Copper-Mediated N-Arylations of Hydantoins

Article abstract of DOI:10.1021/acs.joc.8b02284

A set of two broadly applicable procedures for the N-arylation of hydantoins is reported. The first one relies on the use of stoichiometric copper(I) oxide under ligand- A nd base-free conditions and enables a clean regioselective arylation at the N³ nitrogen atom, while the second one is based on the use of catalytic copper(I) iodide and trans-N,N′-dimethylcyclohexane-1,2-diamine and promotes arylation at the N¹ nitrogen atom. Importantly, the combination of these two procedures affords a straightforward entry to diarylated hydantoins.

Full text of DOI:10.1021/acs.joc.8b02284

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Note
Copper-Mediated N-Arylations of Hydantoins
Pierre Thilmany, Phidéline Gérard, Agathe Vanoost,
Christopher Deldaele, Laurent Petit, and Gwilherm Evano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02284 • Publication Date (Web): 09 Nov 2018
Downloaded from http://pubs.acs.org on November 9, 2018
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Copper-Mediated N-Arylations of Hydantoins
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Pierre Thilmany,a,‡ Phidéline Gérard,a,‡ Agathe Vanoost,b Christopher Deldaele,a
Laurent Petit,*,b and Gwilherm Evano,*,a
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a Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques,
Universitꢀ libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels,
Belgium
b Minakem Recherche, 145 Chemin des Lilas, 59310 Beuvry-La-Forêt, France
laurent.petit@minakem.com, gevano@ulb.ac.be
ABSTRACT. A set of two broadly applicable procedures for the N-arylation of hydantoins is
reported. The first one relies on the use of stoichiometric copper(I) oxide under ligandless and
base-free conditions and enables a clean regioselective arylation at the N3 nitrogen atom while
the second one is based on the use of catalytic copper(I) iodide and trans-N,N′-
dimethylcyclohexane-1,2-diamine and promotes arylation at the N1 nitrogen atom.
Importantly, the combination of these two procedures affords a straightforward entry to
diarylated hydantoins.
Since their discovery by Adolf von Baeyer in 1861,1 imidazolidine-2,4-diones, more
commonly known as hydantoins, have become a major scaffold with applications in many
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areas of science.2 Indeed, in addition to their occurrence in some natural products3 and to
their use in organic synthesis,4 coordination chemistry,5 polymer science,6 or for the design of
molecular switches,7 they had a deep impact in medicinal chemistry and agrochemistry.2 The
most famous and representative hydantoin drugs2 include Sanofi-Aventis’ anti-androgen
Nilutamide 1, Pfizer’s anticonvulsant Fosphenytoin 2 or Shionogi’s antibacterial Nitrofurantoin
3(Figure 1). Various clinical candidates based on the hydantoin skeleton have in addition been
recently reported, Bristol-Myers Squibb’s anti-psoriasis BMS-587101 4 or Galapagos’ anti-
cachexia GLGP-0492 5 being representative examples. Hydantoin derivatives such as
thiohydantoins have in addition also revealed to be important in healthcare, as highlighted
with Medivation/Astellas’ anticancer drug Enzalutamide 6.8
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Figure 1. Representative (thio)hydantoin drugs and clinical candidates.
During the past decade, the interest for hydantoins has not declined, which resulted in more
than 3.000 publications and patents. This has stimulated many efforts for the development of
synthetic routes to hydantoins: in addition to be efficient, reliable and short, they moreover
need to be highly modular in a diversity-oriented approach. Classical synthetic pathways to
hydantoins such as the Read,9 Bucherer-Bergs10 or Blitz11 reactions indeed all suffer from
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limitations and a variety of alternative processes have been reported over the years.2 However,
among all classes of hydantoins, N-arylated ones, that are of particular interest in medicinal
chemistry, are not trivial to access using classical methods, notably in terms of the starting
materials required. An interesting strategy that would, in addition to involve a limited number
of steps from readily available starting materials, be especially relevant for structural
diversification, would be based on direct N-arylations of the bare hydantoin scaffold. For some
reasons, this attractive approach to N-aryl-hydantoins has been mostly restricted to
nucleophilic aromatic substitutions and barely investigated:12-14 we report in this manuscript a
set of efficient procedures for the selective arylation of hydantoins at the two nitrogen atoms.
