N-Acyl-5,5-dimethylhydantoin, a New Mild Acyl-Transfer Reagent in Pd Catalysis: Highly Efficient Synthesis of Functionalized Ketones

Article abstract of DOI:10.1021/acs.oprd.8b00182

The palladium-catalyzed Suzuki-Miyaura cross-coupling of N-acyl-5,5-dimethylhydantoins with arylboronic acids has been developed via selective amides C-N bond cleavage. The new reagent is commercially available and air-/moisture-stable, and it offers a variety of ketones in good yields through Suzuki coupling under mild conditions (up to 95%).

Full text of DOI:10.1021/acs.oprd.8b00182

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Full Paper
N-Acyl-5,5-dimethylhydantoin, a new mild acyl-transfer reagent in
Pd catalysis: highly efficient synthesis of functionalized ketones
Zhongfeng Luo, Tingting Liu, Weijie Guo, Zijia Wang, Jingjun Huang, yulin zhu, and Zhuo Zeng
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00182 • Publication Date (Web): 30 Jul 2018
Downloaded from http://pubs.acs.org on July 31, 2018
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N-Acyl-5,5-dimethylhydantoin, a new mild acyl-transfer reagent
in Pd catalysis: highly efficient synthesis of functionalized
ketones
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Zhongfeng Luo,a† Tingting, Liu,a† Weijie Guo,a Zijia Wang,a Jingjun Huang,ac Yulin Zhu,a Zhuo
Zeng *ab
aCollege of Chemistry and Environment, South China Normal University, Guangzhou 510006,
People’s Republic of China
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai, 200032, China
cCollege of Arts and Sciences, University of Cincinnati, Cincinnati, OH 45221, USA.
*Eꢀmail: zhuoz@scnu.edu.cn
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Table of Contents graphic
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A Straightforward Amide Transformation to ketone
A new acylation process for the synthesis functionalized ketone was developed by cheap, air/moisture
stable NꢀAcylꢀ5,5ꢀdimethylhydantoins and arylboronic acids under palladium catalyzed
Suzuki−Miyaura crossꢀcoupling condition.
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ABSTRACT: The palladiumꢀcatalyzed Suzuki–Miyaura crossꢀcoupling of
NꢀAcylꢀ5,5ꢀdimethylhydantoins with arylboronic acids has been developed via
selective amides CꢀN bond cleavage. The new reagent is commercially available and
air/moistureꢀstable, and it offers a variety of ketones in good yields through Suzuki
coupling under mild conditions (up to 95%).
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KEYWORDS: Palladium catalysis; NꢀAcylꢀ5,5ꢀdimethylhydantoins; Ketones;
Suzuki coupling
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Introduction
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Carbonꢀnitrogen bonds widely exist in chemistry, biology and natural
pharmaceutical molecules.1 In the past decades, tremendous progress has been
reported in the development of transition metalꢀcatalyzed C–N bonds formation
approaches for synthesis of oxazoles,2 quinolines,3 and Nꢀbased heterocycles.4 Despite
decades, chemists have concerned on transition metalꢀcatalyzed C–N bonds cleavage,
and research in this area has been advancing at a snail pace due to the high C–N
bonds dissociation energy. However, the vast source of C–N bonds makes the
cleavage and transformation of C–N bonds attractive.5
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In recent years, researchers focus on construction of carbonꢀcarbon bonds by
selective cleavage of the amide CꢀN bonds.6ꢀ8 A lot of achievements in the field of
amides activation and cleavage have been described by Zou,9 Garg,10 Szostak,11ꢀ13
Yamaguchi,14 Shi,15 and Huang group.16 These reactions were catalyzed by transition
metal from various activated amides with conveniently available coupling partners
(Figure 1).
This research article reports a simple and straightforward route to synthesize a
series of ketones from amides, which offers another option in synthetic chemistry,
material chemistry and biochemistry.
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Figure 1. Previous Suzuki CrossꢀCoupling of Amides
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5
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Traditional Friedel-Crafts acylation
O
O
Lewis acid
Ar
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Ar
Cl
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9
(a) Zou (2015)[9a]
Pd(PCy3)Cl2 (5 mol%)
PCy3 (3 mol%)
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O
O
Ph
Ar
B(OH)2
Ph
N
K2CO3, dioxane
100 ºC, 12 h
Ph
Ar
Ts
(b) Garg (2016)[10e]
Ni(cod)2 (5 mol%)
SIPr (5 mol%)
O
O
O
Bn
Ar(Het) B(OH)2
Ph
N
K3PO4, H2O, toluene
50 ºC, 24 h
Ph
Ph
Ar
Ar
Boc
(c) Szostak
O
[Pd] catalysis
R1
N
Ph
N
Ar(Het) B(OH)2
phosphorus ligand
O
R2
O
O
O
S
R1, R2 =
N
N
,
,
O
O
O
2015[11a]
2016[11d]
2017[13d]
(d) Szostak
O
O
R3
Pd(NHC)
Ph
N
Ph
Ar
Ar(Het) B(OH)2
R4
Boc
N
N
R3, R4 =
N
,
,
Boc
2017[12e]
N
N
2017[13c]
2017[13a]
This work
O
O
O
Pd(NHC)
N
Ph
Ar(Het) B(OH)2
Ph
Ar
NH
O
Commercially available, inexpensive.
Air-moisture-stabilized and high stability
As mentioned above, three features of activated amides (N-PhꢀNꢀTsꢀbenzamide,
N-BnꢀNꢀBocꢀbenzamide and Nꢀacylsaccharins, etc) make themselves be attractive
candidates for further investigation include: a) activated amides are highly active and
air/moistureꢀstable; b) amides give corresponding aryl ketones in good yields with
tolerance of electronꢀrich and‐poor groups; c) the reaction condition is mild because
of using the traditional Lewis acid catalyzed Friedel–Crafts acylation17.
