Ruthenium(II)-Catalyzed C-H Activation of Chromones with Maleimides to Synthesize Succinimide/Maleimide-Containing Chromones

Article abstract of DOI:10.1021/acs.joc.0c01223

An efficient route for the coupling of maleimides with chromones at the C5-position has been developed under Ru(II) catalysis. It could provide 1,4-addition products and oxidative Heck-type products by switching additives. Benzoic acid led to the formation of 1,4-addition products under solvent-free conditions, and silver acetate was promoted to the generation of oxidative Heck-type products. Various maleimides and chromones were suitable for this transformation, affording the desired products with good to excellent yields in a short reaction time. To understand the mechanism of this reaction, deuteration studies and control experiments have been performed.

Full text of DOI:10.1021/acs.joc.0c01223

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Article
Ruthenium(II)-catalyzed C–H activation of chromones with maleimides
to synthesize succinimide/ maleimide-containing chromones
Yan Zhou, Hong Liang, Yaoguang Sheng, Shaoli Wang, Yi Gao, Lingling Zhan, Zhilong
Zheng, Mengjie Yang, Guang Liang, Jianmin zhou, Jun Deng, and Zengqiang Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01223 • Publication Date (Web): 24 Jun 2020
Downloaded from pubs.acs.org on June 24, 2020
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Ruthenium(II)-catalyzed C–H activation of chromones
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with
maleimides
to
synthesize
succinimide/
9
maleimide-containing chromones
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Yan Zhou,‡a Hong Liang,‡b Yaoguang Sheng,‡a Shaoli Wang,a Yi Gao,a Lingling
Zhan,c Zhilong Zheng,a Mengjie Yang,a Guang Liang, a Jianmin Zhou,*a Jun Deng,*b
and Zengqiang Song*a
aChemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical
University, 1210 University Town, Wenzhou, Zhejiang 325035, China
bState Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key
Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of
Sciences, Kunming 650201, Yunnan, China
cThe First Affiliated Hospital, Wenzhou Medical University, 1210 University Town, Wenzhou,
Zhejiang 325035, China
E-mail: zjm@wmu.edu.cn; dengjun@mail.kib.ac.cn; songzengqiang09@163.com
‡ These auhtors contributed equally to this work.
[Ru(p-cymene)Cl2]2 (5 mol%)
AgNTf2 (20 mol%)
[Ru(p-cymene)Cl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
R2
O
R2
O
N
N
H
O
O
AgOAc (3 equiv.)
PhCOOH (0.8 equiv.)
O
O
DCE, Air, 120 o
C
Neat, Air, 80 o
C
O
O
O
O
R1
O
O
R1
R1
R2
N
R2
N
O
O
1,4-Addition product
Heck-type product
Short reaction time
Mechanistic investigation
Solvent-free conditons
Functional group compatibility
Yields up to 95%
50 Examples
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ABSTRACT: An efficient route for the coupling of maleimides with chromones at the C5-position has
been developed under Ru(II) catalysis. It could provide 1,4-addition products and oxidative Heck-type
products by switching additives. Benzoic acid led to the formation of 1,4-addition products under
solvent-free conditions, and silver acetate promoted to the generation of oxidative Heck-type products.
Various maleimides and chromones were suitable for this transformation, affording the desired
products with good to excellent yields in a short reaction time. In order to understand the mechanism of
this reaction, deuteration studies and control experiments have been performed.
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Introduction
The succinimide and maleimide motifs are prevalent in many natural products and drug candidates,
exhibiting a broad spectrum of biological activities.1 Therefore, development of efficient and practical
methods for the preparation of these compounds has drawn considerable attention from chemists.
Transition-metal-catalyzed C–H bond activation is considered as a direct way to construct structurally
diverse molecules. In recent years, several directing groups assisted coupling reactions of maleimides
and (hetero)arenes have been accomplished by transition-metal-catalyzed C–H bond activation.2–5
According to the mechanism (scheme 1), the intermediate I is formed in the coupling reactions of
arenes and maleimides, it does not have β-hydrogen in the syn-periplanar position. There are two ways
for the transformation of intermediate I: one way is acid-promoted protodemetallation, affording
1,4-addition products; the other way is base acetate ion-promoted deprotonation, giving Heck-type
products. In the most of reported reactions, maleimides underwent hydroarylation, providing
1,4-addition products.3 Different metal catalysts (such as Rhodium, Ruthenium, Cobalt, Manganese)
were successfully applied in this transformation. In 2018, the Prabhu group reported the first Heck-type
coupling of maleimides with ketones by Rh(III) catalyzed direct C–H bond activation, the desired
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Scheme 1. Formation of 1,4-Addition Product and Heck-Type Product from Intermediate I
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9
G
DG
D
L
DG
M
base acetate ion
acid
O
O
O
N
R
N
N
R
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O
O
O
R
1,4-addition product
Heck-type product
I
products were obtained in moderate yields.4 Later, they developed an elegant method for the coupling
of maleimides with indoles at the C4-position under Rh(III) catalysis. In this protocol, 1,4-addition
products and Heck-type products could be obtained by switching the additives (scheme 2(a)).3e In 2019,
a Rh(III)-catalyzed alkenylation of maleimides with arylacetamides was achieved by Jeganmohan’s
group.5 Very recently, Sharma and co-workers reported a method on the regioselective C–H alkylation
and alkenylation at the C5-position of 2-amino-1,4-naphthoquinones with maleimides under Rh(III)
catalysis (scheme 2(b)).3f Obviously, approaches for the preparation of 1,4-addition products and
Heck-type products of maleimides with (hetero)arenes via direct C–H bond activation are highly in
demand.
The chromone scaffold is a core structure and ubiquitously present in numerous bioactive
compounds and pharmaceuticals, their derivatives have gained considerable attention in new drug
discovery.6 So far, several strategies have been developed for the functionalization of different
positions of chromone ring to synthesize their derivatives.3b,7,8,9,10 The C5-position of chromones could
be functionalized by chelation-assisted transition-metal-catalyzed transformation. In this case, the keto
group of chromones, which has weakly coordinating ability, was used as a directing group. On the
basis of this strategy, the Jeganmohan group and Antonchick group successfully developed elegant
methods of oxidative cross-coupling of olefins with chromones at the C5-position using Ru(II) and
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Scheme 2. Comparison of Previous Work with Current Work
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previous work:
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9
R
O
R
O
N
N
O
H
CF3
Rh(III)/Ag2CO3
O
O
O
O
CF3
CF3
Rh(III)/AgOAc/AcOH
O
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(a)
O
N
N
R'
N
R'
R'
N
R
N
R
O
O
O
R
O
R
O
N
N
H
O
O
O
Rh(III)/Ag2CO3
Rh(III)/AcOH
O
O
O
(b)
O
NR'R''
N
R
N
R
NR'R''
NR'R''
O
O
O
O
R
O
N
O
H
O
Rh(III)/PivOH
O
O
+
N
R
(c)
(d)
O
O
this work:
O
R
O
R
O
N
N
H
O
Ru(II)/PhCOOH
O
O
Ru(II)/AgOAc
O
O
O
O
O
Neat
O
O
N
R
N R
O
O
Rh(III) catalysts, respectively.8,9 Subsequently, several research groups finished the C5-amination of
chromones with sulfonyl azides using different transition-metal catalysts.10 In 2015, a Ru(II)-catalyzed
hydroxylation of chromones at the C5-position was accomplished by Hong’s group.11 However, the
methods for the coupling of chromones at the C5-position with maleimides are rare. Only one method
was reported for the C5-alkylation of chromones with maleimides under Rh(III) catalysis (scheme
(2c)).3b The protocols for the alkenylation of chromones at the C5-position with maleimides has never
been reported.