Copper-mediated N3-arylation of hydantoins. Indeed, based on our combined interests in
copper-catalysis15,16 and process chemistry,17 we became interested at developing general
processes for the arylation of hydantoins at the two nucleophilic nitrogen atoms. We initiated
our studies by carefully investigating the scope of the copper-mediated arylation at N3, a
reaction that is best performed under ligandless conditions in the presence of stoichiometric
copper(I) oxide,12b-d most certainly due to the starting hydantoins acting as supporting ligands
that can in addition result in the formation of catalytically inactive copper complexes in the
presence of catalytic amounts of copper(I) only. Results from these studies are shown in Figure
2.
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Figure 2. Scope of the copper-mediated N3-arylation of hydantoins.
As illustrated with results from Figure 2, the arylation at N3 was found to be rather general
since upon simple reaction with one equivalent of copper(I) oxide and aryl iodides 7 in DMF at
150 °C for 14 h without an additional base, a range of hydantoins 8 could be readily and
selectively arylated at N3, providing the corresponding N3-aryl-hydantoins 9a-n that could be
isolated in good to excellent yields. The reaction was found to proceed smoothly with a range
of aryl iodides, regardless of their electronic properties and a variety of hydantoins could be
arylated under these conditions. The substitution pattern of the starting hydantoin was
however found to have a significant impact on the selectivity of the reaction starting from
hydantoins unsubstituted at N1. Indeed, while 5,5-disubstituted hydantoins were selectivity
arylated at N3 in all cases, removing one of these substituents led to significant competing
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arylation at N1, as demonstrated with the isolation of 9m and 9m’ in a ca. 2:1 ratio, and the
absence of substituents at this position favored the N1 arylation, N1-phenyl-hydantoin 9n being
now obtained with significant amounts of diarylated product 9n”. Gratifyingly, the reaction
could be successfully extended to the use of aryl bromides, as demonstrated with the arylation
to 9o-r isolated in fair to good yields.
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Copper-catalyzed N1-arylation of hydantoins. After briefly studying the scope of the
arylation at N3, we then moved to the more challenging N1-arylation. To make sure aryl
bromides could be used in this transformation, the optimization was performed using 1.2
equiv of aryl bromide 10 and sterically hindered hydantoin 9f, the resulting N1-arylated
product 11a being an oxygenated analogue of Enzalutamide 6. These model substrates were
therefore reacted with 20 mol % of copper(I) iodide, 40 mol % of various ligands in the
presence of 2 equiv of potassium carbonate in toluene at 110 °C for 64 h: results from these
studies are shown in Figure 3. Most ligands commonly used in copper-catalyzed cross-coupling
reactions including 2,2,6,6-tetramethyl-3,5-heptanedione L1, proline L2, 1,2-dimethylimidazole
L3, 2,2’-bipyridine L4, and 1,10-phenanthroline L5 failed to promote the arylation, most
certainly because of catalyst deactivation due to multiple coordination of the starting
hydantoin, as suggested by its non-total recovery. Excepted for TMEDA, diamine ligands turned
out to be more efficient, trans-N,N′-dimethylcyclohexane-1,2-diamine (Me2CyDA) being by far
the most efficient and promoting the coupling to 11a in 61% yield, a yield that could be further
improved to 70% by using 1.4 equivalents of aryl bromide 10. As for the reaction time, it could
be reduced to 48 h without affecting the yield. Further evaluation of different copper sources
(CuBr, CuCl, CuTC, CuOAc, Cu(CH3CN)4PF6), bases (K3PO4, Cs2CO3), solvents (dioxane,
acetonitrile, DMF, DMSO) and additives (NaI) did not allow a significant further improvement.
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Figure 3. Effect of the ligand on the copper-catalyzed N1-arylation of hydantoins.
Having these optimized conditions in hand, we next turned our attention to the study of
the scope and limitations of the N1-arylation using representative hydantoins 12 and aryl
halides 7 (Figure 4). Gratifyingly, the reaction scope was found to be especially broad, the
arylation proceeding smoothly with eletron-rich (11b-d) and electron-poor (11e-g) aryl
bromides. It could be extended to the introduction of heteroaryl substituents such as a
thiophene (11j), a pyridine (11k) or a benzofuran (11l), the main limitation being the absence
of reactivity starting with ortho-substituted aryl bromides (11i). Not surprisingly, aryl iodides
performed equally well and similar trends were observed with these reagents. The nature of
the substituent(s) at C5 on the starting hydantoin was found to have little effect on the
reaction outcome, as demonstrated with the arylation to 11s-v which all proceeded smoothly.