NꢀAcylꢀ5,5ꢀdimethylhydantoins, activated amides, are commercialꢀavailable,
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cheap and air/moistureꢀstable. The amides in Suzuki crossꢀcoupling would provide a
new approach to synthesize a variety of corresponding aryl ketones and facilitate the
development of amide transformation. However, Suzuki crossꢀcoupling with
NꢀAcylꢀ5,5ꢀdimethylhydantoins, a new type of activated amides, has not yet reported.
The key of employing NꢀAcylꢀ5,5ꢀdimethylhydantoins as crossꢀcoupling partners
in Suzuki reaction is how to disconnect the amide bonds selectively. Hence, we
reported the first case of Suzuki crossꢀcoupling of NꢀAcylꢀ5,5ꢀdimethylhydantoins by
employing a powerful catalyst (IPr)Pd(allyl)Cl, and it also offers a new acylation
approach in the synthesis of a variety of ketones.
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RESULTS AND DISCUSSION
Initially,
we
selected
easily
synthetic,
air/moistureꢀstable
Nꢀacylꢀ5,5ꢀdimethylhydantoin 1a,18 and (4ꢀmethoxyphenyl) boronic acid 2b as model
substrates for our research (Table 1.). We were delighted to find, after optimization of
reaction conditions, that (IPr)Pd(allyl)Cl produced desired crossꢀcoupling ketones
with excellent efficiency (Table 1., Entries 1ꢀ4). By contrast, the target compound 3b
was obtained at low yield in the presence of 5 mol% Pd(dba)2, PdCl2, Pd(OAc)2
catalyst with K2CO3 as base, PCy3 as a ligand in dioxane.
The ligand also makes an influence on the improvement of yield.
1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazolinium chloride was the best ligand in this
protocol since poor yields were observed on employing P(tꢀBu)3, PPh3 and bidentate
phosphines such as dppp, dppf (Table 1., Entries 5–8). Some common bases were
utilized to replace the K2CO3, but none of them provided higher yields (Table 1.,
Entries 9–12).
The solvent has a significant impact on the efficiency of reaction (Table 1., Entries
13−18). Other solvents (DMF, toluene, DMSO, THF and CH3CN) provided poor
results compared to dioxane. But 2ꢀmethy THF as solvent, provided in 82% yield. The
concentration of catalysts influenced reaction yields. When decreasing the
concentration from 6 mol% to 3 mol%, the yields decreased significantly from 93% to
65% (Table 1., Entries 18, 19). So we considered that the dimethylhydantoin liberated
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during the reaction progress acts as a poison.
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Finally, the best condition was set as 6 mol% (IPr)Pd(allyl)Cl, K2CO3 (3 equiv) in
dioxane at 110 °C.
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Table 1. Optimization of the Reaction Conditionsa
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Yieldb
Entry
Catalyst
Ligand
Base
Solvent
(%)
<5
<5
30
85
<5
21
<5
<5
43
20
<5
<5
56
<5
1
2
Pd(dba)2
PdCl2
PCy3
PCy3
PCy3
none
PPh3
P(tꢀBu)3
dppp
dppf
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Na2CO3
CsCO3
KOH
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMF
3
Pd(OAc)2
4
(IPr)Pd(allyl)Cl
PdCl2
5
6
PdCl2
7c
8c
9
PdCl2
PdCl2
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
none
none
none
none
none
none
10
11
12
13
K2CO3
K2CO3
14 (IPr)Pd(allyl)Cl
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(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
none
none
none
none
none
none
K2CO3
K2CO3
K2CO3
DMSO
THF
<5
72
70
82
95
65
CH3CN
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K2CO3 2ꢀmethy THF
19d (IPr)Pd(allyl)Cl
20e (IPr)Pd(allyl)Cl
K2CO3
K2CO3
dioxane
dioxane
a
Reaction conditions (unless otherwise noted): 1a (0.2 mmol, 1.0 equiv), 2b
(2.0 equiv), catalyst (6 mol%), base (3.0 equiv), additive (2.0 equiv), solvent
(2.0 M). The mixture stirred and heated at 110 °C for 15 h. Entries 1ꢀ6: [Pd]
(5 mol%), ligand (10 mol%). b Isolated yield. c ligand (5 mol%). d catalyst (6
mol%). e catalyst (3 mol%).
The scope of reactions was briefly explored (Figure 2.). To study the influence of
electronic and steric effects, a series of arylboronic acids (2bꢀ2d) with
electronꢀdonating substituents in ortho, meta, paraꢀpositions were coupled with
3ꢀbenzoylꢀ5,5ꢀdimethylhydantoins to provide aryl ketones in good yields. Boronic
acids containing electronꢀwithdrawing compounds [(2e), (2f) and (2g)] gave products
in good yields. Steric hindrance on the boronic acid (2h) was wellꢀtolerated.
Also, the diꢀsubstituted arylboronic acids (2iꢀ2k) were added, in 61%, 71% and
90% yields, respectively. Further, the arylboronic acids (2l, 2m) with formyl or acetyl
groups in the paraꢀposition were employed as electronꢀwithdrawing substrates, and it
resulted in moderate yields. Other arylboronic acids (2n–2p) provided aryl ketones in
81–91% yields. To our delight, the utilization of heteroarylboronic acids (2q)
provided excellent yield.
Figure 2. Scope of Boronic Acids Coupling partnersa.
