N-Acyl-5,5-Dimethylhydantoins: Mild Acyl-Transfer Reagents for the Synthesis of Ketones Using Pd-PEPPSI or Pd/Phosphine Catalysts

Article abstract of DOI:10.1021/acs.oprd.0c00054

N-Acyl-hydantoins have emerged as novel acyl-transfer reagents for the synthesis of ketones via selective N-C(O) cleavage. Herein, we report two new protocols for the cross-coupling of N-acyl-5,5-dimethylhydantoins using versatile and readily accessible Pd-PEPPSI or Pd/phosphine catalysts. The acyl Suzuki reactions afford biaryl ketones in good to excellent yields under operationally simple conditions using commercially available, bench- A nd air-stable twisted N-acyl-hydantoins as acyl donors. The method complements and expands on the previous protocol for the cross-coupling of N-acyl-hydantoins (Luo, Z.et al. Org. Process Res. Dev. 2018, 22, 1188).

Full text of DOI:10.1021/acs.oprd.0c00054

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Full Paper
N-Acyl-5,5-Dimethylhydantoins: Mild Acyl-Transfer Reagents for the
Synthesis of Ketones using Pd–PEPPSI or Pd/Phosphine Catalysis
Chang-An Wang, Chengwei Liu, and Michal Szostak
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00054 • Publication Date (Web): 03 Apr 2020
Downloaded from pubs.acs.org on April 9, 2020
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N-Acyl-5,5-Dimethylhydantoins:Mild Acyl-Transfer
Reagentsfor the Synthesis of Ketones using Pd–PEPPSI
or Pd/Phosphine Catalysis
Chang-An Wang,‡,† Chengwei Liu,† and Michal Szostak*,†
‡College of Chemistry and Chemical Engineering, Taishan University, Tai’an, Shandong 271000, China
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†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, USA
Corresponding author: michal.szostak@rutgers.edu
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Table of Contents Graphic
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Abstract: N-Acyl-hydantoins have emerged as novel acyl transfer reagents for the synthesis of ketones
via selective N–C(O) cleavage. Herein, we report two new protocols for the cross-coupling of N-acyl-
5,5-dimethylhydantoins using versatile and readily accessible Pd–PEPPSI or Pd/phosphine catalysts.
The acyl Suzuki reactions afford biaryl ketones in good to excellent yields under operationally-simple
conditions using commercially-available, bench- and air-stable twisted N-acyl-hydantoins as acyl
donors. The method complements and expands on the previous protocol for the cross-coupling of N-
acyl-hydantoins (Org. Process Res. Dev. 2018, 22, 1188).
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Keywords: twisted amides, N-acyl-hydantoins, Suzuki coupling, amide cross-coupling, N–C activation
1. Introduction
Over the past five years, tremendous advances have been made in transition-metal-catalyzed amide
bond cross-coupling.1–3 These reactions are valuable due to the very common presence of amide bonds
in pharmaceuticals, biomolecules and functional materials.4–6 Furthermore, this field has resulted in the
development of new acyclic twisted amides as practical, bench-stable precursors for acyl-transfer
reactions that could also be translated to decarbonylative processes by CO loss.7
In 2018, Zeng and co-workers introduced N-acyl-5,5-dimethylhydantoins as new acyl-transfer
reagents using [Pd(IPr)(allyl)Cl] precatalyst (Org. Process Res. Dev. 2018, 22, 1188).8 Simultaneously,
we have reported a mechanistic study on the structures and energetics on N-acyl-hydantoins (J. Org.
Chem. 2018, 83, 14676), finding that the amide bond in N-acyl-hydantoins is significantly twisted with
the additive Winkler-Dunitz parameter, +N = 70°, for the model compound (Figure 1A).9
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Figure 1. Context of this work: Suzuki cross-coupling of twisted N-acyl-5,5-dimethylhydantoins.
Within our research program on amide bond cross-coupling and Pd-NHC catalysis,2,3 we now report
two new protocols for the cross-coupling of N-acyl-5,5-dimethylhydantoins using versatile and readily
accessible Pd–PEPPSI or Pd/phosphine catalysts (Figure 1B). The following features of our study are
noteworthy: (1) The reactions complement and expand on the previous protocol for the cross-coupling
of N-acyl-hydantoins using [Pd(IPr)(allyl)Cl].8 (2) Pd-PEPPSI represent a completely distinct class of
Pd-NHC catalysts that are (i) cheaper and easier to synthesize than the allyl-type precatalysts,10,11 (ii)
undergo activation under complementary mechanism to the allyl-type precursors, and (iii) many Pd-
PEPPSI-type catalysts have been reported, which is significant for the future developments in amide
bond N–C(O) cross-coupling.12 (3) We demonstrate that, alternatively, cheap and readily accessible
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Pd/phosphine catalysts can also be used for the cross-coupling of N-acyl-5,5-dimethylhydantoins in
excellent yields. (4) The protocols are also applied to the Suzuki cross-coupling of other classes of
twisted amides by selective N–C(O) activation, showing higher reactivity than the use of
[Pd(IPr)(allyl)Cl] catalyst.8,13–15
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The new protocols are compared and contrasted with the [Pd(IPr)(allyl)Cl]-catalyzed cross-coupling
of N-acyl-5,5-dimethylhydantoins reported by Zeng and co-workers.8 More broadly, it should be noted
that (i) phosphines and NHCs represent fundamentally different classes of ligands, resulting in a distinct
monoligated Pd species,10b and (ii) the activation, synthesis and properties of Pd-allyl-type and Pd-
PEPPSI-type catalysts are fundamentally distinct as they belong to different classes of throw-away
ligands.10,11
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Figure 2. Structures of [Pd–NHC] catalysts.