The arylation to 11t is in addition quite remarkable due to the high steric hindrance close to
the reacting center that still did not inhibit the arylation. Finally, it should be noted that various
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functional groups such as an ether (11d,p), an ester (11e,v), a ketone (11f) or a nitro (11r)
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were shown to be compatible with the reaction conditions.
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Figure 4. Scope of the copper-catalyzed N1-arylation of hydantoins.
Interestingly, the N3-aryl-hydantoins 9 resulting from the first arylation were also shown to
be excellent substrates for the copper-catalyzed N1-arylation, as highlighted in Figure 5. Our
two procedures therefore enable clean, selective and efficient iterative arylations to N1,N3-
diaryl-hydantoins 11a,w-ad, attractive scaffolds in medicinal chemistry, and facilitate
diversification by a simple modulation of the two aryl groups introduced.
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Figure 5. Iterative arylations to N1,N3-diaryl-hydantoins.
Copper-mediated iterative arylations of hydantoins on multigram scales. In a final effort
to demonstrate the synthetic potential of our procedures, a scale up of the iterative arylations
was finally explored. As highlighted in Scheme 1, this turned out to be especially efficient, the
first copper-mediated ligandless and base-free arylation of 8a with 13 providing the desired
N3-arylated product 9f in 93% on a 84 g scale, using simple purification by precipitation and
successive washes with DMF, aqueous ammonia and water. The second arylation at N1 was
undertaken on a 50 g scale using iodobenzene 14 as the arylating agent and gave, after
treatment with a mixture of silica and Carcel®, filtration, reslurry in a mixture of toluene and
heptane and filtration, the desired doubly arylated hydantoin 11aa with 82% yield, therefore
demonstrating the robustness of the sequence.
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Scheme 1. Multigram scale iterative arylations.
C4-selective thionation of Diarylhydantoins. We finally turned our attention to the
extension of these procedures to the arylations of thiohydantoins: despite extensive trials, we
could not find conditions enabling these arylations, which might be due to competing
complexation of copper by these substrates which are excellent ligands for copper. Considering
in addition that thiohydantoins are known to coordinate to copper by the sulfur atom,18 their
arylation might proceed at sulfur rather than nitrogen. To circumvent this problem, the
regioselective thionation of N1,N3-diphenylhydantoin 11m with various reagents was
examined: of all reagents evaluated, phosphorus pentasulfide P2S5 was found the most
efficient and enabled a clean and C4-selective thionation to 15 (Scheme 2).19
Scheme 2. C4-selective thionation of a N1,N3-diarylhydantoin.
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Conclusions
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In conclusion, we have developed and studied a set of two efficient and broadly applicable
procedures for the N-arylation of hydantoins at the two nitrogen atoms. The first one relies
on the use of stoichiometric amounts of copper(I) oxide under ligandless and base-free
conditions and enables a clean and regioselective arylation at the N3 nitrogen atom while the
second one is based on the use of catalytic amounts of copper(I) iodide and trans-N,N′-
dimethylcyclohexane-1,2-diamine and promotes arylation at the N1 nitrogen atom. The scope
of these two procedures have been shown to be quite broad and they are both tolerant to a
range of functional groups. Moreover, they rely on simple copper salts and ligands and their
robustness on multigram scale has been demonstrated. Importantly, the combination of these
two procedures affords a straightforward and general entry to diarylated hydantoins,
important scaffolds in medicinal chemistry.
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Experimental Section
General Information. All reactions were carried out in oven-dried glassware under an argon
atmosphere employing standard techniques in handling air-sensitive materials unless
otherwise stated.
All reagents and solvents were reagent grade. N,N-dimethylformamide (99.8%, Extra Dry
over Molecular Sieve, AcroSeal®) and toluene (99.5%, Extra Dry over Molecular Sieve,
AcroSeal®) were purchased from ACROS Organics and used as supplied.
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Copper(I) iodide (99,999% purity) was purchased from Aldrich and used as supplied. Finely
powdered anhydrous cesium carbonate was used for copper-mediated coupling reactions. All
other reagents were used as supplied.
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Reactions were magnetically stirred and monitored by thin layer chromatography using
Merck-Kiesegel 60F254 plates. Flash chromatography was performed with silica gel 60 (particle
size 35-70 m) supplied by Merck. Yields refer to chromatographically and spectroscopically
pure compounds unless otherwise stated.