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a
Reaction conditions (unless otherwise noted): 1a (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), catalyst (6
mol%), base (3.0 equiv), additive (2.0 equiv), solvent (2.0 M). The mixture stirred and heated at
110 °C for 15 h.
Next, the scope of activated amides coupling partners was evaluated. Obviously,
diverse NꢀAcylꢀ5,5ꢀdimethylhydantoins, including electronꢀneutral, rich and poor,
sterically hindered substrates, delivered the corresponding products (3b, 3c, 3r, 3f, 3g,
3e, 3h) in excellent yields, with only a lower yield of 3s. Heterocyclic groups such as
2ꢀfuryl and 2ꢀthienyl also demonstrated good reactivity and provided the desired
products in 66% and 78% yields (3t, 3u), respectively (Figure 3).
Furthermore, 2ꢀnaphthyl was employed in this approach, and the corresponding
aryl ketones were generated in 89% yield. Fluorideꢀcontaining amides provided
ketone in 81% yield, which could be further extended to medicinally relevant.
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Figure 3. Scope of amide coupling partnera.
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a Reaction conditions (unless otherwise noted): 1 (0.2 mmol, 1.0 equiv), 2a (2.0 equiv), catalyst (6
mol %), base (3.0 equiv), additive (2.0 equiv), solvent (2.0 M). The mixture stirred and heated at
110 °C for 15 h.
To demonstrate the high reactivity of NꢀAcylꢀ5,5ꢀdimethylhydantoin, the Xꢀray
structure of 1k was generated (Figure 4). Compared with Nꢀacylsaccharin,
Nꢀacylsuccinimide and NꢀTs amides, the Xꢀray structure indicates that 1k contains a
highly distorted amide bond(τ=49.14°, χΝ =11.05°, χC=1.63°), and the sum of
distortion parameters (Στ+χN) is close 60° (Figure 6).19
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Figure 4．Crystal structure of 1k. CCDC 1841137 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre www.ccdc.cam.ac.uk/data_request/ci
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At the same time, we conducted comparative experiments under standard reaction
conditions in particular catalyst system (Figure 5). The experimental data shows that
the coupling yields of highly twisted Nꢀacylꢀ5,5ꢀdimethylhydantoin,
Nꢀacylsuccinimide and NꢀTs amides reached 90%, 82%, 77%, respectively. However,
the coupling yield of low twisted N-acylsaccharin was only 15%. May be
N-acylsaccharin has made decomposition under the reaction conditions.
Therefore, these parameters and control experiments of amide bonds in
NꢀAcylꢀ5,5ꢀdimethylhydantoin support groundꢀstate destabilization account for its
high reactivity. 20
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Figure 5. Control Reaction
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A: Evaluating of different amides.
O
O
O
O
O
O
O
O
Ts
5
6
7
8
N
N
S
N
N
S
Ph
NH
O
O
O
1k
1n
1o
1p
9
[deg]
[deg]
49.1
20.9
45.9
30.4
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11.1
60.2
10.6
31.5
10.7
56.6
22.3
52.7
[deg]
B: Comparative Reaction
O
O
O
O
2a, (IPr)Pd(allyl)Cl, K2CO3
N
Ph
NH
dioxane, 110 ºC, 15 h
90% yield
1a
O
O
O
O
2a, (IPr)Pd(allyl)Cl, K2CO3
N
S
Ph
dioxane, 110 ºC, 15 h
O
O
15% yield
1n
O
O
2a, (IPr)Pd(allyl)Cl, K2CO3
N
Ph
dioxane, 110 ºC, 15 h
O
82% yield
1o
O
O
Ts
2a, (IPr)Pd(allyl)Cl, K2CO3
N
Ph
Ph
1p
dioxane, 110 ºC, 15 h
77% yield
The scaledꢀup experiment was also carried out by using 1a and 2b as substrates,
methyl THF as green solvent that can be used in the pharmaceutical field, and 78%
yield could be obtained, which indicated its potential applications in industry (Figure
6). And we can obtain products without column chromatography procedure.
Figure 6. A scaled-up of the reaction
On the basis of typical Suzuki crossꢀcoupling, the hypothesis of whole catalytic
cycle was proposed (Figure 7): oxidative addition took place at the C–N bond of the
NꢀAcylꢀ5,5ꢀdimethylhydantoins to form an acylpalladium(II) complex II; following
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transmetallation, the complex III was generated; then, reductive elimination occurred
to form the new C–C bond and regenerate the Pd(0) species.21
7
8
Figure 7. Proposed Mechanism for PdꢀCatalyzed Acylative Suzuki Coupling
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CONCLUSIONS
In conclusion, we have described the first Suzuki coupling of
NꢀAcylꢀ5,5ꢀdimethylhydantoins with arylboronic acid, in the presence of
(IPr)Pd(allyl)Cl catalyst. The easy accessibility and high stability promote us to
employ NꢀAcylꢀ5,5ꢀdimethylhydantoins as new acylꢀtransfer reagents. The new
acylation process of NꢀAcylꢀ5,5ꢀdimethylhydantoin also gives aryl ketones in good
tolerance to a variety of functional groups.
EXPERIMENT SECTION
General method. The reactions were conducted in sealed tube under the protection
of a nitrogen atmosphere. All reactants reported in the manuscript are commercially
available and have been prepared by the method reported previously. N3ꢀacylated
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hydantoins were prepared by the general methods. All solvents were purchased at the
China suppliers and used without any purification. Flash chromatography was
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performed using 200ꢀ300 mesh silica gel. H and 13C and 19F NMR data were
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recorded with AVANCE NEO Bruker (600 MHz) and Varian AS (400 MHz)
spectrometers in CDCl3 or DMSO with tetramethylsiliane as an internal standard.
