
4
5
S
O
O
S
S
R2
O
O
Cl
R2
O
O
O
O
5b, R2 = H, 0.5 h, 98%
, R2 = 2-F, 4 h, 98%
, R2 = H, 0.5 h, 87%
, R2 = 4-Me, 0.5 h, 89%
5g
5c
5f
5a
, 24 h, 63%
2 = 4-Me, 0.5 h, 96%
5d,
R
, R2 = 4-Cl, 4 h, 93%
5e
aReaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), PIFA (1 equiv.), in DCM (2 mL)
at room temperature in air.
2 | J. Name., 2012, 00, 1-3
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coumarins.9c,13 To our delight, this novel protocol is also suitable
for the direct regioselective sulfenylation of coumarins at the C3-
position, and the corresponding products were obtained in good to
excellent yields (table 3, 5a–5g).
PIFA (1 equiv.)
View Article Online
DOI: 10.1039/C9CC09001K
SePh
TEMPO (2 equiv.)
+
PhSeSePh
(a)
O
O
DCM, rt, 12 h
O
O
1a
2a
3a
no detected
Gratifyingly, this method allows selenation of various
(hetero)arenes with diphenyl diselenide under standard reaction
conditions. Reactions of chromone, benzoquinones and 1-
methylquinolin-4(1H)-one with diphenyl diselenide proceeded
smoothly, the desired products were obtained in good to excellent
yields (table 4, 7a–7d). Diselenation occurred when
benzo[b]thiophene was used as a substrate, and the corresponding
product was obtained in 68% yield in 12 h (7e). The application
of 7-azaindole and indazole in this transformation was successful,
affording the desired products in 67% and 81% yields,
respectively (7f, 7g). Moreover, reactions of diphenyl diselenide
with different imidazoheterocycles worked well, providing the
desired products in good to excellent yields (7h–7m). This
method was also suitable for C–H selenation of monocyclic and
bicyclic arenes. When anisole was subjected to this protocol, the
product 7n was obtained in 84% yield in 5 min. Reactions of
PIFA (1 equiv.)
SePh
BHT (2 equiv.)
+
PhSeSePh
(b)
O
O
DCM, rt, 12 h
O
O
1a
2a
3a
no detected
PIFA (1 equiv.)
1,1-diphenylethylene
(2 equiv.)
SePh
+
Ph
Ph
SePh
+
O
PhSeSePh
(c)
DCM, rt, 12 h
O
O
O
1a
2a
3a
8
no detected
54%
Scheme 2 Control experiments
unprecedented selenating route, we conducted the control
experiments. Initially, radical trapping experiments of coumarin
(1a) and diphenyl diselenide (2a) were examined in the presence
of 2 equiv. of TEMPO (2,2,6,6-tetramethyl-1- piperidinyloxy) or
BHT (butylhydroxytoluene) under the standard reaction
conditions (Scheme 2a, 2b). After 12 h, no reactions were
detected. These results suggested that this transformation might
proceed by a radical pathway. In order to confirm the formation
of selenyl radicals, a reaction was carried out under the standard
reaction conditions in the presence of 2.0 equiv. of 1,1-
diphenylethylene. After 12 h, no 3a was observed; a new spot 8
was generated, it was confirmed as the adduct of selenyl radical
and 1,1-diphenylethylene (scheme 2c).14 Subsequently, reactions
of all (hetero)arenes (6a–6q) with diphenyl diselenide (2a) were
tried under the standard reaction conditions with 2 equiv. of
TEMPO, BHT or 1,1-diphenylethylene. All of the reactions
were suppressed, and the 8 was observed. These results indicated
that the selenation of (hetero)arenes probably involved the
selenyl radical.
diphenyl
diselenide
with
2-methoxynaphthalene,
methyl(naphthalen-2-yl)sulfane and N-methylnaphthalen-2-amine
proceeded smoothly, giving the expected products in good yields
in a short reaction time (7o–7q).
To gain some insights into the mechanism of this
Table 4 Selenation of (hetero)arenes and diphenyl diselenidesa
s
s
e
e
n
n
PIFA (1 equiv.)
DCM, rt
+
PhSeSePh
(hetero)are
7
(hetero)are
Se
Ph
H
6
2a
O
O
N
O
Se
Se
Se
R
O
O
7b
, R = H, 1 h, 78%
7a
5d
, 4 h, 90%
, 0.5 h, 94%
7c
, R = Me, 6 h, 67%
On the basis of relevant reports5,6,11,15 and our experimental
results, a tentative mechanism for this novel transformation was
proposed by taking coumarin 1a and diphenyl diselenide 2a as
examples (scheme 3). Initially, reaction of PIFA with diphenyl
diselenide provides intermediate I, which undergoes thermal
homolytic cleavage to generate phenyl selenide radical II and
radical III. Subsequently, electrophilic attack of radical II to 1a
produces intermediate IV. Oxidation of IV by III affords ationic
intermediate V. Finally, deprotonation of V delivers the desired
product 3a.