In continuation of our studies on the direct functionalization of unactivated C–H bonds,7d,12 we are
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interested in the exploration of transition-metal-catalyzed protocols for the coupling of maleimides
with chromones at the C5-position. Inspired by the aforementioned background, and our experiences in
this field,12 we herein wish to disclose a Ru(II)-catalyzed novel protocol for hydroarylation and
oxidative Heck-type coupling of chromones at the C5-position with maleimides by switching the
additives (scheme (2d)).
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We started our exploration using chromone 1a and maleimide 2a as model substrates. Different
additives, solvents, amounts of the additive, reaction temperature, equivalents of maleimide and
catalysts were screened for this transformation (Table S1–S5, ESI†). Finally, the optimal conditions for
the hydroarylation of maleimides and chromones were obtained: N-ethylmaleimide (2.5 equiv.),
[Ru(p-cymene)Cl2]2 (2.5 mol%), AgNTf2 (10 mol%), benzoic acid (0.8 equiv.) without solvent at 80 oC
in air (entry 3, Table S3, ESI†); the optimal conditions for the Heck-type coupling of maleimides and
chromones were obtained: N-ethylmaleimide (2.5 equiv.), [Ru(p-cymene)Cl2]2 (5 mol%), AgNTf2 (20
o
mol%), and AgOAc (3 equiv.) in DCE (2 mL) at 120 C in air (entry 1, Table S5, ESI†). Moreover,
gram-scale reactions were carried out under the optimal conditions, the desired products 3a and 4a
were obtained in 84% and 81% yields, respectively (entry 11, Table S3; entry 13, Table S5, ESI†). The
structure of product 4a was further confirmed by single-crystal X-ray analysis (CCDC 1901928, see the
ESI†).
Having the optimized conditions in hand, we explored the scope for the hydroarylation reaction.
Chromones and maleimides with diverse substituents were examined under the solvent-free reaction
conditions. Various substituents were tolerated in this transformation, and the desired products were
obtained in good to excellent yields in 5-8 h (Table 1, 3b–3n). The reaction of xanthone gave the
desired in 82% yield in 2 h (Table 1, 3o).13
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Table 1. Hydroarylation of Chromones and Maleimidesa
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R2
O
7
8
9
N
O
[Ru(p-cymene)Cl2]2 (2.5 mol%)
O
O
AgNTf2 (10 mol%)
O
O
O
N
R2
+
R1
PhCOOH (0.8 equiv)
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Neat, Air, 80 o
C
R1
O
1
2
3
O
O
O
O
N
N
N
N
O
O
O
O
O
O
O
O
O
O
Cl
O
O
3a
3b
3c
3d
, 6 h, 87%
, 4.5 h, 91%
, 6 h, 87%
, 6 h, 93%
O
O
O
N
O
N
O
O
N
HN
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3f
3i, 6.5 h, 89%
, 6 h, 85%
3g
3h
, 12 h, 79%
3e
, 6 h, 89%
R3
, 4 h, 87%
O
O
O
N
O
O
O
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
, R3 = H, 6 h, 81%
3l
3o
, 2 h, 82%
, R3 = Et, 6.5 h, 86%
, R3 = Br, 6.5 h, 89%
3m
3j
3k
, 6.5 h, 90%
, 5 h, 91%
3n
aReaction conditions: 1 (0.2 mmol, 1 equiv), 2 (0.5 mmol, 2.5 equiv), [Ru(p-cymene)Cl2]2 (0.005 mmol, 0.025
equiv), AgNTf2 (0.02 mmol, 0.1 equiv), benzoic acid (0.16 mmol, 0.8 equiv.) without solvent at 80 oC in air.
Next, we turned our attention to evaluate the generality for the Heck-type coupling reaction.
Chromone derivatives with diverse electron-donating or -withdrawing groups at the different positions
were tested with N-ethylmaleimide under optimum conditions. Generally, the reactions proceeded
smoothly, providing the corresponding products in good to excellent yields in a short reaction time
(Table 2, 4b–4q). Notably, chromone derivatives containing halogens or ester groups were tolerated in
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Table 2. Heck-Type Coupling of Chromones and Maleimidesa
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9
R2
N
O
O
[Ru(p-cymene)Cl2]2 (5 mol%)
O
O
AgNTf2 (20 mol%)
O
O
O
N
R2
+
R1
AgOAc (3 equiv)
DCE, Air, 120 o
C
R1
O
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1
2
4
O
O
O
N
N
N
O
F
O
O
O
O
O
O
R1
O
R1
O
, R1 = Me, 0.5 h, 92%
, R1 = Br, 4 h, 92%
, R1 = Ph, 1 h, 93%
, R1 = 2-Me-Ph, 1 h, 93%
, R1 = 3-Cl-Ph, 1.5 h, 92%
4d
4eb
4a,
R
1 = H, 1 h, 92%
, R1 = Me, 0.5 h, 95%
4b
4f
4ib
, 1 h, 79%
4cb
4g
4h
, R1 = Ph, 0.5 h, 75%
O
N
R2
O
O
N
N
O
O
O
O
O
O
O
O
R1
, R1 = Me, 0.5 h, 91%
, R1 = OMe, 0.5 h, 90%
, R1 = OAc, 1 h, 95%
, R1 = F, 2 h, 94%
, R1 = Cl, 2 h, 83%
, R1 = Br, 1 h, 84%
O
R1
4j
4k
4l
, R2 =H, 12 h, 62%
4r
, R1 = Me, 0.5 h, 93%
, R1 = Cl, 1 h, 85%
4p
4q
, R2 = Me, 0.5 h, 89%
4s
4t
4m
4n
4ob
, R2 = t-Bu, 1 h, 69%
, R2 = Cy, 1 h, 88%
4u
R3
O
O
O
N
O
O
N
N
O
O
O
O
O
O
O
O
O
, R3 = H, 2 h, 78%
4x
4yb
, R3 = 2-Br, 1 h, 86%
, R3 = 4-Et, 0.5 h, 79%
4z
4v
4w
, 0.5 h, 87%
, 3.5 h, 88%
4aab
, R3 = 4-Ac, 1 h, 73%
, R3 = 4-Br, 0.5 h, 75%
, R3 = 4-NO2, 4 h, 61%
4ab
4ac
O
O
O
O
O
O
O
O
O
S O
O
O
O
O
O
O
O
4ad
4ae
4af
4ag
, 0.5 h, 93%
, 1 h, 80%
, 1 h, 81%
, 1 h, 90%
aReaction conditions: 1 (0.2 mmol, 1 equiv), 2 (0.5 mmol, 2.5 equiv), [Ru(p-cymene)Cl2]2 (0.01 mmol, 0.05 equiv),
AgNTf2 (0.04 mmol, 0.2 equiv), AgOAc (0.6 mmol, 3 equiv) in DCE (2 mL, 0.1 M) at 120 oC in air. b0.015 mmol
(0.075 equiv) of [Ru(p-cymene)Cl2]2 and 0.06 mmol (0.3 equiv) of AgNTf2 were used.
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this transformation, providing an opportunity for further modification of the related products at the
remaining reactive sites (4e, 4h, 4i, 4l–4o, 4q). Subsequently, we turned our attention to investigate the
scope of the reaction with respect to maleimide reactants with chromone under the optimal conditions.
Changing the ethyl group to hydrogen or other alkyl groups at the nitrogen position of maleimides, the
related products were gained in good yields (4r–4v). N-benzylmaleimide as well as
N-phenylmaleimides with various substituents (bromo, ethyl, acetyl, nitro) were tolerated in this
transformation, furnishing the desired products in good yields in a short reaction time (4w–4ac). To our
delight, this protocol was also suitable for acrylates, the corresponding products were obtained in good
yields in 1 h (4ad–4af). Furthermore, application of phenyl vinyl sulfone was successful, providing the
desired product in 93% yield in 0.5 h (4ag).