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General procedure for synthesis of N3-acylated hydantoins: 18
An ovenꢀdried roundꢀbottomed flask (25 mL) equipped with a stir bar was charged
with 5,5ꢀDimethylhydantoin (5.0 mmol, 1.0 equiv), pyridine (typically, 4 mL) and
Acyl chloride (typically, 1.0 equiv) was added dropwise to the reaction mixture with
stirred at room temperature overnight. After the reaction was complete, the solvent
was evaporated under vacuum without any heating or under a stream of N2 gas. The
residue was dissolved in ethyl acetate and filtered with suction through a short pad of
silica gel packed with ethyl acetate in a 50 mL fritted funnel. Then the silica gel pad
was washed with ethyl acetate (3 × 20 mL) and the organic phases were combined
and the combined organic phases were concentrated by rotary evaporation to provide
the crude product. The crude isolate was purified by recrystallization from ethyl
acetate/ petroleum ether. The mother liquor was then concentrated and the residue
was reꢀsubjected to recrystallization to provide a second crop of products.
General procedure for Suzuki coupling of N3-acylated hydantoins:
O
O
O
3
6mol% PdNHC, K2CO3
dioxane, 110 ºC, 15 h
Ar(Het) B(OH)2
R
N
R
Ar
NH
O
1
2
An ovenꢀdried sealed tube (10 mL) equipped with a stir bar was charged with aryl
boronic acid 2a-2q (0.4 mmol, 2.0 equiv), N3ꢀacylated hydantoins 1a-1m (1.0 equiv),
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K2CO3 (3.0 equiv) and (IPr)Pd(allyl)Cl (typically, 6 mol %). Dioxane (typically, 2 mL)
was added with vigorous stirring at room temperature, the reaction mixture was
placed in an oil bath and stirred for 15 h at 110 °C after standard cycles of evacuation
and backfilling with dry nitrogen. After cooling to room temperature, the solvents was
removed, the crude product was purified by silica gel column chromatography using
Petroleum ether/EtOAc (20/1) as eluent afforded aryl ketone.
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General procedure for the scaled-up experiment:
An ovenꢀdried sealed tube (48 mL) equipped with a stir bar was charged with
N3ꢀacylated hydantoins 1a (5 mmol, 1.0 equiv), aryl boronic acid 2b (2.0 equiv),
K2CO3 (3.0 equiv) and (IPr)Pd(allyl)Cl (typically, 6 mol %). 2ꢀmethyl THF (typically,
15 mL) was added with vigorous stirring at room temperature, the reaction mixture
was placed in an oil bath and stirred for 15 h at 110 °C after standard cycles of
evacuation and backfilling with dry nitrogen. After cooling to room temperature, the
solvent was evaporated under vacuum. The residue was dissolved in Petroleum
ether/EtOAc (=30/1) and filtered with suction through a short pad of silica gel packed
with Petroleum ether/EtOAc (30/1) in a 50 mL fritted funnel. Then the silica gel pad
was washed with Petroleum ether/EtOAc (30/1) 350ml solvent and the organic phases
were combined and the combined organic phases were concentrated by rotary
evaporation to provide the crude product. The crude isolate was purified by
recrystallization from ethyl acetate/ petroleum ether (1/20). The mother liquor was
then concentrated and the residue was reꢀsubjected to recrystallization to provide a
second crop of products.
This approach could be
give
78%
(4ꢀmethoxyphenyl)(phenyl)methanone.
Characterization Data of N3-acylated hydantoins:
O
O
N
NH
O
3-Benzoyl-5,5-dimethylhydantoin (1a).18 Following general procedure, 1a was
purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford a white
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solid (997.94 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.7 Hz, 2H), 7.68
5
6
– 7.62 (m, 1H), 7.52 – 7.47 (m, 2H), 6.30 (s, 1H), 1.56 (s, 6H).
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3-(4-Methoxybenzoyl)-5,5-dimethylhydantoin (1b). Following general procedure,
1b was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford
1
a white solid (877.70 mg, 67%). H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.9 Hz,
2H), 6.99 – 6.94 (m, 2H), 6.91 (s, 1H), 3.88 (s, 3H), 1.52 (s, 6H). 13C NMR (150 MHz,
CDCl3) δ 175.27, 165.21, 165.05, 153.68, 133.17, 124.30, 114.17, 59.29, 55.69, 25.19.
HRMS(EI) m/z: [M]+ Calcd for; C13H15O4N2 262.0961; found 262.0954.
3-(4-Methylbenzoyl)-5,5-dimethylhydantoin (1c). Following general procedure,
1c was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford a
white solid (811.80 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.1 Hz, 2H),
7.33 – 7.26 (m, 2H), 6.27 (s, 1H), 2.44 (s, 3H), 1.55 (s, 6H). 13C NMR (150 MHz,
CDCl3) δ 190.50, 175.26, 166.16, 153.53, 146.12, 130.61, 129.51, 129.33, 59.26,
25.10, 21.93. HRMS(EI) m/z: [M]+ Calcd for; C13H15O3N2 246.1013; found 246.1004.
3-(3-Methylbenzoyl)-5,5-dimethylhydantoin (1d). Following general procedure,
1d was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford
a white solid (861.00 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.58 (d,
J = 7.7 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.93 (s, 1H), 2.41 (s,
3H), 1.50 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 175.06, 166.50, 153.29, 138.68,
135.54, 132.00, 130.73, 128.51, 127.56, 59.22, 25.11, 21.28. HRMS(EI) m/z: [M+H]+
Calcd for; C13H15O3N2 246.1008; found 246.1004.