2. Results and Discussion
In 2018, during our structural studies, we performed preliminary catalytic investigations establishing
that N-benzoyl-5,5-dimethylhydantoin could undergo the cross-coupling with 4-Tol-B(OH)2 under Pd–
PEPPSI and Pd/PCy3 conditions (eq 1). Interestingly, the parent N-benzoylhydantoin without the 5,5-
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gem-dimethyl substitution resulted in significantly lower yields, likely due to low stability under the
reaction conditions (eq. 2).
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Further optimization indicated that the reaction of N-benzoyl-5,5-dimethylhydantoin with 4-Tol-
B(OH)2 produced the desired ketone product in close to quantitative yield using either Pd–PEPPSI–IPr
(Table 1, entry 1, Figure 2) or Pd/PCy3 catalyst systems (Table 1, entry 2) at 3 mol% of [Pd] loading at
80 °C or 120 °C, respectively, while the previous report required 6 mol% of the [Pd(IPr)(allyl)Cl]
catalyst at 110 °C. Optimization studies revealed that for the Pd/PCy3-catalyzed conditions (Table 1,
entries 3-10), the stoichiometry of boronic acid and base are critical parameters (entries 3-6).
Importantly, decomposition was observed at higher boronic acid and base loading. Furthermore, the
optimum results were obtained with 3 mol% of [Pd] loading (entries 7-8). A base screen revealed that
Na2CO3 is a superior base to K2CO3 (entries 9-10). More interesting is the optimization using Pd–
PEPPSI catalysts (entries 11-25). Extensive evaluation of various bases showed that K2CO3 is the
preferred base under these conditions (entries 11-15). Excess of the boronic acid and the base was
tolerated under the Pd–PEPPSI conditions (entry 16), consistent with more facile oxidative addition
using Pd-NHC systems. Optimization of stoichiometry and temperature (entries 17-22) revealed that
efficient coupling ensued at 80 °C (entry 1 cf. [Pd(IPr)(allyl)Cl] at 110 °C). Cross-coupling was not
observed at 23 °C, resulting in recovery of starting material (entry 21). Interestingly, water could also be
used as a co-solvent, which could lead to the development of green organic processes using water-
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soluble NHC ligands (entry 19). Moreover, 2-MeTHF serves as a convenient green solvent in this cross-
coupling12c (97% yield, Pd-PEPPSI-IPr; 69% yield, Pd(OAc)2/PCy3HBF4 conditions, not shown).
Furthermore, evaluation of various NHC ancillary ligands (entries 1, 23-24) indicated that IPr is the
optimum NHC ligand for the cross-coupling, while significantly lower yields were observed using both
the less sterically-demanding IMes (entry 23) and the more sterically-hindered IPent (entry 24). Finally,
3-chloropyridine throw-away ligand was found to be superior to pyridine throw-away ligand in the
PEPPSI scaffold (entry 25). Taken together with previous examples,2a the present study decidedly
highlights that IPr might be the privileged NHC ligand for amide bond cross-coupling.
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Table 1. Optimization of the Reaction Conditionsa
base
(eq)
1.5
2.0
3.0
3.0
1.5
2.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
yield
(%)b
entry
[Pd]
ligand
base
T (°C)
1
Pd-PEPPSI-IPr
Pd(OAc)2
-
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K3PO4
80
96
92
61
28
69
72
65
25
<5
53
69
<2
19
2c
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
PCy3HBF4
-
120
120
120
120
120
120
120
120
80
3
Pd(OAc)2
4d
5d
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
7c,e
8c,f
9c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
10c
11
12
13
Pd(OAc)2
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
120
120
120
-
-
Na2CO3
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14
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16g
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18c
19h
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Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IMes
Pd-PEPPSI-IPent
Pd-PEPPSIpy-IPr
-
-
-
-
-
-
-
-
-
-
-
-
Cs2CO3
KOH
3.0
3.0
4.5
2.0
2.0
2.0
1.5
1.5
1.5
1.5
1.5
1.5
120
120
120
120
120
120
120
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<2
5
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
81
80
50
71
93
<2
25
57
79
82
9
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aConditions: 1 (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd] (3 mol %), PCy3HBF4 (12 mol %), base, (1.5-
4.5 equiv), dioxane (0.25 M), T, 15 h. GC/1H NMR yields. Ar-B(OH)2 (1.5 equiv). Ar-B(OH)2 (1.2
equiv). ePd(OAc)2 (6 mol %), PCy3HBF4 (12 mol %). fPd(OAc)2 (1 mol %), PCy3HBF4 (4 mol %). gAr-
B(OH)2 (3.0 equiv). hH2O (5 equiv).