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Scheme 3. Synthetic Applications
O
N
O
ii
O
O
Ot-Bu
O
O
O
5b
N
N
, 56%
O
O
O
O
i
O
O
Se
O
N
O
5a
, 64%
4a
O
O
iii
O
O
5c
, 52%
aReaction conditions: (i) 4a (53.8 mg, 0.2 mmol), diphenyl diselenide (31.2 mg, 0.1 mmol), NIS (6.7 mg, 0.03
o
mmol), TBHP (70% in H2O, 11 μL, 0.8 mmol), DMF (2 mL, 0.1 M), 70 C, 12 h; (ii) 4a (53.8 mg, 0.2
mmol),tert-butyl acrylate (58 μL, 0.4 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), Cu(OAc)2 (109.0 mg, 0.6 mmol),
Ag2CO3 (165.4 mg, 0.6 mmol), PivOH (2 mL, 0.1 M), 120 oC, 8 h; (iii) 4a (53.8 mg, 0.2 mmol),1,4-benzoquinone
(86.5 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol), AgOAc (83.4 mg, 0.5 mmol), PivOH (46 μL, 0.4 mmol),
1,4-dioxane (2 mL, 0.1 M), 100 oC, 12 h.
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After successfully developing the protocol for the preparation of Heck-type products of succinimides
with chromones, we tried to modify the C3-position of chromone ring of the products using reported
methods to demonstrate their further synthetic utility (Scheme 3). Selenation of the product 4a with
diphenyl diselenide employing the method from our group was successful,7d affording the desired
product 5a in 68% isolated yield. The product 4a could be further alkenylated with tert- butyl acrylate7a
or benzoquinone7b by palladium catalysis, the expected products 5b and 5c were obtained in moderate
yields.
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In order to gain some insights into the mechanism of this interesting approach, we conducted the
deuterium labelling experiments. 1a was treated with 2 equiv of D2O under the optimal conditions in
the absence of maleimide, leading to the incorporation of deuterium at the C5-position of 1a according
to the proton NMR spectrum (Scheme 4 (a), see the ESI† for details). Then we performed the same
reaction with 2.2 equiv of 2a. No incorporation of deuterium was observed for the isolated product
(Scheme 4 (b), see the ESI† for details). These results suggest that the initial C–H activation step might
be reversible, and the C–H activation exclusively occurs at the C5-position with the assistance of the
keto group. Moreover, 1,4-addition product 3a was examined under the optimum conditions. After 12
h, 84% of 3a was recovered, 4a was obtained in 10% isolated yield (Scheme 4 (c), see the ESI† for
details). The result of this experiment indicates that 4a is not formed by the oxidation of 3a in this
transformation. Additionally, the kinetic isotope effect (KIE) value of the parallel and competitive
reactions were obtained, these results suggest that the C–H metallation might be involved in the
rate-determining step (Scheme 4 (d), see the ESI† for details).
On the basis of control studies and the reported literatures,2–5,8–14 a plausible mechanism of the
reactions of maleimides with chromones at the C5-position was proposed (Scheme 5). Initially,
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Scheme 4. Mechanistic Investigation
5
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9
67%
D
[Ru(p-cymene)Cl2]2 (6.1 mg, 0.01 mmol)
O
O
O
AgNTf2 (15.5 mg, 0.04 mmol)
(a)
AgOAc (100.1 mg, 0.6 mmol),
D2O (7 L, 0.4 mmol)
O
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DCE (2 mL, 0.1 M), Air, 120 oC, 1h
1a
1aa
, 96%
(29.2 mg, 0.2 mmol)
O
[Ru(p-cymene)Cl2]2 (6.1 mg, 0.01 mmol)
O
N
O
O
AgNTf2 (15.5 mg, 0.04 mmol)
O
+
O
N
AgOAc (100.1 mg,0.6 mmol),
D2O (7 L, 0.4 mmol)
O
(b)
DCE (2 mL, 0.1 M), Air, 120 oC, 1h
O
1a
2a
(62.6 mg, 0.5 mmol)
4a
, 89%
(29.2 mg, 0.2 mmol)
O
N
O
N
[Ru(p-cymene)Cl2]2 (6.1 mg, 0.01 mmol)
O
O
O
AgNTf2 (15.5 mg, 0.04 mmol)
O
(c)
AgOAc (100.1 mg,0.6 mmol)
DCE (2 mL, 0.1 M), Air, 120 oC, 12 h
O
O
3a
4a
, 10%
(54.2 mg, 0.2 mmol)
KIE experiment
Competition rection:
O
[Ru(p-cymene)Cl2]2 (6.1 mg, 0.01 mmol)
O
N
H/D
O
O
AgNTf2 (15.5 mg, 0.04 mmol)
O
+
O
O
N
(d)
AgOAc (100.1 mg,0.6 mmol)
DCE (2 mL, 0.1 M), Air, 120 oC, 20 min
KH/KD = 3.00
H/D
O
D/H
1a/1a'
2a
(14.6 mg, 0.1 mmol + 14.8 mg, 0.1 mmol) (62.5 mg, 0.5 mmol)
4a/4a'
combined yield, 73%
parallel reaction:
O
N
O
O
D
O
O
H
O
same conditions
with (d), 20 min
same conditions
with (d), 20 min
O
O
O
+
N
+
N
(e)
D
H
O
O
O
D/H
2a
(31.2 mg, 0.25 mmol)
1a'
1a
(14.6 mg, 0.1 mmol)
2a
(31.2 mg, 0.25 mmol)
4a/4a'
(14.8 mg, 0.1 mmol)
combined yield, 72%
KH/KD = 2.03
[Ru(p-cymene)Cl2]2 reacts with AgNTf2 and benzoic acid or AgOAc to generate a more active
monomeric A or A' and AgCl. Coordination between ruthenium species and the oxygen atom of keto
group, followed by C–H bond activation provides a five membered metallocycle B. Subsequently,
maleimide 2a inserts into the carbon–ruthenium bond of B and produces a bicyclic intermediate C, in
which the β-hydride elimination is restricted due to the lack of β-hydrogen in a syn-periplanar manner.
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If the additive is benzoic acid, the reaction gives 1,4-addition product 3a along with the species A by
protodemetallation. If the additive is silver acetate, the Heck-type product 4a along with Ru(0) species
are generated by deprotonation of the acidic β-hydrogen of intermediate C by OAc-. Oxidation of Ru(0)
species by silver acetate regenerates the active Ru(II) catalyst.
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Scheme 5. Proposed Mechanism
[Ru(p-cymene)Cl2]2
AgNTf2
PhCOOH
AgCl
AgOAc
AgCl
Ru
O
Ru
O
PhCOO
AcO
O
O
O
Ph
N
L: p-cymene
(RuLX2)
A
(RuLX'2)
A'
O
X: OAc, X': PhCOO
Y = X or X'
O
O
RuLY2
O
O
A
A'
or
4a
OAc-
O
H
O
O
O
O
Ru(0)
pathwAa gOAc
1a
Ru
N
AgOAc
RuLX'2
A'
Y
H
L
H
y
O
O
b
HY
D
Y
Ru
Y
L
N
H
L Ru
O
O
O
a
y
O
N
C
pathwa
O
PhCOOH
O
B
RuLX2
+
O
A
O
N
3a
O
2a
In conclusion, we have reported a Ru(II)-catalyzed coupling reaction of chromones at the
C5-position with maleimides using keto as a weak directing group. Succinimide-containing
chromones and maleimide-containing chromones can be generated by switching the additives in
this transformation: benzoic acid leads to the formation of 1,4-addition products under
solvent-free conditions; silver acetate furnishes Heck-type products. This protocol features short
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reaction time, good tolerance with various functional groups as well as wide substrate scopes,
providing the desired products in good to excellent yields.