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3-(4-(Trifluoromethyl)benzoyl)-5,5-dimethylhydantoin (1e). Following general
procedure, 1e was purified by column chromatography (Petroleum ether/EtOAc = 3/1)
to afford a white solid (1.20 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.0
Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 5.78 (s, 1H), 1.57 (s, 6H). 13C NMR (100 MHz,
DMSO) δ 175.68, 166.41, 151.71, 136.96, 133.48 (q, J2 = 32.4 Hz), 130.98, 125.90 (q,
J3 = 3.6 Hz), 124.05 (q, J1 = 271.7 Hz), 58.71, 25.13. 19F NMR (376 MHz, CDCl3)
δ 63.34. HRMS(EI) m/z: [M+H]+ Calcd for; C13H12O3N2F3 301.0795; found
301.0795.
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3-(4-Cyanobenzoyl)-5,5-dimethylhydantoin (1f). Following general procedure, 1f
was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford a
white solid (0.98 g, 76%).1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz, 2H),
7.78 (d, J = 8.5 Hz, 2H), 6.51 (s, 1H), 1.56 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
174.48, 165.00, 152.24, 135.71, 132.30, 130.39, 117.55, 117.41, 59.22, 25.29;
HRMS(EI) m/z: [M]+ Calcd for; C13H15O4N2 257.0797; found 257.0800.
3-(4-Methoxycarbonylbenzoyl)-5,5-dimethylhydantoin (1g). Following general
procedure, 1g was purified by column chromatography (Petroleum ether/EtOAc = 3/1)
1
to afford a white solid (0.94 g, 65%). H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.6
Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 5.73 (s, 1H), 3.96 (s, 3H), 1.58 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 174.45, 165.24, 152.27, 135.67, 135.54, 135.34, 135.14, 130.43,
125.72, 125.68, 125.64, 125.60, 124.64, 121.93, 59.20, 25.35. HRMS(EI) m/z:
[M+H]+ Calcd for; C14H15O5N2 291.0973; found 291.0975.
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3-(2-Methylbenzoyl)-5,5-dimethylhydantoin (1h). Following general procedure,
1h was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford
a white solid (0.77 g, 63%). 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 2H), 7.29 (d, J =
7.6 Hz, 1H), 7.25 (dd, J = 7.9, 7.3 Hz, 1H), 6.86 (s, 1H), 2.52 (s, 3H), 1.47 (s, 6H).
13C NMR (100 MHz, CDCl3) δ 174.69, 166.63, 152.94, 139.44, 132.79, 132.32,
131.73, 129.76, 125.80, 58.79, 25.12, 20.49. HRMS(EI) m/z: [M+H]+ Calcd for;
C13H15O3N2 247.1076; found 247.1077.
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3-(2-Methoxybenzoyl)-5,5-dimethylhydantoin (1i). Following general procedure,
1i was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford a
1
white solid (0.79 g, 60%). H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.6 Hz, 1H),
7.53 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H),
3.81 (s, 3H), 1.49 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 174.30, 164.65, 158.01,
152.94, 134.78, 131.96, 122.85, 121.06, 111.13, 58.48, 55.76, 25.00. HRMS(EI) m/z:
[M+H]+ Calcd for; C13H15O4N2 263.1025; found 263.1026.
3-(Furan-2-carbonyl)-5,5-dimethylhydantoin (1j). Following general procedure,
1j was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford a
1
white solid (0.61 g, 55%). H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 0.7 Hz, 1H),
7.38 (d, J = 3.7 Hz, 1H), 6.74 (s, 1H), 6.64 – 6.60 (m, 1H), 1.53 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 174.41, 154.72, 152.67, 148.53, 146.73, 122.85, 113.22, 59.32,
25.06. HRMS(EI) m/z: [M+H]+ Calcd for; C10H11O4N2 223.0712; found 223.0713.
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3-(Thiophene-2-carbonyl)-5,5-dimethylhydantoin (1k). Following general
procedure, 1k was purified by column chromatography (Petroleum ether/EtOAc = 3/1)
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to afford a white solid (0.77 g, 65%). H NMR (400 MHz, CDCl3) δ 7.85 – 7.77 (m,
1H), 7.74 – 7.69 (m, 1H), 7.19 – 7.14 (m, 1H), 6.95 (s, 1H), 1.53 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 174.79, 159.26, 153.11, 137.03, 136.63, 128.46, 59.37, 25.09.
HRMS(EI) m/z: [M+H]+ Calcd for; C10H11O3N2S 239.0484; found 239.0485.
3-(2-Naphthoyl)-5,5-dimethylhydantoin (1l). Following general procedure, 1l
was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford a
white solid (1.16 g, 82%). 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.94 (d, J = 8.2
Hz, 1H), 7.89 (t, J = 8.7 Hz, 2H), 7.83 (dd, J = 8.6, 1.2 Hz, 1H), 7.63 (t, J = 7.4 Hz,
1H), 7.55 (t, J = 7.4 Hz, 1H), 7.20 (s, 1H), 1.47 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 175.25, 166.51, 153.43, 136.21, 132.83, 132.21, 129.76, 129.40, 129.32, 128.59,
127.86, 127.13, 125.03, 59.30, 25.01. HRMS(EI) m/z: [M+H]+ Calcd for; C16H15O3N2
283.1075; found 283.1077.