b
c
d
With the optimized conditions in hand, the scope of these two new protocols was examined (Schemes
1-2). For comparison, yields obtained by Zeng and co-workers using the [Pd(IPr)(allyl)Cl] catalyst are
shown in brackets for all examples.8 With respect to the boronic acid scope (Scheme 1), we were
pleased to find that the reaction accommodates a broad range of boronic acids, including electronically-
neutral (3a-b), electron-donating (3c) and electron-withdrawing substrates (3d-g). Steric hindrance was
well-tolerated (3h). Furthermore, the scope includes meta-substitution (3i-j), polyarenes (3k) and
heterocycles (3l). A noteworthy feature is functional group tolerance to sensitive electrophiles, such as
ester (3d) and aldehyde (3g), which would not be tolerated under classical Weinreb amide conditions.
Overall, both of the protocols showed comparable or superior performance to the [Pd(IPr)(allyl)Cl]
catalysis at lower catalyst loading. Typically, Pd–PEPPSI gave slightly higher yields than Pd/PCy3
catalysis.
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Scheme1. Suzuki Cross-Coupling of N-Acyl-5,5-dimethylhydantoin: Scope of Boronic Acidsa
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aConditions: A: Pd–PEPPSI–IPr: amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), Pd–PEPPSI–IPr (3
mol%), K2CO3 (1.5 equiv), dioxane (0.25 M), 80 °C, 15 h. B: Pd/PCy3: amide (1.0 equiv), Ar-B(OH)2
(1.5 equiv), Pd(OAc)2 (3 mol%), PCy3HBF4 (12 mol%), Na2CO3 (2.0 equiv), dioxane (0.25 M), 120 °C,
15 h. C: [Pd(IPr)(allyl)Cl] (Ref. 8): amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd(IPr)(allyl)Cl] (6
mol%), K2CO3 (3.0 equiv), dioxane (2.0 M), 110 °C, 15 h. bPd(OAc)2 (6 mol%), PCy3HBF4 (24 mol%).
Note: Conditions C: [Pd(IPr)(allyl)Cl] correspond to the yields obtained in ref. 8.
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Scheme 2 summarizes the scope of the reaction with respect to the N-acyl-5,5-dimethylhydantoin
component. As mentioned (eq 1-2), 5,5-gem-dimethyl-subsitution is preferred over the unsubstituted
variant. Regarding the amide scope, we were pleased to find that neutral (3b), electron-rich (3c) and
electron-deficient (3d-e) amides underwent coupling in high to excellent yields under both reaction
conditions. Moreover, sterically-hindered (3h) and heterocyclic amides (3m) afforded the desired
ketone products catalyzed by both systems. The results obtained with N-acyl-5,5-dimethylhydantoins
using Pd–PEPPSI and Pd/PCy3 compare favorably with the [Pd(IPr)(allyl)Cl] catalysis.
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To demonstrate scalability, a gram scale reaction was performed (1a, 1.0 g, 4.31 mmol), Ph-B(OH)2
(1.5 equiv, 6.46 mmol, 0.79 g), Pd(OAc)2 (3 mol%, 29 mg), PCy3HBF4 (12 mol%, 190 mg), Na2CO3
(2.0 equiv, 8.62 mmol, 0.91 g), dioxane (0.25 M), 120 °C, 15 h, resulting in 87% isolated yield (0.685
g), attesting to the scalability of the cross-coupling (not shown).
We were further interested to test the generality of the catalyst systems and applied the reaction
conditions to the Suzuki cross-coupling of other classes of twisted amides (Scheme 3). For comparison,
the yields obtained using the [Pd(IPr)(allyl)Cl] catalyst by Zeng and co-workers for the same amide
substrate combinations are presented in brackets.8 Thus, the Suzuki cross-coupling of N-benzoyl-5,5-
dimethylhydantoin (1a), N-benzoylsuccinimide (1h),16,13g N-benzoylsaccharin (1i)17,13i and N-Ts-N-
phenylbenzamide (1j)2a all occurred in high to excellent yields, comparing favorably with the
[Pd(IPr)(allyl)Cl] conditions.
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Scheme2. Suzuki Cross-Coupling of N-Acyl-5,5-dimethylhydantoin: Scope of Amides
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aConditions: A: Pd–PEPPSI–IPr: amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), Pd–PEPPSI–IPr (3
mol%), K2CO3 (1.5 equiv), dioxane (0.25 M), 80 °C, 15 h. B: Pd/PCy3: amide (1.0 equiv), Ar-B(OH)2
(1.5 equiv), Pd(OAc)2 (3 mol%), PCy3HBF4 (12 mol%), Na2CO3 (2.0 equiv), dioxane (0.25 M), 120 °C,
15 h. C: [Pd(IPr)(allyl)Cl] (Ref. 8): amide (1.0 equiv), Ar-B(OH)2 (2.0 equiv), [Pd(IPr)(allyl)Cl] (6
mol%), K2CO3 (3.0 equiv), dioxane (2.0 M), 110 °C, 15 h. bAr-B(OH)2 (3.0 equiv), Na2CO3 (4.5 equiv).
d
cPd(OAc)2 (6 mol%), PCy3HBF4 (24 mol%). Pd–PEPPSI–IPr (6 mol%). Note: Conditions C:
[Pd(IPr)(allyl)Cl] correspond to the yields obtained in ref. 8.