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Experimental Section
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1. General Information:
Unless otherwise noted, all commercially available compounds were used as provided without
further purification. Solvents for chromatography were technical grade. Column chromatography
was performed using silica gel Merck 60 (particle size 0.040-0.063 mm). Solvent mixtures are
understood as volume/volume. 1H-NMR, 13C-NMR, 19F-NMR were recorded on a Bruker
DRX500 (500 MHz) spectrometer in CDCl3 (δ = 7.26 ppm for 1H, δ = 77.00 ppm for 13C) and in
DMSO-d6 (δ = 2.50 ppm for 1H, δ = 39.43 ppm for 13C). Data are reported in the following order:
chemical shift (δ) in ppm; multiplicities are indicated s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet); coupling constants (J) are given in Hertz (Hz). High resolution mass spectra were
recorded on a ESI-Q-TOF mass spectrometer. Chemical yields refer to isolated pure substances.
2. General procedure for synthesis:
(1) General procedure for the preparation of substituted chromones (others are
commercially available):
1) General Procedure for the preparation of 3-(o-tolyl)-4H-chromen-4-one and
3-(3-chlorophenyl)-4H-chromen-4-one15
3-Bromochromone (0.5 mmol, 1 equiv), phenylboronic acid (1.5 mmol, 3 equiv) and (2M)
Na2CO3 solution were taken in toluene (3 mL, 0.17 M) in a 25 mL round bottom flask. The
solvent was purged with argon for 30 min to remove the dissolved oxygen from solvent. Then
Pd(PPh3)4 (0.025 mmol, 0.05 equiv) was added to the reaction mixture and it was refluxed for
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18-24 h. After completion of the reaction, it was allowed to come to room temperature. The
reaction mixture was extracted with ethyl acetate, washed with water, brine and dried over
anhydrous MgSO4. Purified by normal silica gel column chromatography (20-30% ethyl
acetate/pet. Ether) to afford the corresponding isoflavones.
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2)
General
procedure
for
the
preparation
of
7-methyl-4H-chromen-4-one,
7-chloro-4H-chromen-4-one, 8-methyl-4H-chromen-4-one, and 8-chloro-4H-chromen-4-one16
The corresponding 1-(2-hydroxyphenyl)ethan-1-one (0.5 mmol, 1 equiv) was placed in a
flame-dried flask with stir bar in 0.5 M ethyl formate and cooled to 0 °C. NaH (60% in mineral oil,
3 mmol, 6 equiv) was added portion-wise to the cooled solution over 2 hours. If necessary for
stirring, minimal amounts of dry THF were added to the flask in portions as needed. After addition
of all of the NaH, the solution was warmed to room temperature and quenched with methanol (5
mm0l, 10 equiv). Concentrated HCl (25 mmol, 50 equiv) was then added slowly and allowed to
stir overnight at room temperature. The reaction was then diluted with ethyl acetate, washed with
water, NaHCO3 (sat. aq.), and brine, dried with Na2SO4, and concentrated under vacuum to afford
the crude chromone. The chromones were then recrystallized with ethyl acetate/hexanes or
dichloromethane/hexanes to afford pure materials.
3) General procedure for the preparation of 4-oxo-4H-chromen-7-yl acetate16,17
i) 7-hydroxy-4H-chromen-4-one was prepared according to the procedure 2).
ii) Acetyl chloride (0.282 mL, 3.96 mmol) was added dropwise to a solution of
4-oxo-4H-chromen-7-yl acetate (0.5 g, 3.3 mmol) and pyridine (0.294 mL, 3.63mmol) in
dichloromethane (2.5 mL). After 3 h, the mixture was washed, in sequence, with water (2.5 mL),
10% HCl (2.5 mL), water (1.2 mL), and a saturated solution of NaHCO3 (2.5 mL). The organic
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(2) General procedure for the synthesis of products 3:
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Chromones 1 (0.2 mmol, 1 equiv), maleimides 2 (0.5 mmol, 2.5 equiv), [Ru(p-cymene)Cl2]2
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(0.005 mmol, 0.025 equiv), AgNTf2 (0.02 mmol, 0.1 equiv) and benzoic acid (0.16 mmol, 0.8
equiv) were added in a 12 mL screw capped tube at room temperature in air. The reaction mixture
was allowed to warm up to 80 °C in heating mantle and stirred for 1-12 h. When the reaction was
completed, it was mixed with water and ethyl acetate. The reaction mixture was extracted three
times with ethyl acetate. The combined organic layer was washed two times with a little amount
of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under
vacuum and the residue was purified by flash column chromatography on silica gel (eluting with
petroleum ether-ethyl acetate) to provide the desired products 3.
(3) General procedure for the synthesis of products 4:
Chromones 1 (0.2 mmol, 1 equiv) and maleimides 2 (0.5 mmol, 2.5 equiv) were dissolved in a 12
mL screw capped tube with 2 mL of DCE (0.1 M). Then [Ru(p-cymene)Cl2]2 (0.01 mmol, 0.05
equiv), AgNTf2 (0.04 mmol, 0.2 equiv) and AgOAc (0.6 mmol, 3 equiv) were added to the
reaction mixture at room temperature in air. The reaction mixture was allowed to warm up to
120 °C in heating mantle and stirred for 1-12 h. After finishing the reaction, the reaction mixture
was directly loaded on a silica gel column and purified with petroleum ether/EtOAc mixture to
provide the desired products 4.
(4) Procedure for the synthesis of product 5a:7d
A mixture of 4a (53.8 mg, 0.2 mmol), diphenyl diselenide (31.2 mg, 0.1 mmol), NIS (6.7 mg, 0.03
mmol), TBHP (70% in H2O, 11 L, 0.8 mmol) and DMF (2 mL, 0.1 M) were added in a 5 mL
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glass tube, which was stirred at 70 C for 12 h. When the reaction was completed, it was mixed
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with water and ethyl acetate. The reaction mixture was extracted three times with ethyl acetate.
The combined organic layer was washed two times with a little amount of water, dried over
anhydrous magnesium sulfate and filtered. The filtrate was evaporated under vacuum and the
residue was purified by flash column chromatography on silica gel (eluting with petroleum
ether-ethyl acetate) to provide the desired product 5a.
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(5) Procedure for the synthesis of product 5b:7a
4a (53.8 mg, 0.2 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), Cu(OAc)2 (109.0 mg, 0.6 mmol), and
Ag2CO3 (165.4 mg, 0.6 mmol) were combined in PivOH (2 mL, 0.1 M). The tert-butyl acrylate
(58 L, 0.4 mmol) was added slowly and the reaction mixture was heated to 120 oC. The
reaction was monitored by TLC using EtOAc/petroleum ether as the mobile phase. The reaction
mixture was diluted with CH2Cl2 and the excess NaHCO3 was added to neutralize PivOH.
After stirring the mixture for 10 min, the residue was washed with sequentially aqueous NaHCO3
and NH4Cl. The organic layer was dried over MgSO4. After removal of solvent, the
residue was purified by flash chromatography on silica gel to give the desired product 5b.
(6) Procedure for the synthesis of product 5c:7b
4a (53.8 mg, 0.2 mmol), 1,4-benzoquinone (86.5 mg, 0.8 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol),
AgOAc (83.4 mg, 0.5 mmol) and PivOH (46 L, 0.4 mmol) were combined in 1,4-dioxane (2 mL,
0.1 M) in a cap test tube. The reaction mixture was heated to 100 oC. The reaction was stirred for
12 h until 4a disappeared (monitored by TLC using EtOAc/petroleum ether as the mobile phase).