Proton NMR spectra were recorded using an internal deuterium lock at ambient
temperature on Bruker 300 or Jeol 400 and 600 MHz spectrometers. Internal reference of
δH 7.26 was used for CDCl3, δH 2.05 was used for acetone-d6 and δH 2.50 was used for DMSO-d6.
Data are presented as follows: chemical shift (in ppm on the δ scale relative to δTMS = 0),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sext. = sextuplet, m = multiplet,
br. = broad, app. = apparent), coupling constant (J/Hz) and integration. Carbon-13 NMR spectra
were recorded at 100 or 150 MHz using CDCl3 (δC 77.16), acetone-d6 (δC 29.84) or
DMSO-d6 (δC 39.52) as internal reference. Fluorine-19 NMR spectra were recorded at 376 MHz
using CF3CH2OH (δF -77.59) as internal reference.
Melting points were recorded on a Stuart Scientific Analogue SMP11. Infrared spectra were
recorded on a Bruker Alpha (ATR). High-resolution mass-spectra were recorded using a Agilent
QTOF 6520 spectrometer.
N3-Arylation of Hydantoins
General Procedure. A 15 mL pressure tube was charged with the hydantoin (3.0 mmol) and
copper oxide (I) (286 mg, 2.0 mmol); the aryl halide (2.0 mmol) was added at this stage if solid.
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The tube was fitted with a rubber septum, evacuated under high vacuum and backfilled with
argon (three times) before adding the aryl halide (added at this stage if liquid) (2.0 mmol) and
anhydrous DMF (5mL). The rubber septum was then replaced by a Teflon-coated screw cap
before heating the heterogeneous reaction mixture at 150 °C for 14 hours. The suspension
was cooled to room temperature, filtered through a pad of Celite® (washed with EtOAc) and
the filtrate was concentrated to ca. one tenth of its volume under reduced pressure, poured
into a mixture of ice and water (10 mL) and stirred for 30 minutes before adding a 28%
aqueous ammonia solution (3 mL). The resulting suspension was stirred for 30 minutes and
the precipitate collected by filtration then dried under high vacuum to give the desired
arylated hydantoin which was, whenever required, further purified by flash column
chromatography over silica gel.
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5,5-Dimethyl-3-phenylhydantoin 9a. Yield: 69% (280 mg, 1.37 mmol). White solid. Solvent
system for flash column chromatography: petroleum ether/EtOAc: 60/40. This compound has
been previously reported.20
3-(1,1'-Biphenyl-4-yl)-5,5-dimethylhydantoin 9b. Yield: 87% (404 mg, 1.44 mmol). White
solid, Mp: 185 °C; 1H NMR (600 MHz, acetone-d6): δ 7.74 (d, J = 8.6 Hz, 2H), 7.72-7.68 (m, 2H),
7.55 (d, J = 8.6 Hz, 2H), 7.53-7.43 (m, 3H), 7.38 (t, J = 7.4 Hz, 1H), 1.52 (s, 6H); 13C{1H} NMR
(150 MHz, acetone-d6): δ 177.1, 155.2, 141.1, 141.0, 133.0, 129.8, 128.4, 127.8, 127.8, 127.6,
58.9, 25.4; IR (neat): νmax 1713, 1428, 1303, 1144, 837, 768 cm-1; ESIHRMS m/z calcd for
C17H17N2O2 [M+H]+ 281.1285, found 281.1290.
5,5-Dimethyl-3-(3-methoxyphenyl)-hydantoin 9c. Yield: 73% (344 mg, 1.47 mmol). Solvent
system for flash column chromatography: cyclohexane/EtOAc: 60/40; Beige solid, Mp: 106 °C;
1H NMR (400 MHz, CDCl3): δ 7.36 (app. t, J = 8.2 Hz, 1H), 7.12-7.01 (m, 1H), 6.99 (d, J = 7.9 Hz,
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1H), 6.96-6.90 (m, 2H), 3.81 (br. s, 3H), 1.49 (br. s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.4,
160.1, 155.8, 132.7, 129.8, 118.6, 114.2, 112.1, 58.7, 55.5, 25.1; IR (neat): νmax 2976, 1716,
1418, 1151, 1043, 782, 702 cm-1; ESIHRMS m/z calcd for C12H15N2O3 [M+H]+ 235.1077, found
235.1080.