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Scheme 3. Suzuki Cross-Coupling of N-Acyl-5,5-dimethylhydantoin: Various Amidesa
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aSee Scheme 1.
At this stage, electronic and structural parameters of all of amides shown in Scheme 3 have been
determined by our group (Table 2).6 It is absolutely critical to point out that the reactivity of twisted
amides in N–C(O) cross-coupling correlates with amide bond resonance (cf. twist), and is significantly
influenced by the stability of the N–C(O) amide bond and/or N-activating group to the reaction
conditions. There is no doubt that the most reactive amides as determined by resonance and/or twist, a
leading example of which are perfectly perpendicular N-acyl-glutarimides (RE = 0 kcal/mol, 1k),3a are
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not always preferred substrates for select cross-couplings due to the stability of the amide bond under a
given set of reaction conditions. All future design should be based on consideration of amidic resonance
and amide bond twist of precursors.18,19
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Table 2. Steric and Energetic Properties of Amidesa,b
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1a
1h
1i
1j
1k
entry
hydantoin
49.5
13.3
62.8
0.0
succinimide
46.1
saccharin
23.0
12.5
35.5
2.0
Ts
glutarimide
87.5
18.8
19.9
38.7
9.7

9.5
5.6
N
(+N)5g
RE
55.6
93.1
-0.3
-1.4
aWinker-Dunitz parameters, , N [deg]. Additive Winkler-Dunitz parameter, (+N) [deg]. See ref.
5,6. bRE, resonance energy (kcal/mol) calculated at B3LYP/6-311++G(d,p). See ref. 5d,6.
3. Conclusions
In summary, we have developed conditions for the cross-coupling of N-acyl-5,5-dimethylhydantoins
using versatile Pd–PEPPSI and Pd/phosphine catalysts. The acyl Suzuki reactions occur in high yields
to afford biaryl ketone products under operationally-simple conditions. The reactions feature twisted N-
acyl-hydantoins as mild, commercially-available, bench- and air-stable acyl donors. The protocols
expand the previous study on the use of [Pd(IPr)(allyl)Cl] catalyst. Another important feature involved
the finding that IPr is the preferred NHC ancillary ligand for the cross-coupling of N-acyl-5,5-
dimethylhydantoins in terms of steric demand in lieu of less bulky IMes and more sterically-demanding
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IPent, while 3-chloropyridine throw-away ligand is preferred over pyridine throw-away ligand. More
generally, the study provides further evidence that the optimum results in amide bond cross-coupling are
obtained by using Pd-NHC catalysts with different classes of throw-away ligands, including PEPPSI-
type and allyl-type, as well as Pd/phosphine catalysts. Studies directed on application of amide bond
cross-coupling in the synthesis of bioactive molecules are ongoing and will be reported in due course.
We anticipate that further progress in amide bond cross-coupling will be achieved by studies on ligand
design and the development of new twisted amide precursors for cross-coupling.
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Experimental Section
General Methods. All starting materials reported in the manuscript have been previously described in
literature.8 All products reported in the manuscript have been previously described.8 All experiments
were performed using standard Schlenk techniques under argon or nitrogen atmosphere. All solvents
were purchased at the highest commercial grade and used as received or after purification by passing
through activated alumina columns or distillation from sodium/benzophenone under nitrogen. All other
chemicals were purchased at the highest commercial grade and used as received. All other general
methods have been published.3a 1H NMR and 13C NMR data are given for all compounds in the
1
Supporting Experimental for characterization purposes. H NMR, 13C NMR and HRMS data are
reported for all new compounds.
General Procedure for Suzuki-Miyaura Cross-Coupling of Amides. Pd–PEPPSI: An oven-dried
vial equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv), K2CO3 (typically,
1.5 equiv), boronic acid (typically, 2.0 equiv), Pd–NHC catalyst (typically, 3.0 mol%), placed under a
positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum.
Dioxane (typically, 0.25 M) was added with vigorous stirring at room temperature, the reaction mixture
was placed in a preheated oil bath at 80 °C and stirred for the indicated time. After the indicated time,
the reaction mixture was cooled down to room temperature, diluted with CH2Cl2 (10 mL), filtered, and
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concentrated. A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion,
selectivity and yield using internal standard and comparison with authentic samples. Purification by
chromatography on silica gel (EtOAc/hexanes = 20/1) afforded the tile product.