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After cooled to room temperature, the 1,4-dioxane solvent was removed under reduced pressure.
The reaction mixture was diluted with CH2Cl2 and the aqueous NaHCO3 was added to neutralize
the PivOH. After stirring the mixture for 10 min, the residue was extracted with aqueous NH4Cl.
The organic layer was dried over MgSO4. After removal of solvent, the residue was purified by
flash chromatography on silica gel to give the desired product 5c.
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3. Characterization of synthesized substituted chromones:
3-(o-tolyl)-4H-chromen-4-one.18 The isolated yield is 77%. 1H NMR (600 MHz, CDCl3) δ 8.31 (dd, J =
7.9, 1.0 Hz, 1H), 7.89 (s, 1H), 7.75 – 7.68 (m, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H),
7.35 – 7.28 (m, 2H), 7.27 – 7.23 (m, 1H), 7.19 (d, J = 7.4 Hz, 1H), 2.27 (s, 3H) ppm.
1
3-(3-chlorophenyl)-4H-chromen-4-one.19 The isolated yield is 45%. H NMR (600 MHz, CDCl3) δ
8.35 – 8.29 (m, 1H), 8.04 (s, 1H), 7.74 – 7.68 (m, 1H), 7.59 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.48 –
7.42 (m, 2H), 7.39 – 7.37 (m, 2H) ppm.
1
7-methyl-4H-chromen-4-one.20 The isolated yield is 60%. H NMR (600 MHz, CDCl3) δ 8.08 (d, J =
8.1 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.25 – 7.19 (m, 2H), 6.30 (d, J = 6.0 Hz, 1H), 2.48 (s, 3H) ppm.
4-oxo-4H-chromen-7-yl acetate.21 The isolated yield is 48%. 1H NMR (600 MHz, CDCl3) δ 8.21 (d, J =
8.7 Hz, 1H), 7.83 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.7, 2.1 Hz, 1H), 6.32 (d, J
= 6.0 Hz, 1H), 2.34 (s, 3H) ppm.
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7-chloro-4H-chromen-4-one.22 The isolated yield is 52%. H NMR (600 MHz, CDCl3) δ 8.13 (d, J =
5
6
7
8
9
8.6 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.6, 1.9 Hz, 1H), 6.33 (d, J
= 6.0 Hz, 1H) ppm. 13C{1H}NMR (151 MHz, CDCl3) δ 176.69, 156.53, 155.29, 139.81, 127.19,
126.11, 123.35, 118.19, 113.24 ppm. HRMS (EI) m/z: [M] calcd for C9H5ClO2: 179.9978, found:
179.9981.
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8-methyl-4H-chromen-4-one.22 The isolated yield is 57%. H NMR (600 MHz, CDCl3) δ 8.03 (d, J =
8.0 Hz, 1H), 7.88 (dd, J = 5.9, 3.0 Hz, 1H), 7.48 (d, J = 6.5 Hz, 1H), 7.27 (td, J = 7.7, 2.9 Hz, 1H), 6.32
(dd, J = 5.9, 2.9 Hz, 1H), 2.45 (d, J = 2.6 Hz, 3H) ppm. 13C{1H}NMR (151 MHz, CDCl3) δ 177.95,
155.02, 154.98, 134.61, 127.57, 124.71, 124.68, 123.28, 112.72, 15.53 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C10H8O2: 161.0602, found: 161.0598.
1
8-chloro-4H-chromen-4-one.22 The isolated yield is 61%. H NMR (600 MHz, CDCl3) δ 8.08 (dd, J =
8.0, 1.2 Hz, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.71 (dd, J = 7.7, 1.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 6.36
(d, J = 6.0 Hz, 1H) ppm; 13C NMR (151 MHz, CDCl3) δ 176.76, 155.16, 152.17, 134.02, 126.13,
125.21, 124.38, 123.14, 113.17 ppm. HRMS (EI) m/z: [M] calcd for C9H5ClO2: 179.9978, found:
179.9980.
4. Characterization of products 3, 4 and 5:
(S)-1-Ethyl-3-(4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3a was obtained as a white
solid (49.3 mg, 91%) after purification through a chromatography column (elution: 17% EtOAc in
o
1
petroleum ether), mp 136–137 C. H NMR (500 MHz, DMSO-d6) δ 8.26 (d, J = 5.9 Hz, 1H), 7.77 –
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7.74 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.38 (m, 1H), 6.30 (d, J = 5.9 Hz, 1H), 4.40 (m, 1H), 3.50 –
3.45 (m, 2H), 2.98 (m, 1H), 2.57 (dd, J = 17.3, 6.5 Hz, 1H), 1.14 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}
NMR (126 MHz, DMSO-d6) δ 177.5, 176.9, 176.0, 157.6, 155.8, 136.2, 133.6, 130.8, 121.6, 119.0,
112.9, 47.0, 36.8, 32.9, 12.6 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H14NO4, 272.0923;
found, 272.0918.
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(S)-1-Ethyl-3-(2-methyl-4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3b was
obtained as a white solid (49.5 mg, 87%) after purification through a chromatography column
(elution: 50% EtOAc in petroleum ether), mp 164–165 oC. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd,
J = 8.4, 7.5 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 6.09 (s, 1H), 4.05 (m, 1H), 3.72 – 3.63
(m, 2H), 3.02 (m, 1H), 2.76 (m, 1H), 2.35 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR
(151 MHz, CDCl3) δ 178.6, 177.5, 176.3, 165.1, 158.2, 135.7, 133.0, 130.4, 120.8, 119.1, 111.3,
48.4, 37.3, 33.8, 20.0, 12.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16NO4: 286.1079,
found: 286.1073.
(S)-1-Ethyl-3-(3-methyl-4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3c was
obtained as a white solid (53.0 mg, 93%) after purification through a chromatography column
(elution: 40% EtOAc in petroleum ether), mp158–159 oC. 1H NMR (600 MHz, CDCl3) δ 7.75 (s,
1H), 7.58 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.18 (s, 1H), 4.06 (m, 1H), 3.69 (q, J = 7.0
Hz, 2H), 2.99 (m, 1H), 2.79 (m, 1H), 1.93 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H) ppm. 13C{1H}NMR
(151 MHz, CDCl3) δ 178.7, 177.3, 176.4, 158.4, 150.7, 132.8, 130.3, 128.1, 121.4, 121.0, 119.3,
48.6, 37.6, 34.0, 12.8, 11.1 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16NO4: 286.1079,
found: 286.1072.
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(S)-3-(3-(3-Chlorophenyl)-4-oxo-4H-chromen-5-yl)-1-ethylpyrrolidine-2,5-dione. The product
3d was obtained as an amorphous solid (66.4 mg, 87%) after purification through a
chromatography column (elution: 40% EtOAc in petroleum ether). 1H NMR (400 MHz, CDCl3) δ
7.99 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.33 – 7.26 (m, 4H), 4.10 (m, 1H),
3.67 (dd, J = 14.0, 6.9 Hz, 2H), 3.02 (m, 1H), 2.81 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H) ppm.
13C{1H}NMR (126 MHz, CDCl3) δ 177.3, 176.6, 176.1.0, 157.9, 152.3, 135.4, 134.2, 133.4, 133.1,
121.0, 129.6, 129.0, 128.4, 127.0, 124.8, 121.9, 119.1, 77.2, 77.0, 76.8, 48.6, 37.6, 34.0, 12.8 ppm.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H17ClNO4: 382.0846, found: 382.0841.