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5,5-Dimethyl-3-(4-trifluoromethylphenyl)hydantoin 9d. Yield: 88% (479 mg, 1.76 mmol). Off
white solid, Mp: 179 °C; 1H NMR (300 MHz, acetone-d6): δ 7.79 (dd, J = 21.3 and 8.6 Hz, 4H),
7.59 (br. s, 1H), 1.52 (s, 6H); 13C{1H} NMR (100 MHz, acetone-d6): δ 176.8, 154.6, 137.4,
129.4 (q, JC-F = 32.5 Hz), 127.3, 126.4 (q, JC-F = 3.9 Hz), 123.8, 59.0, 25.3; 19F NMR (376 MHz,
CDCl3): δ -58.4 (s); IR (neat): νmax 2361, 1732, 1719, 1410, 1324, 1172, 1110, 1066, 836,
709 cm-1; ESIHRMS m/z calcd for C12H12F3N2O2 [M+H]+ 273.0845, found 273.0849.
5,5-Dimethyl-3-(4-nitrophenyl)hydantoin 9e. Yield: 80% (397 mg, 1.59 mmol). Beige solid,
Mp: 168 °C; 1H NMR (400 MHz, acetone-d6): δ 8.35 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 9.2 Hz, 2H),
7.68 (br. s, 1H), 1.54 (s, 6H); 13C{1H} NMR (100 MHz, acetone-d6): δ 176.7, 154.3, 147.0, 139.6,
127.1, 124.6, 59.0, 25.3; IR (neat): νmax 2360, 1721, 1522, 1401, 1342, 1135, 841, 726 cm-1;
ESIHRMS m/z calcd for C11H11N3O4 [M+H]+ 250.0822, found 250.0829.
5,5-Dimethyl-3-(3-trifluoromethyl-4-cyano-phenyl)hydantoin 9f. Yield: 82% (6.8 g,
22.9 mmol). White solid. Solvent system for flash column chromatography:
cyclohexane/EtOAc: 90/10. This compound has been previously reported.21
1-Methyl-3-phenylhydantoin 9g. Yield: 54% (207 mg, 1.09 mmol). Off white solid. Solvent
system for flash column chromatography: petroleum ether/EtOAc: 50/50. This compound has
been previously reported.22
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1-Butyl-3-phenylhydantoin 9h. Yield: 58% (270 mg, 1.16 mmol). Solvent system for flash
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column chromatography: petroleum ether/EtOAc: 70/30; Pale yellow oil; H NMR (400 MHz,
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CDCl3): δ 7.49-7.33 (m, 5H), 4.02 (s, 2H), 3.48 (t, J = 7.3 Hz, 2H), 1.69-1.53 (m, 2H), 1.40 (sext.,
J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.1, 155.6, 132.0,
129.2, 128.2, 126.2, 49.7, 42.8, 29.9, 20.0, 13.8; IR (neat): νmax 2960, 1713, 1503, 1456, 1420,
1244, 1193, 1136, 760, 692 cm-1; ESIHRMS m/z calcd for C13H16N2O2Na [M+Na]+ 255.1104,
found 255.1109.
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1-Benzyl-3-phenylhydantoin 9i. Yield: 56% (297 mg, 1.11 mmol). Pale yellow solid. Solvent
system for flash column chromatography: petroleum ether/EtOAc: 70/30. This compound has
been previously reported.23
5-Ethyl-5-methyl-3-phenylhydantoin 9j. Yield: 68% (298 mg, 1.36 mmol). Solvent system for
flash column chromatography: petroleum ether/EtOAc: 70/30; White solid, Mp: 114 °C;
1H NMR (400 MHz, CDCl3): δ 7.50-7.44 (m, 2H), 7.42-7.34 (m, 3H), 6.97 (br. s, 1H), 1.93 (A of
ABX3 syst., J = 14.7 and 7.4 Hz, 1H), 1.71 (B of ABX3 syst., J = 14.7 and 7.4 Hz, 1H), 1.47 (s, 3H),
0.94 (X of ABX3 syst., J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.1, 156.4, 131.7,
129.2, 128.3, 126.3, 62.4, 31.2, 23.7, 7.9; IR (neat): νmax 2934, 2368, 1714, 1504, 1412, 1134,
846, 709 cm-1; ESIHRMS m/z calcd for C12H15N2O2 [M+H]+ 219.1128, found 219.1143.