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General Procedure for Suzuki-Miyaura Cross-Coupling of Amides. Pd/PCy3: An oven-dried vial
equipped with a stir bar was charged with an amide substrate (neat, 1.0 equiv), Na2CO3 (typically, 2.0
equiv), boronic acid (typically, 1.5 equiv), Pd(OAc)2 (typically, 3.0 mol%), PCy3HBF4 (typically, 12
mol%), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles
under high vacuum. Dioxane (typically, 0.25 M) was added with vigorous stirring at room temperature,
the reaction mixture was placed in a preheated oil bath at 120 °C, and stirred for the indicated time.
After the indicated time, the reaction mixture was cooled down to room temperature, diluted with
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CH2Cl2 (10 mL), filtered, and concentrated. The sample was analyzed by H NMR (CDCl3, 500 MHz)
and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with
authentic samples. Purification by chromatography on silica gel (hexanes/ethyl acetate = 20/1) afforded
the title product.
Representative Procedure for Suzuki-Miyaura Cross-Coupling of Amides. Pd–PEPPSI. 1.0
Mmol Scale. An oven dried vial equipped with a stir bar was charged with 3-benzoyl-5,5,-
dimethylhydantoin (neat, 232.2 mg, 1.0 mmol), K2CO3 (1.5 mmol, 207.3 mg, 1.5 equiv), 4-tolylboronic
acid (2.0 mmol, 272.1 mg, 2.0 equiv), Pd–PEPPSI–IPr (20.4 mg, 3 mol%) placed under a positive
pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Dioxane
(0.25 M) was added with vigorous stirring at room temperature, and the reaction mixture was stirred for
15 h at 80 °C. After the indicated time, the reaction mixture was cooled down to room temperature,
diluted with CH2Cl2 (20 mL), filtered, and concentrated. Purification by chromatography on silica gel
(EtOAc/hexanes = 20/1) afforded the title product. White solid. Yield 82% (160.9 mg). Characterization
data are included in the section below.
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Representative Procedure for Suzuki-Miyaura Cross-Coupling of Amides. Pd/PCy3. 1.0 Mmol
Scale. An oven dried vial equipped with a stir bar was charged with 3-benzoyl-5,5,-dimethylhydantoin
(neat, 232.2 mg, 1.0 mmol), Na2CO3 (2.0 mmol, 212.0 mg, 2.0 equiv), 4-tolylboronic acid (1.5 mmol,
204.1 mg, 1.5 equiv), Pd(OAc)2 (6.7 mg, 3 mol%), PCy3HBF4 (44.2 mg, 12 mol%), placed under a
positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum.
Dioxane (0.25 M) was added with vigorous stirring at room temperature, and the reaction mixture was
stirred for 15 h at 120 °C. After the indicated time, the reaction mixture was cooled down to room
temperature, diluted with CH2Cl2 (20 mL), filtered, and concentrated. Purification by chromatography
on silica gel (EtOAc/hexanes = 20/1) afforded the title product. White solid. Yield 95% (186.4 mg).
Characterization data are included in the section below.
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Characterization Data of Products. All products reported in the manuscript have been previously
reported.8 Spectroscopic data match those reported in the literature.
Benzophenone (3a). According to the general procedure, the reaction of 3-benzoyl-5,5-
dimethylhydantoin (0.10 mmol), phenylboronic acid (2.0 equiv), K2CO3 (1.5 equiv) and Pd–PEPPSI–IPr
(3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and chromatography
1
(hexanes/ethyl acetate = 20/1) the title product in 96% yield (17.5 mg). White solid. H NMR (500
MHz, CDCl3) δ 7.90-7.77 (m, 4H), 7.61 (dd, J = 10.6, 4.2 Hz, 2H), 7.50 (t, J = 7.6 Hz, 4H). 13C NMR
(125 MHz, CDCl3) δ 196.63, 137.54, 132.33, 129.97, 128.20. Pd/PCy3: 82% yield (14.9 mg).
Phenyl(p-tolyl)methanone (3b). According to the general procedure, the reaction of 3-benzoyl-5,5-
dimethylhydantoin (0.10 mmol), p-tolylboronic acid (2.0 equiv), K2CO3 (1.5 equiv) and Pd–PEPPSI–
IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and chromatography
1
(hexanes/ethyl acetate = 20/1) the title product in 96% yield (18.8 mg). White solid. H NMR (500
MHz, CDCl3) δ 7.85-7.78 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz,
2H), 7.30 (d, J = 7.9 Hz, 2H), 2.46 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 196.51, 143.26, 137.98,
134.91, 132.18, 130.33, 129.95, 129.00, 128.23, 21.68. Pd/PCy3: 92% yield (18.0 mg).
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(4-Methoxyphenyl)(phenyl)methanone (3c). According to the general procedure, the reaction of 3-
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benzoyl-5,5-dimethylhydantoin (0.10 mmol), p-methoxyphenylboronic acid (2.0 equiv), K2CO3 (1.5
equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration
and chromatography (hexanes/ethyl acetate = 20/1) the title product in 91% yield (19.3 mg). White
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solid. H NMR (500 MHz, CDCl3) δ 7.88-7.83 (m, 2H), 7.80-7.75 (m, 2H), 7.58 (dd, J = 10.6, 4.3 Hz,
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1H), 7.49 (t, J = 7.6 Hz, 2H), 7.01-6.95 (m, 2H), 3.91 (s, 3H). C NMR (125 MHz, CDCl3) δ 195.55,
163.24, 138.32, 132.57, 131.89, 130.20, 129.74, 128.19, 113.57, 55.51. Pd/PCy3: 86% yield (18.2 mg).