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(S)-1-Ethyl-3-(7-methoxy-4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3e was
obtained as a white solid (52.4 mg, 87%) after purification through a chromatography column
(elution: 40% EtOAc in petroleum ether), mp 164–165 oC. 1H NMR (500 MHz, CDCl3) δ 7.71 (d,
J = 5.8 Hz, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 6.19 (d, J = 5.7 Hz, 1H), 3.89 (s, 3H), 3.71 – 3.63 (m,
2H), 2.99 (m, 1H), 2.75 (m, 1H), 1.82 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (151
MHz, CDCl3) δ 177.3, 176.8, 176.3, 162.9, 160.2, 153.7, 137.2, 120.5, 116.0, 113.6, 100.8, 55.8,
48.6, 37.1, 33.9, 12.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16NO5: 302.1028, found:
302.1021.
(S)-5-(1-Ethyl-2,5-dioxopyrrolidin-3-yl)-4-oxo-4H-chromen-7-yl acetate. The product 3f was
obtained as a white solid (55.9 mg, 85%) after purification through a chromatography column
(elution: 50% EtOAc in petroleum ether), mp 118–119 oC. 1H NMR (400 MHz, CDCl3) δ 7.78 (d,
J = 5.9 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 6.99 (s, 1H), 6.25 (d, J = 5.9 Hz, 1H), 4.01 (m, 1H), 3.71
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– 3.62 (m, 2H), 3.05 (m, 1H), 2.74 (m, 1H), 2.33 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm.
13C{1H}NMR (151 MHz, CDCl3) δ 177.5, 176.6, 176.0, 168.2, 158.7, 154.3, 153.5, 137.5, 124.7,
119.9, 113.8, 111.8, 48.2, 37.1, 33.9, 21.1, 12.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C17H16NO6: 330.0978, found: 330.0970.
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(S)-1-Ethyl-3-(8-methyl-4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3g was
obtained as a white solid (50.7 mg, 89%) after purification through a chromatography column
(elution: 40% EtOAc in petroleum ether), mp 165–166 oC. 1H NMR (400 MHz, CDCl3) δ 7.83 (d,
J = 5.8 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.08 (s, 1H), 6.23 (d, J = 5.4 Hz, 1H), 4.00 (m, 1H), 3.69
– 3.60 (m, 2H), 2.97 (m, 1H), 2.71 (m, 1H), 2.41 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) ppm.
13C{1H}NMR (151 MHz, CDCl3) δ 178.5, 177.3, 176.4, 156.6, 154.1, 134.2, 133.1, 130.3, 128.9,
122.0, 113.6, 48.4, 37.4, 33.8, 15.9, 12.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H16NO4:
286.1079, found: 286.1072.
(S)-3-(4-Oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3h was obtained as a white
solid (38.4 mg, 79%) after purification through a chromatography column (elution: 70% EtOAc in
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petroleum ether), mp 153–154 C. H NMR (600 MHz, DMSO-d6) δ 11.05 (brs, 1H), 8.27 (d, J =
5.6 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 5.6 Hz, 1H), 6.39 –
6.23 (m, 1H), 4.41 (m, 1H), 2.91 (m, 1H), 2.57 (dd, J = 17.3, 6.6 Hz, 1H) ppm. 13C{1H}NMR (151
MHz, DMSO-d6) δ 179.1, 178.3, 178.1, 158.1, 156.4, 136.9, 134.2, 131.2, 122.2, 119.5, 113.5,
49.1, 38.6 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H10NO4: 244.0610, found: 244.0605.
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EtOAc in petroleum ether), mp 92–93 C. H NMR (600 MHz, DMSO-d6) δ 8.26 (d, J = 5.8 Hz,
1H), 7.75 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 6.30 (d, J = 5.9 Hz, 1H), 4.34
(m, 1H), 3.86 (t, J = 12.2 Hz, 1H), 2.90 (m, 1H), 2.56 – 2.51 (m, 1H), 2.12 – 2.03 (m, 2H), 1.78 (d,
J = 12.9 Hz, 2H), 1.69 (t, J = 14.3 Hz, 2H), 1.61 (d, J = 12.6 Hz, 1H), 1.25 (dd, J = 24.4, 11.1 Hz,
2H), 1.12 (dd, J = 26.0, 13.0 Hz, 1H) ppm. 13C{1H}NMR (151 MHz, DMSO-d6) δ 177.4, 177.1,
176.3, 157.7, 155.9, 136.5, 133.7, 130.9, 121.6, 119.2, 113.1, 50.8, 46.8,36.6, 28.6, 28.2, 25.5,
25.4, 25.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H20NO4: 326.1392, found: 326.1385.
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Methyl (S)-3-(2,5-dioxo-3-(4-oxo-4H-chromen-5-yl)pyrrolidin-1-yl)propanoate. The product 3j
was obtained as a white solid (59.9 mg, 91%) after purification through a chromatography column
(elution: 40% EtOAc in petroleum ether), mp 122–123 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.25
(t, J = 5.5 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 6.31 – 6.30 (m,
1H), 4.39 (m, 1H), 3.69 (t, J = 7.5 Hz, 2H), 3.60 (s, 3H), 3.01 (m, 1H), 2.69 – 2.60 (m, 2H), 2.56
(dd, J = 17.5, 6.3 Hz, 1H) ppm. 13C{1H}NMR (151 MHz, DMSO-d6) δ 177.8, 177.0, 176.2, 171.2,
157.8, 156.1, 136.1, 133.8, 131.0, 121.6, 119.3, 113.0, 51.6, 47.0, 36.8, 34.0, 31.4 ppm. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C17H16NO6: 330.0978, found: 330.0971.
(S)-1-Benzyl-3-(4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3k was obtained as a
white solid (60.0 mg, 90%) after purification through a chromatography column (elution: 40%
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EtOAc in petroleum ether), mp 125–126 C. H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 5.9 Hz,
1H), 7.78 (t, J = 7.9 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.40 – 7.26 (m, 6H), 6.32 (d, J = 5.9 Hz, 1H),
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4.65 (dd, J = 47.1, 15.0 Hz, 2H), 3.08 (m, 1H), 2.66 (dd, J = 17.4, 6.5 Hz, 1H), 2.54 (m, 1H) ppm.
13C{1H}NMR (151 MHz, DMSO-d6) δ 177.7, 177.2, 176.3, 157.7, 156.1, 136.5, 133.8, 130.9, 129.6,
128.4, 127.5, 127.2, 121.6, 119.3, 113.0, 47.2, 41.4, 36.8 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C20H16NO4: 334.1079, found: 334.1072.
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(S)-3-(4-Oxo-4H-chromen-5-yl)-1-phenylpyrrolidine-2,5-dione. The product 3l was obtained as a
white solid (51.7 mg, 81%) after purification through a chromatography column (elution: 40%
EtOAc in petroleum ether), mp 135–136 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 5.9 Hz,
1H), 7.80 (dd, J = 8.4, 7.5 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.47 (d, J =
7.0 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 7.3 Hz, 2H), 6.39 (d, J = 5.9 Hz, 1H), 4.62 (m,
1H), 3.17 (m, 1H), 2.76 (dd, J = 17.5, 6.7 Hz, 1H) ppm. 13C{1H}NMR (151 MHz, DMSO-d6) δ
177.8, 176.3, 175.5, 157.8, 156.1, 136.1, 133.8, 133.2, 130.9, 128.8, 128.1, 127.3, 121.5, 119.3,
113.0, 47.2, 4.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H14NO4: 320.0923, found:
320.0916.
(S)-1-(4-Ethylphenyl)-3-(4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3m was
obtained as a white solid (59.7 mg, 86%) after purification through a chromatography column
(elution: 40% EtOAc in petroleum ether), mp 201–202 oC. 1H NMR (400 MHz, CDCl3) δ 7.82 (d,
J = 5.9 Hz, 1H), 7.65 (t, J = 8.0 Hz,1H), 7.51 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 7.7 Hz, 2H), 7.33 –
7.29 (m, 3H), 6.32 (d, J = 5.9 Hz, 1H), 4.28 (m, 1H), 3.18 (m, 1H), 2.97 (m, 1H), 2.69 (q, J = 7.6
Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H) ppm. 13C{1H}NMR (151 MHz, CDCl3) δ 178.2, 176.2, 175.8,
158.4, 154.4, 144.5, 135.8, 133.4, 130.8, 130.3, 128.6, 126.9, 122.1, 119.6, 113.8, 48.4, 37.4, 28.6,
15.4 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H18NO4: 348.1236, found: 348.1228.