3-(4-Fluorobenzoyl)-5,5-dimethylhydantoin (1m). Following general procedure,
1m was purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford
a white solid (1.05 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.82 (m, 2H), 7.16
(t, J = 8.6 Hz, 2H), 6.97 (s, 1H), 1.52 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 174.99,
166.64 (d, J1 = 257.0 Hz), 165.04, 153.15, 133.22 (d, J3 = 10.0Hz,), 128.27 (d, J4 =
3.0 Hz), 116.08 (d, J2 = 22.0 Hz), 59.25, 25.12. F NMR (376 MHz, DMSO)
19
δ 108.32. HRMS(EI) m/z: [M+H]+ Calcd for; C12H12O3N2F 251.0825; found
251.0826.
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N-Benzoylsaccharin (1n).6a Following general procedure of the literature, 1n was
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purified by column chromatography (Petroleum ether/EtOAc = 3/1) to afford a white
1
solid. H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.6 Hz, 1H), 8.00 (d, 2H), 7.95 –
7.88 (m, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.7 Hz,
2H).
N-Benzoylsuccinimide (1o).13d Following general procedure of the literature, 1o
was purified by column chromatography (Petroleum ether/EtOAc = 3/1,
1
dichloromethane) to afford a white solid. H NMR (600 MHz, CDCl3) δ 7.84 (d, J =
8.0 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 2.90 (s, 4H).
N-phenyl-N-tosyl benzamide (1p).6a Following general procedure of literature, 1p
was was purified by column chromatography (Petroleum ether/EtOAc = 2/1) to afford
a white solid. 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.1
Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.30 – 7.26 (m, 4H), 7.21 – 7.13 (m, 4H), 2.45 (s,
3H).
Characterization Data of Ketones
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Benzophenone (3a).22 Following general procedure for Suzuki coupling of
N3ꢀacylated hydantoins, 3a was purified by column chromatography (Petroleum
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ether/EtOAc = 40/1) to afford a white solid (32.9 mg, 90%). H NMR (400 MHz,
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CDCl3) δ 7.88 – 7.75 (m, 4H), 7.62 – 7.56 (m, 2H), 7.48 (dd, J = 13.6, 7.6 Hz, 4H).
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(4-Methoxyphenyl)(phenyl)methanone (3b).22 Following general procedure for
Suzuki coupling of N3ꢀacylated hydantoins, 3b was purified by column
chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (40.3 mg,
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95%). H NMR (400 MHz, CDCl3) δ 7.90 – 7.79 (m, 2H), 7.76 (dd, J = 7.6, 0.4 Hz,
2H), 7.57 (td, J = 7.2, 1.2 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.02 – 6.92 (m, 2H), 3.89
(s, 3H).
Phenyl(p-tolyl)methanone (3c).22 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3c was purified by column chromatography
1
(Petroleum ether/EtOAc = 40/1) to afford a white solid (36.1 mg, 92%). H NMR
(400 MHz, CDCl3) δ 7.81 – 7.76 (m, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.58 (t, J = 7.4 Hz,
1H), 7.47 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H).
(3-Methoxyphenyl)(phenyl)methanone (3d).23 Following general procedure for
Suzuki coupling of N3ꢀacylated hydantoins, 3d was purified by column
chromatography (Petroleum ether/ EtOAc = 20/1) to afford a colourless oil (33.9 mg,
80%). 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, J = 7.6, 0.4 Hz, 2H), 7.58 (dd, J = 14.4,
7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.40 – 7.32 (m, 3H), 7.13 (m, 1H), 3.86 (s, 3H).
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Methyl-4-benzoylbenzoate (3e).10e Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3e was purified by column chromatography
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(Petroleum ether/EtOAc = 20/1) to afford a white solid (38.9 mg, 81%). H NMR
(400 MHz, CDCl3) δ 8.14 (dd, J = 8.0, 6.4 Hz, 2H), 7.86 – 7.82 (m, 2H), 7.82 – 7.77
(m, 2H), 7.61 (dt, J = 8.4, 0.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H).
Phenyl(4-(trifluoromethyl)phenyl)methanone
(3f).22
Following
general
procedure for Suzuki coupling of N3ꢀacylated hydantoins, 3f was purified by column
chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (28.0 mg,
56%). 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.86 (m, 2H), 7.85 – 7.79 (m, 2H), 7.78 –
7.72 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (dd, J = 15.2, 7.6 Hz, 2H). 19F NMR (376
MHz, CDCl3) δ 63.03.
4-Benzoylbenzonitrile (3g).22 Following general procedure for Suzuki coupling of
N3ꢀacylated hydantoins, 3g was purified by column chromatography (Petroleum
1
ether/EtOAc = 20/1) to afford a white solid (31.9 mg, 77%). H NMR (400 MHz,
CDCl3) δ 7.87 (d, J = 8.1 Hz, 2H), 7.81 – 7.78 (m, 2H), 7.78 – 7.71 (m, 2H), 7.67 –
7.61 (m, 1H), 7.54 – 7.48 (m, 2H).
Phenyl(o-tolyl)methanone (3h).23 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3h was purified by column chromatography
1
(Petroleum ether/ EtOAc = 40/1) to afford a colourless oil (34.5 mg, 88%). H NMR
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(400 MHz, CDCl3) δ 7.81 (dd, J = 8.0, 0.8 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.6 Hz, 2H), 7.39 (dd, J = 13.6, 7.6 Hz, 1H), 7.31 (t, J = 8.4 Hz, 2H), 7.25 (t, J = 7.4
Hz, 1H), 2.34 (s, 3H).
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(3,4-Dimethoxyphenyl)(phenyl)methanone (3i).24 Following general procedure
for Suzuki coupling of N3ꢀacylated hydantoins, 3i was purified by column
chromatography (Petroleum ether/EtOAc = 10/1) to afford a white solid (29.5 mg,
61%). 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 7.6, 0.8 Hz, 2H), 7.56 (ddd, J = 7.6,
5.6, 1.2 Hz, 1H), 7.47 (dd, J = 10.0, 2.0 Hz, 3H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 6.89
(d, J = 8.4 Hz, 1H), 3.94 (d, J = 6.7 Hz, 6H).