Methyl 4-benzoylbenzoate (3d). According to the general procedure, the reaction of 3-benzoyl-5,5-
dimethylhydantoin (0.10 mmol), 4-(methoxycarbonyl)phenylboronic acid (2.0 equiv), K2CO3 (1.5
equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration
and chromatography (hexanes/ethyl acetate = 20/1) the title product in 79% yield (18.9 mg). White
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solid. H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 7.84-7.80 (m,
13
2H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 3.99 (s, 3H). C NMR (125 MHz, CDCl3) δ
196.03, 166.33, 141.35, 136.98, 133.24, 132.95, 130.11, 129.78, 129.51, 128.47, 52.47. Pd/PCy3: 88%
yield (21.1 mg).
Phenyl(4-(trifluoromethyl)phenyl)methanone (3e). According to the general procedure, the
reaction of 3-benzoyl-5,5-dimethylhydantoin (0.10 mmol), 4-(methoxycarbonyl)phenylboronic acid (2.0
equiv), K2CO3 (1.5 equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C,
afforded after filtration and chromatography (hexanes/ethyl acetate = 20/1) the title product in 72%
yield (18.0 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.85-7.80 (m, 2H),
7.78 (d, J = 8.1 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H). 13C NMR (125 MHz, CDCl3)
δ 195.52, 140.74, 136.74, 133.86, 133.84 (q, JF = 32.7 Hz), 130.13, 130.10, 128.53, 125.47 (q, J = 3.7
Hz), 123.80 (q, JF = 272.6 Hz). 19F NMR (471 MHz, CDCl3) δ -63.00. Pd/PCy3: 63% yield (15.8 mg).
(4-Fluorophenyl)(phenyl)methanone (3f). According to the general procedure, the reaction of 3-
benzoyl-5,5-dimethylhydantoin (0.10 mmol), 4-(methoxycarbonyl)phenylboronic acid (2.0 equiv),
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K2CO3 (1.5 equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after
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filtration and chromatography (hexanes/ethyl acetate = 20/1) the title product in 95% yield (19.0 mg).
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White solid. H NMR (500 MHz, CDCl3) δ 7.93-7.84 (m, 2H), 7.82-7.75 (m, 2H), 7.62 (t, J = 7.4 Hz,
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1H), 7.51 (t, J = 7.7 Hz, 2H), 7.18 (dd, J = 12.1, 5.2 Hz, 2H). C NMR (125 MHz, CDCl3) δ 195.30,
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165.41 (d, JF = 252.5 Hz), 137.52, 133.82 (d, JF = 2.9 Hz), 132.69 (d, JF = 9.1 Hz), 132.49, 129.90,
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128.38, 115.48 (d, JF = 21.7 Hz). F NMR (471 MHz, CDCl3) δ -105.98. Pd/PCy3: 55% yield (11.0
mg).
4-Benzoylbenzaldehyde (3g). According to the general procedure, the reaction of 3-benzoyl-5,5-
dimethylhydantoin (0.10 mmol), 4-formylphenylboronic acid (2.0 equiv), K2CO3 (1.5 equiv) and Pd–
PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and
chromatography (hexanes/ethyl acetate = 20/1) the title product in 71% yield (14.9 mg). White solid. 1H
NMR (500 MHz, CDCl3) δ 10.16 (s, 1H), 8.03 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.86-7.79
13
(m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H). C NMR (125 MHz, CDCl3) δ 195.82,
191.61, 142.60, 138.51, 136.77, 133.14, 130.34, 130.13, 129.51, 128.55. Pd/PCy3: 58% yield (12.2 mg).
Phenyl(o-tolyl)methanone (3h). According to the general procedure, the reaction of 3-benzoyl-5,5-
dimethylhydantoin (0.10 mmol), 3-methoxyphenylboronic acid (2.0 equiv), K2CO3 (1.5 equiv) and Pd–
PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and
chromatography (hexanes/ethyl acetate = 20/1) the title product in 88% yield (17.2 mg). Colorless oil.
1H NMR (500 MHz, CDCl3) δ 7.76-7.70 (m, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.31
(td, J = 7.6, 1.2 Hz, 1H), 7.23 (dd, J = 11.5, 7.3 Hz, 1H), 7.17 (dd, J = 9.9, 5.0 Hz, 1H), 2.26 (s, 2H). 13C
NMR (125 MHz, CDCl3) δ 198.61, 138.59, 137.72, 136.72, 133.10, 130.97, 130.21, 130.10, 128.49,
128.43, 125.16, 19.95. Pd/PCy3: 65% yield (12.7 mg).