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(S)-1-(4-Bromophenyl)-3-(4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione. The product 3n was
obtained as a white solid (70.8 mg, 89%) after purification through a chromatography column
(elution: 40% EtOAc in petroleum ether), mp 184–185 oC. 1H NMR (600 MHz, DMSO-d6) δ 8.32
(d, J = 5.9 Hz, 1H), 7.2 (t, J = 7.2 Hz, 1H), 7.75 – 7.73 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.47 (d,
J = 7.0 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 5.9 Hz, 1H), 4.61 (m, 1H), 3.18 (dd, J =
16.1, 8.8 Hz, 1H), 2.75 (dd, J = 17.6, 6.7 Hz, 1H) ppm. 13C{1H}NMR (151 MHz, CDCl3) δ 178.2,
175.8, 175.2, 158.4, 154.5, 135.4, 133.4, 132.2, 131.8, 130.8, 128.7, 122.2, 121.9, 119.7, 113.6,
48.25, 37.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H13BrNO4: 398.0028, found:
398.0024.
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Ethyl-3-(9-oxo-9H-xanthen-1-yl)pyrrolidine-2,5-dione. The product 3o was obtained as a white solid
(52.7 mg, 82%) after purification through a chromatography column (elution: 25% EtOAc in petroleum
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ether), mp 230–231 C. H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 5.6 Hz, 1H), 7.71 – 7.65 (m, 2H),
7.52 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.19 (m, 1H), 4.12 (m, 1H),
3.73 (q, J = 7.1 Hz, 2H), 3.07 (m, 1H), 2.86 (m, 1H), 1.34 (m, 3H) ppm. 13C{1H}NMR (151 MHz,
CDCl3) δ 177.80, 177.41, 176.49, 158.00, 155.21, 137.01, 135.02, 134.37, 130.04, 128.39, 126.88,
124.09, 122.06, 119.21, 117.47, 48.71, 37.27, 34.09, 12.97 ppm. HRMS (ESI-TOF) m/z: [M+Na]+
calcd for C19H15NO4: 344.0898, found: 344.0896.
1-Ethyl-3-(4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4a was obtained as a white
solid (49.5 mg, 92%) after purification through a chromatography column (elution: 10% EtOAc in
petroleum ether), mp 159–160 oC. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 6.0 Hz, 1H), 7.71 –7.67
(m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 6.42 (s, 1H), 6.28 (d, J = 6.0 Hz, 1H), 3.63
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(q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 177.0, 170.5,
169.3, 157.0, 154.8, 149.4, 133.2, 129.5, 126.9, 124.5, 123.4, 120.5, 113.7, 33.2, 14.0 ppm. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C15H12NO4: 270.0766, found: 270.0762.
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1-Ethyl-3-(2-methyl-4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4b was obtained as a
white solid (53.8 mg, 95%) after purification through a chromatography column (elution: 13% EtOAc
in petroleum ether), mp 182–183 oC. 1H NMR (600 MHz, CDCl3) δ 7.65 (t, J = 7.9 Hz, 1H), 7.52 (d, J
= 8.5 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 6.40 (s, 1H), 6.10 (s, 1H), 3.62 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H),
1.24 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 177.6, 170.5, 169.3, 165.8, 157.0,
149.6, 132.8, 129.2, 126.6, 124.3, 122.2, 120.1, 111.3, 33.1, 20.3, 14.0 ppm. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C16H14NO4: 284.0923, found: 284.0916.
1-Ethyl-3-(4-oxo-2-phenyl-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4c was obtained as a
white solid (51.8 mg, 75%) after purification through a chromatography column (elution: 8% EtOAc in
petroleum ether), mp 235–236 oC. 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.3 Hz, 2H), 7.76 – 7.70
(m, 2H), 7.58 – 7.53 (m, 3H), 7.27 (d, J = 6.9 Hz, 1H), 6.78 (s, 1H), 6.48 (s, 1H), 3.68 (t, J = 7.2 Hz,
2H), 1.30 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 177.9, 170.6, 169.4, 163.1,
156.8, 149.5, 133.2, 131.9, 131.3, 129.4, 129.2, 126.9, 126.4, 124.5, 122.6, 120.4, 108.3, 33.2, 14.0
ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H16NO4: 346.1079, found: 346.1073.
1-Ethyl-3-(3-methyl-4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4d was obtained as a
white solid (52.1 mg, 92%) after purification through a chromatography column (elution: 10% EtOAc
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in petroleum ether), mp 193–194 C. H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.66 (t, J = 7.9 Hz,
1H), 7.54 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 6.41 (s, 1H), 3.65 (q, J = 7.2 Hz, 2H), 1.95 (s,
3H), 1.25 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 177.8, 170.5, 169.4, 157.2,
151.3, 149.9, 132.7, 129.4, 126.5, 124.3, 122.1, 121.6, 120.4, 33.2, 14.0, 11.1 ppm. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C16H14NO4: 284.0923, found: 284.0915.
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3-(3-Bromo-4-oxo-4H-chromen-5-yl)-1-ethyl-1H-pyrrole-2,5-dione. The product 4e was obtained as a
white solid (63.7 mg, 92%) after purification through a chromatography column (elution: 8% EtOAc in
petroleum ether), mp 214–215 oC. 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.75 (t, J = 7.9 Hz, 1H),
7.62 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 6.45 (s, 1H), 3.66 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2
Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 171.8, 170.4, 169.2, 156.7, 153.4, 148.8, 133.6,
130.0, 127.6, 125.1, 121.5, 120.4, 111.3, 33.4, 14.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C15H11BrNO4: 347.9872, found: 347.9865.
1-Ethyl-3-(4-oxo-3-phenyl-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4f was obtained as a
white solid (64.2 mg, 93%) after purification through a chromatography column (elution: 6% EtOAc in
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petroleum ether), mp 158–159 C. H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.73 – 7.70 (m, 1H),
7.62 – 7.61 (m, 1H), 7.48 – 7.46 (m, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.38 – 7.35 (m, 1H), 7.27 – 7.25 (m,
1H), 6.43 (s, 1H), 3.65 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz,
CDCl3) δ 176.0, 170.6, 169.4, 156.8, 152.5, 149.8, 133.1, 131.3, 130.0, 129.0, 128.6, 128.4, 127.1,
126.3, 124.2, 123.2, 120.5 33.3, 14.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H16NO4:
346.1079, found: 346.1072.
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1-Ethyl-3-(4-oxo-3-o-tolyl-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4g was obtained as a
white solid (66.8 mg, 93%) after purification through a chromatography column (elution: 8% EtOAc in
petroleum ether), mp 165–166 oC. 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.69 (t, J = 7.9 Hz, 1H),
7.59 (d, J = 8.5 Hz, 1H), 7.25 – 7.21 (m, 3H), 7.16 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.38 (s,
1H), 3.56 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz,
CDCl3) δ 175.9, 170.6, 169.4, 157.0, 153.0, 149.7, 138.2, 133.1, 131.0, 130.4, 130.3, 130.0, 128.9,
127.4, 127.0, 125.9, 124.0, 123.0, 120.5, 33.2, 20.0, 14.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C22H18NO4: 360.1236, found: 360.1228.