(3,5-Dimethoxyphenyl)(phenyl)methanone (3j).25 Following general procedure
for Suzuki coupling of N3ꢀacylated hydantoins, 3j was purified by column
chromatography (Petroleum ether/EtOAc = 10/1) to afford a yellow solid (33.9 mg,
70%). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.2 Hz, 2H), 7.58 (dd, J = 13.6, 7.6
Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 6.92 (d, J = 2.4 Hz, 2H), 6.67 (t, J = 2.3 Hz, 1H),
3.82 (s, 6H).
Benzo[d][1,3]dioxol-5-yl(phenyl)methanone (3k).26 Following general procedure
for Suzuki coupling of N3ꢀacylated hydantoins, 3k was purified by column
chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (40.7 mg,
1
90%). H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 7.6, 8.4 Hz, 2H), 7.56 (t, J = 7.4
Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.40 – 7.33 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.05
(s, 2H).
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1-(4-Benzoylphenyl)ethenone (3l).10e Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3l was purified by column chromatography
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(Petroleum ether/EtOAc = 10/1) to afford a white solid (36.7 mg, 82%). H NMR
(400 MHz, CDCl3) δ 10.13 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H),
7.80 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H).
4-Benzoylbenzaldehyde (3m).12e Following general procedure for Suzuki coupling
of N3ꢀacylated hydantoins, 3m was purified by column chromatography (Petroleum
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ether/EtOAc = 10/1) to afford a white solid (23.9 mg, 57%). H NMR (400 MHz,
CDCl3) δ 10.13 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.80 (d, J =
8.0 Hz, 2H), 7.65 – 7.60 (m, 1H), 7.51 (d, J = 7.6 Hz, 2H).
(4-Fluorophenyl)(phenyl)methanone (3n).23 Following general procedure for
Suzuki coupling of N3ꢀacylated hydantoins, 3n was purified by column
chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (34.4 mg,
86%). 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.82 (m, 2H), 7.80 – 7.73 (m, 2H), 7.60 (t,
J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.16 (dd, J = 15.6, 8.0 Hz, 2H). 19F NMR
(376 MHz, CDCl3) δ 106.02.
(1,1'-Biphenyl)-4-yl-(Phenyl)methanone (3o).27 Following general procedure for
Suzuki coupling of N3ꢀacylated hydantoins, 3o was purified by column
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chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (39.2 mg,
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76%). H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 2H), 7.85 (dd, J = 7.6, 0.4
Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.68 – 7.65 (m, 2H), 7.61 (dd, J = 13.6, 7.2 Hz, 1H),
7.50 (dd, J = 15.2, 8.0 Hz, 4H), 7.42 (dd, J = 8.2, 6.4 Hz, 1H).
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Naphthalen-2-yl(phenyl)methanone (3p).23 Following general procedure for
Suzuki coupling of N3ꢀacylated hydantoins, 3p was purified by column
chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (40.0 mg,
84%).1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.2 Hz, 2H), 7.88 – 7.81 (m, 2H),
7.72 (d, J = 8.2 Hz, 2H), 7.68 – 7.65 (m, 2H), 7.64 – 7.59 (m, 1H), 7.50 (dd, J = 15.3,
7.8 Hz, 4H), 7.44 – 7.39 (m, 1H).
Phenyl(thiophen-3-yl)methanone (3q).22 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3q was purified by column chromatography
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(Petroleum ether/EtOAc = 20/1) to afford a pale yellow oil (30.1 mg, 80%). H NMR
(400 MHz, CDCl3) δ 7.93 (d, J = 2.8 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.59 (dd, J = 9.2,
5.2 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (dd, J = 4.8, 2.8 Hz, 1H).
(4-Methoxyphenyl)(phenyl)methanone (3b).22 Following general procedure for
Suzuki coupling of N3ꢀacylated hydantoins, 3b was purified by column
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chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (36.9 mg,
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87%). H NMR (400 MHz, CDCl3) δ 7.90 – 7.79 (m, 2H), 7.76 (dd, J = 7.6, 0.4 Hz,
2H), 7.57 (td, J = 7.2, 1.2 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.02 – 6.92 (m, 2H), 3.89
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(s, 3H).
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Phenyl(p-tolyl)methanone (3c).22 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3c was purified by column chromatography
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(Petroleum ether/EtOAc = 40/1) to afford a white solid (33.3 mg, 85%). H NMR
(400 MHz, CDCl3) δ 7.81 – 7.76 (m, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.58 (t, J = 7.4 Hz,
1H), 7.47 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H).
Phenyl(m-tolyl)methanone (3r).23 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3r was purified by column chromatography
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(Petroleum ether/ EtOAc = 40/1) to afford a colourless oil (34.5 mg, 88%). H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 7.2 Hz, 2H), 7.60 (dd, J = 16.3, 8.8 Hz, 3H), 7.48 (t,
J = 7.6 Hz, 2H), 7.38 (dt, J = 14.8, 7.5 Hz, 2H), 2.42 (s, 3H).
Phenyl(4-(trifluoromethyl)phenyl)methanone
(3f).22
Following
general
procedure for Suzuki coupling of N3ꢀacylated hydantoins, 3f was purified by column
chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (30.5 mg,
61%). 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.86 (m, 2H), 7.85 – 7.79 (m, 2H), 7.78 –
7.72 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (dd, J = 15.2, 7.6 Hz, 2H).