3,5-Diphenyl-5-methylhydantoin 9k. Yield: 89% (1.6 g, 5.86 mmol). White solid. This
compound has been previously reported.24
3,5,5-Triphenylhydantoin 9l. Yield: 98% (642 mg, 1.95 mmol). White solid. This compound has
been previously reported.25
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5-Methyl-3-phenylhydantoin 9m. Yield: 24% (92 mg, 483 μmol). White solid. Solvent system
for flash column chromatography: petroleum ether/EtOAc: 60/40. This compound has been
previously reported.26
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5-Methyl-1-phenylhydantoin 9m’. Yield: 14% (53 mg, 279 μmol). White solid. Solvent system
for flash column chromatography: petroleum ether/EtOAc: 60/40. This compound has been
previously reported.27
1-Phenylhydantoin 9n. Yield: 31% (110 mg, 625 μmol). White solid. Solvent system for flash
column chromatography: petroleum ether/EtOAc: 60/40. This compound has been previously
reported.28
1,3-Diphenylhydantoin 9n’’. Yield: 21% (52 mg, 206 μmol). Off white solid. Solvent system for
flash column chromatography: petroleum ether/EtOAc: 60/40. This compound has been
previously reported.29
3-(4-tert-Butylphenyl)-5,5-dimethylhydantoin 9o. Yield: 79% (412 mg, 1.58 mmol). White
solid, Mp: 177 °C; 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H),
6.09 (br. s, 1H), 1.54 (s, 6H), 1.33 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.4, 155.7, 151.4,
129.0, 126.2 (br.), 125.8 (br.), 58.7, 34.8, 31.5 (br.), 25.4 (br.); IR (neat): νmax 2970, 1715, 1520,
1422, 1145, 831 cm-1; ESIHRMS m/z calcd for C15H21N2O2 [M+H]+ 261.1598, found 261.1594.
5,5-Dimethyl-3-(naphthalen-2-yl)hydantoin 9p. Yield: 91% (461 mg, 1.81 mmol). White solid,
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Mp: 212 °C; H NMR (400 MHz, CDCl3): δ 7.96-7.92 (m, 2H), 7.90-7.85 (m, 2H), 7.55-7.49
(m, 3H), 6.26 (br. s, 1H), 1.57 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.4, 155.7, 133.3,
132.8, 129.1 (2C), 128.3, 127.9, 126.9, 126.7, 125.3, 123.9, 58.9, 25.5; IR (neat): νmax 1722,
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1426, 1151, 811, 749 cm-1; ESIHRMS m/z calcd for C15H15N2O2 [M+H]+ 255.1128, found
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255.1138.
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5,5-Dimethyl-3-(4-trifluoromethoxyphenyl)hydantoin 9q. Yield: 75% (431 mg, 1.50 mmol).
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Off white solid, Mp: 146 °C; H NMR (600 MHz, acetone-d6): δ 7.62 (d, J = 9.0 Hz, 2H), 7.52
(br. s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 1.51 (s, 6H); C{1H} NMR (100 MHz, acetone-d6): δ 176.9,
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154.9, 148.5, 132.7, 128.8, 122.1, 121.4 (q, JC-F = 255.5 Hz), 59.0, 25.3; 19F NMR (376 MHz,
CDCl3): δ -63.2 (s); IR (neat): νmax 2937, 2361, 1719, 1513, 1407, 1255, 1186, 1135, 839 cm-1;
ESIHRMS m/z calcd for C12H12F3N2O3 [M+H]+ 289.0795, found 289.0799.
5,5-Dimethyl-3-(4-methoxycarbonylphenyl)hydantoin 9r. This compound was prepared
according to the general procedure with an additional extraction (EtOAc) of the filtrate. Yield:
51% (267 mg, 1.02 mmol). Solvent system for flash column chromatography:
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cyclohexane/EtOAc: 60/40; White solid, Mp: 141 °C; H NMR (300 MHz, acetone-d6): δ 8.09
(d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.56 (br. s, 1H), 3.90 (s, 3H), 1.52 (s, 6H); 13C{1H} NMR
(100 MHz, acetone-d6): δ 176.8, 166.6, 154.7, 137.9, 130.4, 129.7, 126.7, 58.9, 52.5, 25.3;
IR (neat): νmax 1729, 1715, 1412, 1276, 1143, 773, 726, 697 cm-1; ESIHRMS m/z calcd for
C13H15N2O4 [M+H]+ 263.1026, found 263.1030.