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3-(3-(3-Chlorophenyl)-4-oxo-4H-chromen-5-yl)-1-ethyl-1H-pyrrole-2,5-dione. The product 4h was
obtained as a white solid (69.8 mg, 92%) after purification through a chromatography column (elution:
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8% EtOAc in petroleum ether), mp 195–196 C. H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H), 7.75 –
7.71 (m, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.47 (d, 1H), 7.38 – 7.35 (m, 1H), 7.34 – 7.33 (m, 2H), 7.28 –
7.27 (m, 1H), 6.44 (s, 1H), 3.65 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126
MHz, CDCl3) δ 175.6, 170.5, 169.3, 156.7, 152.8, 149.6, 134.4, 133.3, 133.0, 130.0, 129.8, 128.9,
128.5, 127.3, 127.2, 125.1, 124.4, 123.1, 120.5, 33.3, 14.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C21H15ClNO4: 380.0690, found: 380.0684.
1-Ethyl-3-(6-fluoro-4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4i was obtained as a
white solid (45.4 mg, 79%) after purification through a chromatography column (elution: 12% EtOAc
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in petroleum ether), mp 193–194 C. H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 5.9 Hz, 1H), 7.60 –
7.58 (m, 1H), 7.50 (t, J = 8.7 Hz, 1H), 6.57 (s, 1H), 6.28 (d, J = 5.9 Hz, 1H), 3.66 (q, J = 7.2 Hz, 2H),
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1.27 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 176.8 (d, J = 1.9 Hz), 170.2, 169.1,
156.6 (d, J = 249.7 Hz), 154.9, 153.2 (d, J = 1.3 Hz), 141.1, 127.7 (d, J = 2.3 Hz), 124.3 (d, J = 1.3 Hz),
121.9 (d, J = 1.5 Hz), 121.9 (d, J = 32.3 Hz), 114.9 (d, J = 17.2 Hz), 113.2, 33.3, 14.0 ppm. 19F NMR
(471 MHz, ) δ -116.10 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H11FNO4: 288.0672, found:
288.0664.
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1-Ethyl-3-(7-methyl-4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4j was obtained as a
white solid (51.5 mg, 91%) after purification through a chromatography column (elution: 10% EtOAc
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in petroleum ether), mp 212–213 C. H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 6.0 Hz, 1H), 7.35 (s,
1H), 7.04 (s, 1H), 6.40 (s, 1H), 6.24 (d, J = 5.9 Hz, 1H), 3.63 (q, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.24 (t,
J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 176.9, 170.5, 169.3, 157.15, 154.6, 149.5,
144.6, 129.2, 128.3, 124.4, 121.2, 120.1, 113.6, 33.1, 21.6, 14.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H14NO4: 284.0923, found: 284.0915.
1-Ethyl-3-(7-methoxy-4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4k was obtained as
a white solid (53.8 mg, 90%) after purification through a chromatography column (elution: 13% EtOAc
in petroleum ether), mp 222–223 oC. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 6.0 Hz, 1H), 6.94 (d, J
= 2.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.41 (s, 1H), 6.23 (d, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.65 (q, J =
7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 176.4, 170.5, 169.2,
163.1, 158.9, 154.4, 149.2, 130.9, 124.6, 117.3, 116.5, 113.6, 102.1, 56.1, 33.2, 14.0 ppm. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C16H14NO5: 300.0872, found: 300.0865.
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5-(1-Ethyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-4-oxo-4H-chromen-7-yl acetate. The product 4l was
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obtained as a white solid (65.4 mg, 95%) after purification through a chromatography column (elution:
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12% EtOAc in petroleum ether), mp 158–159 C. H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 6.0 Hz,
1H), 7.41 (d, J = 2.2 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.45 (s, 1H), 6.28 (d, J = 6.0 Hz, 1H), 3.65 (q, J
= 7.2 Hz, 2H), 2.35 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 176.4,
170.2, 168.9, 168.2, 157.6, 154.9, 153.6, 148.5, 130.9, 125.1, 121.2, 121.1, 113.8, 113.0 33.2, 21.1,
14.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H14NO6: 328.0821, found: 328.0814.
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1-Ethyl-3-(7-fluoro-4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4m was obtained as a
white solid (54.0 mg, 94%) after purification through a chromatography column (elution: 10% EtOAc
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in petroleum ether), mp 146–147 C. H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 6.0 Hz, 1H), 7.28 –
7.26 (m, 1H), 7.01 (dd, J = 8.2, 2.3 Hz, 1H), 6.46 (s, 1H), 6.28 (d, J = 6.0 Hz, 1H), 3.65 (q, J = 7.2 Hz,
2H), 1.26 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 171.4 (s), 165.3 (s), 164.0 (s),
159.6 (d, J = 256.9 Hz), 153.4 (d, J = 13.6 Hz), 150.1 (s), 143.5 (d, J = 1.6 Hz), 127.4 (d, J = 10.7 Hz),
120.4 (s), 115.7 (d, J = 2.6 Hz), 111.1 (d, J = 24.1 Hz), 109.1 (s), 102.0 (d, J = 24.6 Hz), 28.5, 9.2 ppm;
19F NMR (471 MHz, ) δ -107.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H11FNO4: 288.0672,
found: 288.0665.
3-(7-Chloro-4-oxo-4H-chromen-5-yl)-1-ethyl-1H-pyrrole-2,5-dione. The product 4n was obtained as a
white solid (50.3 mg, 83%) after purification through a chromatography column (elution: 10% EtOAc
in petroleum ether), mp 205–206 oC. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 6.0 Hz, 1H), 7.59 (d, J
= 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 1H), 6.46 (s, 1H), 6.28 (d, J = 6.0 Hz, 1H), 3.64 (q, J = 7.2 Hz, 2H),
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1.25 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 176.2, 170.0, 168.8, 157.2, 154.8,
148.0, 139.2, 131.0, 127.4, 125.2, 122.0, 120.2, 114.0, 33.3, 13.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+
calcd for C15H11ClNO4: 304.0377, found: 304.0370.
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3-(7-Bromo-4-oxo-4H-chromen-5-yl)-1-ethyl-1H-pyrrole-2,5-dione. The product 4o was obtained as a
white solid (58.1 mg, 84%) after purification through a chromatography column (elution: 7% EtOAc in
petroleum ether), mp 187–188 oC. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 6.0 Hz, 1H), 7.76 (s, 1H),
7.37 (s, 1H), 6.46 (s, 1H), 6.29 (d, J = 6.0 Hz, 1H), 3.64 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H)
ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 176.3, 170.0, 168.8, 156.9, 154.7, 147.8, 130.9, 130.0, 127.2,
125.1, 123.2, 122.3, 114.0, 33.2, 13.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H11BrNO4:
347.9872, found: 347.9865.
1-Ethyl-3-(8-methyl-4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione. The product 4p was obtained as a
white solid (52.6 mg, 93%) after purification through a chromatography column (elution: 10% EtOAc
in petroleum ether), mp 157–158 oC. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 5.8 Hz, 1H), 7.53 (d, J
= 7.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.38 (s, 1H), 6.29 (d, J = 5.8 Hz, 1H), 3.63 (q, J = 7.1 Hz, 2H),
2.49 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) ppm. 13C{1H}NMR (126 MHz, CDCl3) δ 177.4, 170.6, 169.4,
155.5, 154.6, 149.8, 134.0, 130.4, 126.9, 126.4, 124.0, 123.3, 113.6, 33.1, 15.9, 14.0 ppm. HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C16H14NO4: 284.0923, found:284.0915.
3-(8-Chloro-4-oxo-4H-chromen-5-yl)-1-ethyl-1H-pyrrole-2,5-dione. The product 4q was obtained as a
white solid (51.5 mg, 85%) after purification through a chromatography column (elution: 7% EtOAc in
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