Se
Se
Se
N
Se
S
N
N
N
H
H
5eb
5f
5g
, 1h, 81%
, 12 h, 68%
, 5 min, 67%
Se
Se
Se
N
N
N
N
N
S
N
S
5h
5i
5j
, 0.5 h, 93%
, 0.5 h, 90%
, 5 min, 89%
In conclusion, an efficient and simple approach for
Se
Se
N
Se
N
N
F3CCO2
O2CCF3
F3CCO2
SePh
PhSeSePh
2a
I
I
N
N
N
N
N
PhSe
II
5k
5l
5m
, 5 min, 92%
, 5 min, 93%
O
, 5 min, 88%
PhSeO2CCF3
F3CCO2
I
I
Se
X
O
O
Se
1a
III
5o
5p
5q
, X = O, 5 min, 68%
, X = S, 5 min, 77%
, X = NH, 5 min, 84%
-H+
SePh
O
SePh
SePh
O
5n
, 5 min, 84%
O
O
O
O
CF3CO2
PhI +
3a
IV
V
aReaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), PIFA (1 equiv.), in DCM (2 mL)
at room temperature in air. b2.4 equiv. of 2a were used.
Scheme 3 Proposed mechanism
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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6
7
8
(a) P. Dai, X. Yu, P. Teng, W.-H. Zhang and C. DenVigew, OArrtigcl.eLOentlitn.e,
regioselective formation of C–Se bond at the C3-postion of
coumarin skeleton is realized by using PIFA as a promoter at
room temperature. Mild reaction conditions, good tolerance with
different functional groups, broad substrate scope and short
reaction time are the remarkable features of this transformation.
Additionally, this protocol is suitable for the direct regioselective
sulfenylation of coumarines at the C3-position and selenation of
other (hetero)arenes. Further investigations into the applications
of this new type of selenyl-coumarin compounds in synthetic
chemistry and drug discovery are currently underway in our
laboratory.
2018, 20, 6901; (b)C. Jin, Z. Yan, B. Sun and J. Yang, Org. Lett.,
DOI: 10.1039/C9CC09001K
2019, 21, 2064.
(a) S. G. Modha, V. P. Mehtab and E. V. V.der Eycken, Chem.
Soc. Rev., 2013, 42, 5042; (b) R. L. Brutchey, Acc. Chem. Res.,
2015, 48, 2918.
For selected publication on selenation, see: (a) D. Kundu, S.
Ahammed and B. C. Ranu, Green. Chem., 2012, 14, 2024; (b)
D. Kundu, S. Ahammed and B. C. Ranu, Org. Lett., 2014, 16,
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Glorius, Angew. Chem. Int. Ed., 2015, 54, 5772; (d) A. J.
Brown, D. Pinkowicz, M. R. Saber and K. R. Dunbar, Angew.
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H. Liu, Y. Fang, S.-Y. Wang and S.-J. Ji, Org. Lett., 2018, 20,
930; (h) C. Ding, Y. Yu, Q. Yu, Z. Xie, Y. Zhou, J. Zhou, G. Liang
and Z. Song, ChemCatChem. 2018, 10, 5397.
This
work
was
supported
by
the National Key Research Project (2017YFA0506000), National
Natural Science Foundation of China (21807080), Natural
Science Foundation of Zhejiang Province (LQ18B020004),
Wenzhou Medical University Research Start-up Fund
(QTJ17007).
9
(a) A. Jana, A. K. Panday, R. Mishra, T. Parvin, L. H.
Choudhury, ChemistrySelect. 2017, 2, 9420; (b) D. Yang, G. Li,
C. Xing, W. Cui, K. Li and W, Wei. Org. Chem. Front., 2018, 5,
2974; (c)D. Das, P. Mukherjee and A. R. Das, ChemistrySelect.,
2019, 4, 1971.
Conflicts of interest
There are no conflicts to declare.
10 (a) Y. Yu, Y. Zhou, Z. Song and G. Liang, Org. Biomol. Chem.,
2018, 16, 4958; (b)Z. Song, Y. Zhou, W. Zhang, L. Zhan, Y. Yu,
Y. Chen, W. Jia, Z. Liu, J. Qian, Y. Zhang, C. Li andG. Liang, Eur.
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14 In scheme 2c, the reaction of coumarin and diphenyl
diselenide was hampered by adding 1,1-diphenyl ethylene;
the 8, which was formed by the reaction of selenyl radical
and 1,1-diphenyl ethylene, was isolated. These results
suggested that the reaction might proceed via a radical
process. In many reports, 1,1-diphenyl ethylene was added
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC09001K
XR2
O
H
O
R1
R2XXR2
R1
+
O
O
PIFA (1.0 equiv.)
air, DCM, rt
s
s
e
e
n
n
+
PhSeSePh
(hetero)are
(hetero)are
Se
Ph
H
X = Se, S
Metal-free
56 examples
Mild reaction conditions
Short reaction time
up to 98% yields
A novel and practical method for the direct regioselective selenation of coumarins at the
C3-postion has been achieved using PIFA as a promoter at room temperature, this protocol is
applicable for the direct regioselective formation of C–S bond at the C3-position of coumarins
and selenation of other (hetero)arenes.