N1-Arylation of Hydantoins
General Procedure. A 15 mL pressure tube was charged with the arylated hydantoin (1.0
mmol), copper iodide (38 mg, 0.2 mmol) and potassium carbonate (276 mg, 2.0 mmol); the
aryl halide (1.4 mmol) was added at this stage if solid. The tube was fitted with a rubber
septum, evacuated under high vacuum and backfilled with argon (three times) before adding
the aryl halide (added at this stage if liquid) (1.4 mmol), anhydrous toluene (1.5 mL) and
trans-N,N’-dimethylcyclohexane-1,2-diamine (0.4 mmol). The rubber septum was then
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replaced by a Teflon-coated screw cap before heating the reaction mixture at 110 °C for
48 hours. The suspension was cooled to room temperature, filtered over a plug of silica
gel/Celite® (washed with EtOAc) and concentrated. The crude residue was finally purified by
flash chromatography over silica gel.
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5,5-Dimethyl-1-(4-methylcarbamoylphenyl)-3-(3-trifluoromethyl-4-cyano-
phenyl)hydantoin 11a. Yield: 70% (2.9 g, 6.38 mmol). White solid. Solvent system for flash
column chromatography: cyclohexane/EtOAc: 50/50. This compound has been previously
reported.30
1-(4-tert-Butylphenyl)-5,5-dimethyl-3-phenylhydantoin 11b. Yield: 75% (251 mg, 746 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 90/10; Off white solid,
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Mp: 141 °C; H NMR (600 MHz, CDCl3): δ 7.53-7.49 (m, 2H), 7.49-7.45 (m, 4H), 7.39-7.35
(app. tt, J = 7.3 and 1.4 Hz, 1H), 7.25-7.22 (d, J = 8.6 Hz, 2H), 1.55 (s, 6H), 1.35 (s, 9H); 13C{1H}
NMR (150 MHz, CDCl3): δ 175.4, 154.1, 151.7, 132.0, 131.2, 129.1, 128.6, 128.1, 126.6, 126.2,
63.5, 34.8, 31.4, 24.2; IR (neat): νmax 2968, 1715, 1396, 1204, 1138, 766 cm-1; ESIHRMS m/z
calcd for C21H25N2O2 [M+H]+ 337.1911, found 337.1913.
5,5-Dimethyl-1-(naphthalen-2-yl)-3-phenylhydantoin 11c. Yield: 91% (300 mg, 908 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 80/20; Beige solid,
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Mp: 163 °C; H NMR (600 MHz, CDCl3): δ 7.95 (d, J = 8.7 Hz, 1 H), 7.92-7.85 (m, 2H), 7.84
(d, J = 2.0 Hz, 1H), 7.58-7.54 (m, 4H), 7.52-7.48 (m, 2H), 7.43 (dd, J = 8.7 and 2.1 Hz, 1H), 7.39
(tt, J = 7.4 and 1.3 Hz, 1H), 1.62 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3): δ 175.3, 154.2, 133.6,
133.0, 131.9, 131.6, 129.6, 129.1, 128.2, 128.1, 127.9, 127.9, 127.0, 126.9, 126.6, 126.3, 63.8,
24.4; IR (neat): νmax 2981, 1716, 1504, 1401, 1201, 1143, 779 cm-1; ESIHRMS m/z calcd for
C21H19N2O2 [M+H]+ 331.1441, found 331.1440.
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5,5-Dimethyl-3-phenyl-1-(4-trifluoromethoxyphenyl)hydantoin 11d. Yield: 96% (349 mg,
958 μmol). Solvent system for flash column chromatography: cyclohexane/EtOAc: 95/5; Pale
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yellow solid, Mp: 96 °C; H NMR (400 MHz, CDCl3): δ 7.53-7.44 (m, 4H), 7.40-7.34 (m, 3H),
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7.32-7.27 (m, 2H), 1.53 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.8, 153.8, 148.8, 132.6,
131.7, 130.3, 129.0, 128.2, 126.1, 121.9, 120.4 (q, J = 258.0 Hz), 63.5, 24.0; 19F NMR (376 MHz,
CDCl3): δ -58.3 (s); IR (neat): νmax 1715, 1506, 1411, 1266, 1200, 1156, 770 cm-1; ESIHRMS m/z
calcd for C18H16F3N2O3 [M+H]+ 365.1108, found 365.1109.