(3-Methoxyphenyl)(phenyl)methanone (3i). According to the general procedure, the reaction of 3-
benzoyl-5,5-dimethylhydantoin (0.10 mmol), 3-methoxyphenylboronic acid (2.0 equiv), K2CO3 (1.5
equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration
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and chromatography (hexanes/ethyl acetate = 20/1) the title product in 88% yield (18.7 mg). White
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solid. H NMR (500 MHz, CDCl3) δ 7.92-7.79 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz,
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2H), 7.44-7.32 (m, 3H), 7.16 (ddd, J = 7.9, 2.6, 1.1 Hz, 1H), 3.88 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 196.52, 159.60, 138.93, 137.65, 132.42, 130.05, 129.22, 128.26, 122.88, 118.87, 114.34, 55.49.
Pd/PCy3: 66% yield (13.9 mg).
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(3,4-Dimethoxyphenyl)(phenyl)methanone (3j). According to the general procedure, the reaction of
3-benzoyl-5,5-dimethylhydantoin (0.10 mmol), 3,4-dimethoxyphenylboronic acid (2.0 equiv), K2CO3
(1.5 equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after
filtration and chromatography (hexanes/ethyl acetate = 20/1) the title product in 82% yield (19.8 mg).
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White solid. H NMR (500 MHz, CDCl3) δ 7.82-7.74 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.54-7.47 (m,
31H), 7.40 (dd, J = 8.3, 1.9 Hz, 1H), 6.93-6.90 (m, 1H), 3.98 (s, 3H), 3.97 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 195.58, 153.05, 149.04, 138.32, 131.88, 130.26, 129.73, 128.18, 125.51, 112.16, 109.76,
56.11, 56.07. Pd/PCy3: 72% yield (17.4 mg).
Naphthalen-2-yl(phenyl)methanone (3k). According to the general procedure, the reaction of 3-
benzoyl-5,5-dimethylhydantoin (0.10 mmol), naphthalen-2-ylboronic acid (2.0 equiv), K2CO3 (1.5
equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration
and chromatography (hexanes/ethyl acetate = 20/1) the title product in 98% yield (22.7 mg). White
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solid. H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.97 (s, 2H), 7.96-7.92 (m, 2H), 7.91-7.87 (m, 2H),
13
7.68-7.62 (m, 2H), 7.57 (ddd, J = 17.4, 11.7, 4.3 Hz, 3H). C NMR (125 MHz, CDCl3) δ 196.72,
137.91, 135.26, 134.83, 132.35, 132.25, 131.84, 130.08, 129.40, 128.32, 128.30, 128.28, 127.80,
126.78, 125.77. Pd/PCy3: 59% yield (13.7 mg).
Phenyl(thiophen-3-yl)methanone (3l). According to the general procedure, the reaction of 3-
benzoyl-5,5-dimethylhydantoin (0.10 mmol), thiophen-3-ylboronic acid (2.0 equiv), K2CO3 (1.5 equiv)
and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and
chromatography (hexanes/ethyl acetate = 20/1) the title product in 72% yield (22.7 mg). White solid. 1H
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NMR (500 MHz, CDCl3) δ 7.94 (dd, J = 2.9, 1.1 Hz, 1H), 7.89-7.84 (m, 2H), 7.64-7.57 (m, 2H), 7.50 (t,
J = 7.6 Hz, 2H), 7.39 (dd, J = 5.1, 2.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 189.88, 141.22, 138.56,
133.82, 132.22, 129.28, 128.52, 128.30, 126.13. Pd/PCy3: 79% yield (14.9 mg).
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Phenyl(p-tolyl)methanone (3b). According to the general procedure, the reaction of 3-(4-
methylbenzoyl)-5,5-dimethylhydantoin (0.10 mmol), phenylboronic acid (2.0 equiv), K2CO3 (1.5 equiv)
and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and
chromatography (hexanes/ethyl acetate = 20/1) the title product in 98% yield (19.2 mg). White solid. 1H
NMR (500 MHz, CDCl3) δ 7.85-7.78 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.49 (t,
J = 7.6 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 2.46 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 196.51, 143.26,
137.98, 134.91, 132.18, 130.33, 129.95, 129.00, 128.23, 21.68. Pd/PCy3: 85% yield (16.7 mg).
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(4-Methoxyphenyl)(phenyl)methanone (3c). According to the general procedure, the reaction of 3-
(4-methoxybenzoyl)-5,5-dimethylhydantoin (0.10 mmol), phenylboronic acid (2.0 equiv), K2CO3 (1.5
equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration
and chromatography (hexanes/ethyl acetate = 20/1) the title product in 91% yield (19.3 mg). White
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solid. H NMR (500 MHz, CDCl3) δ 7.88-7.83 (m, 2H), 7.80-7.75 (m, 2H), 7.58 (dd, J = 10.6, 4.3 Hz,
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1H), 7.49 (t, J = 7.6 Hz, 2H), 7.01-6.95 (m, 2H), 3.91 (s, 3H). C NMR (125 MHz, CDCl3) δ 195.55,
163.24, 138.32, 132.57, 131.89, 130.20, 129.74, 128.19, 113.57, 55.51. Pd/PCy3: 68% yield (14.4 mg).