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4-Benzoylbenzonitrile (3g).22 Following general procedure for Suzuki coupling of
N3ꢀacylated hydantoins, 3g was purified by column chromatography (Petroleum
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ether/EtOAc = 20/1) to afford a white solid (33.9 mg, 82%). H NMR (400 MHz,
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CDCl3) δ 7.87 (d, J = 8.1 Hz, 2H), 7.81 – 7.78 (m, 2H), 7.78 – 7.71 (m, 2H), 7.67 –
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7.61 (m, 1H), 7.54 – 7.48 (m, 2H).
Methyl-4-benzoylbenzoate (3e).10e Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3e was purified by column chromatography
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(Petroleum ether/EtOAc = 20/1) to afford a white solid (43.2 mg, 90%). H NMR
(400 MHz, CDCl3) δ 8.14 (dd, J = 8.0, 6.4 Hz, 2H), 7.86 – 7.82 (m, 2H), 7.82 – 7.77
(m, 2H), 7.61 (dt, J = 8.4, 0.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H).
Phenyl(o-tolyl)methanone (3h ).23 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3h was purified by column chromatography
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(Petroleum ether/ EtOAc = 40/1) to afford a colourless oil (29.0 mg, 76%). H NMR
(400 MHz, CDCl3) δ 7.81 (dd, J = 8.0, 0.8 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.6 Hz, 2H), 7.39 (dd, J = 13.6, 7.6 Hz, 1H), 7.31 (t, J = 8.4 Hz, 2H), 7.25 (t, J = 7.4
Hz, 1H), 2.34 (s, 3H).
(2-Methoxyphenyl)(phenyl)methanone (3s).22 Following general procedure for
Suzuki coupling of N3ꢀacylated hydantoins, 3s was purified by column
chromatography (Petroleum ether/ EtOAc = 20/1) to afford a white solid (19.1 mg,
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45%). H NMR (400 MHz, CDCl3) δ 7.87 – 7.76 (m, 1H), 7.56 (t, J = 7.4 Hz, 1H),
7.46 (m, 2H), 7.36 (dd, J = 7.5, 1.6 Hz, 1H), 7.04 (dd, J = 7.7, 7.2 Hz, 1H), 7.00 (d, J
= 8.4 Hz, 1H), 3.73 (s, 2H).
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Furan-2-yl(phenyl)methanone (3t).23 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3t was purified by column chromatography
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(Petroleum ether/EtOAc = 20/1) to afford a pale yellow oil (22.7 mg, 66%). H NMR
(400 MHz, CDCl3) δ 7.97 (dd, J = 7.6, 0.4 Hz, 2H), 7.71 (d, J = 1.2 Hz, 1H), 7.60 (t, J
= 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 3.6 Hz, 1H), 6.60 (dd, J = 3.6, 1.6
Hz, 1H).
Phenyl(thiophen-2-yl)methanone (3u).23 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3u was purified by column chromatography
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(Petroleum ether/EtOAc = 20/1) to afford a pale yellow oil (29.3 mg, 78%). H NMR
(400 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 2H), 7.73 (dd, J =4.8, 0.8 Hz, 1H), 7.65 (dd,
J =3.6, 0.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 8.0 Hz, 7.2H), 7.17 (dd, J =
4.4, 3.6 Hz, 1H).
Naphthalenꢀ2ꢀyl(phenyl)methanone (3p).23 Following general procedure for Suzuki
coupling of N3ꢀacylated hydantoins, 3p was purified by column chromatography
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(Petroleum ether/EtOAc = 20/1) to afford a white solid (41.3 mg, 89%). H NMR
(400 MHz, CDCl3) δ 7.91 (d, J = 8.2 Hz, 2H), 7.88 – 7.81 (m, 2H), 7.72 (d, J = 8.2 Hz,
2H), 7.68 – 7.65 (m, 2H), 7.64 – 7.59 (m, 1H), 7.50 (dd, J = 15.3, 7.8 Hz, 4H), 7.44 –
7.39 (m, 1H).
(4-Fluorophenyl)(phenyl)methanone (3n).23 Following general procedure for
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Suzuki coupling of N3ꢀacylated hydantoins, 3n was purified by column
chromatography (Petroleum ether/EtOAc = 20/1) to afford a white solid (32.4 mg,
81%). 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.82 (m, 2H), 7.80 – 7.73 (m, 2H), 7.60 (t,
J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.16 (dd, J = 15.6, 8.0 Hz, 2H).
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ASSOCIATED CONTENT
Supporting Information
Experiment procedures and H NMR, 19F NMR and 13C NMR spectra for all
1
compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: zhuoz@scnu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
† These authors contributed equally to this work.
The authors gratefully acknowledge the support of the Science and Technology
Planning Project of Guangdong Province (2017A010103017), Special Innovation
Projects of Common Universities in Guangdong Province (20178S0182).
REFERENCES
(1) (a) Koehn, F. E.; Carter, G. T. The evolving role of natural products in drug discovery, Nat
Rev Drug Discov. 2005, 4, 206ꢀ220. (b) Myers, S. H.; Brunton, V. G.; UncitiꢀBroceta, A. AXL
Inhibitors in Cancer: A Medicinal Chemistry Perspective, J. Med. Chem. 2016, 59, 3593ꢀ3608. (c)
Yang, B.; Vasbinder, M. M.; Hird, A. W.; Su, Q.; Wang, H.; Yu, Y.; Toader, D.; Lyne, P. D.;
Read, J. A.; Breed, J.; Ioannidis, S.; Deng, C.; Grondine, M.; DeGrace, N.; Whitston, D.; Brassil,
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