Phenyl(4-(trifluoromethyl)phenyl)methanone (3e). According to the general procedure, the
reaction of 3-(4-(trifluoromethyl)benzoyl)-5,5-dimethylhydantoin (0.10 mmol), phenylboronic acid (2.0
equiv), K2CO3 (1.5 equiv) and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C,
afforded after filtration and chromatography (hexanes/ethyl acetate = 20/1) the title product in 98%
yield (24.5 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.85-7.80 (m, 2H),
7.78 (d, J = 8.1 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H). 13C NMR (125 MHz, CDCl3)
δ 195.52, 140.74, 136.74, 133.86, 133.84 (q, JF = 32.7 Hz), 130.13, 130.10, 128.53, 125.47 (q, J = 3.7
Hz), 123.80 (q, JF = 272.6 Hz). 19F NMR (471 MHz, CDCl3) δ -63.00. Pd/PCy3: 95% yield (23.8 mg).
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(4-Fluorophenyl)(phenyl)methanone (3f). According to the general procedure, the reaction of 3-(4-
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fluorobenzoyl)-5,5-dimethylhydantoin (0.10 mmol), phenylboronic acid (2.0 equiv), K2CO3 (1.5 equiv)
and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and
chromatography (hexanes/ethyl acetate = 20/1) the title product in 98% yield (24.5 mg). White solid. 1H
NMR (500 MHz, CDCl3) δ 7.93-7.84 (m, 2H), 7.82-7.75 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J =
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7.7 Hz, 2H), 7.18 (dd, J = 12.1, 5.2 Hz, 2H). C NMR (125 MHz, CDCl3) δ 195.30, 165.41 (d, JF =
252.5 Hz), 137.52, 133.82 (d, JF = 2.9 Hz), 132.69 (d, JF = 9.1 Hz), 132.49, 129.90, 128.38, 115.48 (d,
JF = 21.7 Hz). 19F NMR (471 MHz, CDCl3) δ -105.98. Pd/PCy3: 61% yield (12.2 mg).
Phenyl(o-tolyl)methanone (3h). According to the general procedure, the reaction of 3-(2-
methylbenzoyl)-5,5-dimethylhydantoin (0.10 mmol), phenylboronic acid (2.0 equiv), K2CO3 (1.5 equiv)
and Pd–PEPPSI–IPr (6.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and
chromatography (hexanes/ethyl acetate = 20/1) the title product in 72% yield (14.1 mg). Colorless oil.
1H NMR (500 MHz, CDCl3) δ 7.76-7.70 (m, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.31
(td, J = 7.6, 1.2 Hz, 1H), 7.23 (dd, J = 11.5, 7.3 Hz, 1H), 7.17 (dd, J = 9.9, 5.0 Hz, 1H), 2.26 (s, 2H). 13C
NMR (125 MHz, CDCl3) δ 198.61, 138.59, 137.72, 136.72, 133.10, 130.97, 130.21, 130.10, 128.49,
128.43, 125.16, 19.95. Pd/PCy3: 70% yield (13.7 mg).
Phenyl(thiophen-2-yl)methanone (3m). According to the general procedure, the reaction of 3-(2-
methylbenzoyl)-5,5-dimethylhydantoin (0.10 mmol), phenylboronic acid (2.0 equiv), K2CO3 (1.5 equiv)
and Pd–PEPPSI–IPr (3.0 mol%) in dioxane (0.25 M) for 15 h at 80 °C, afforded after filtration and
chromatography (hexanes/ethyl acetate = 20/1) the title product in 88% yield (16.5 mg). White solid. 1H
NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.4 Hz, 2H), 7.75 (d, J = 4.9 Hz, 1H), 7.67 (d, J = 3.7 Hz, 1H),
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7.62 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.22-7.16 (m, 1H). C NMR (125 MHz, CDCl3) δ
188.24, 143.68, 138.19, 134.83, 134.19, 132.27, 129.19, 128.43, 127.95. Pd/PCy3: 57% yield (10.7 mg).
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Acknowledgements. Rutgers University and the NSF (CAREER CHE-1650766) are gratefully
acknowledged for support. The 500 MHz spectrometer used in this study was supported by the NSF-
MRI grant (CHE-1229030). C.A.W. thanks Shandong Outstanding Youth Innovation Team Program
(No. 2019KJC032) for a fellowship.
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Supporting Information. Copies of NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Author Information. Corresponding author: michal.szostak@rutgers.edu
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(19) It is further interesting to note that Winkler-Dunitz parameters of 1g (N-(2-thienyol)-5,5-
dimthylhydantoin) determined by Zeng and co-workers8 are  = 49.1°, N = 11.1°, (+N) = 60.2° (cf.
1a,  = 49.5°, N = 13.3°, (+N) = 62.8°), indicating a minimal impact of relieving steric-strain by
removal of one of the ortho C–H bonds in a 2-substituted five-membered ring on amide bond twist.
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