5,5-Dimethyl-1-(4-methoxycarbonylphenyl)-3-phenylhydantoin 11e. Yield: 68% (231 mg,
682 μmol). Solvent system for flash column chromatography: cyclohexane/EtOAc: 80/20;
White solid, Mp: 101 °C; 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 8.6 Hz, 2H), 7.50-7.43 (m, 6H),
7.42-7.35 (m, 1H), 3.93 (s, 3H), 1.59 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.8, 166.3,
153.8, 138.9, 131.6, 130.9, 129.7, 129.1, 128.4, 127.8, 136.2, 63.9, 52.4, 24.4; IR (neat):
νmax 2977, 1708, 1414, 1276, 1201, 1112, 769 cm-1; ESIHRMS m/z calcd for C19H19N2O4 [M+H]+
339.1339, found 339.1341.
1-(4-Acetylphenyl)-5,5-dimethyl-3-phenylhydantoin 11f. Yield: 95% (305 mg, 947 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 70/30; Yellow solid,
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Mp: 138 °C; H NMR (400 MHz, CDCl3): δ 8.06-8.01 (d, J = 8.4 Hz, 2H), 7.51-7.44 (m, 6H),
7.41-7.35 (m, 1H), 2.61 (s, 3H), 1.60 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 197.0, 174.8,
153.7, 139.0, 136.4, 131.6, 129.6, 129.1, 128.4, 127.8, 126.2, 63.9, 26.7, 24.4; IR (neat): νmax
2969, 1710, 1675, 1405, 1363, 1202, 766 cm-1; ESIHRMS m/z calcd for C19H19N2O3 [M+H]+
323.1390, found 323.1399.
1-(3,5-Difluorophenyl)-5,5-dimethyl-3-phenylhydantoin 11g. Yield: 84% (267 mg, 847 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 95/5; Beige solid, Mp:
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122 °C; 1H NMR (400 MHz, CDCl3): δ 7.51-7.45 (m, 4H), 7.43-7.36 (m, 1H), 6.96 (app. dd, J = 7.7
and 2.2 Hz, 2H), 6.86 (app. tt, J = 8.8 and 2.3 Hz, 1H), 1.59 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 174.5, 163.3 (d, J = 249.6 Hz), 163.2 (d, J = 249.5 Hz), 153.6,
136.9 (app. t, J = 12.4 Hz), 131.5, 129.2, 128.5, 126.2, 111.4 (d, J = 27.1 Hz), 111.4 (d, J = 11.7
Hz), 104.0 (app. t, J = 25.2 Hz), 63.9, 24.2; 19F NMR (376 MHz, CDCl3): δ -106.1 (t, JC-F = 8.1 Hz);
IR (neat): νmax 1717, 1412, 1304, 1120, 990, 859, 731 cm-1; ESIHRMS m/z calcd for
C17H15F2N2O2 [M+H]+ 317.1096, found 317.1107.
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5,5-Dimethyl-1-(4-cyano-phenyl)-3-phenylhydantoin 11h. Yield: 83% (124 mg, 407 μmol).
Solvent system for flash column chromatography: petroleum ether/EtOAc: 75/25; White solid,
Mp: 169 °C; 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.52-
7.45 (m, 4H), 7.43-7.38 (m, 1H), 1.63 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.5, 153.7,
139.2, 133.6, 131.4, 129.3, 128.6, 127.9, 126.2, 118.1, 111.7, 64.1, 24.6; IR (neat): νmax 2225,
1780, 1722, 1503, 1406, 1350, 1198, 838, 742 cm-1; ESIHRMS m/z calcd for C18H15N3O2Na
[M+Na]+ 328.1056, found 328.1056.
5,5-Dimethyl-3-phenyl-1-(thiophen-2-yl)hydantoin 11j. Yield: 96% (274 mg, 956 μmol).
Solvent system for flash column chromatographyz: cyclohexane/EtOAc: 80/20; Beige solid,
Mp: 99 °C; 1H NMR (400 MHz, CDCl3): δ 7.53-7.44 (m, 4H), 7.41-7.35 (m, 2H), 7.34-7.30 (m, 1H),
7.20-7.15 (m, 1H), 1.60 (br. s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.0, 153.4, 132.3, 131.7,
129.1, 128.2, 126.2, 125.7, 125.4, 119.6, 63.3, 23.9; IR (neat): νmax 1711, 1412, 1338, 1200,
736, 690 cm-1; ESIHRMS m/z calcd for C15H15N2O2S [M+H]+ 287.0849, found 287.0860.
5,5-Dimethyl-3-phenyl-1-(pyridin-2-yl)hydantoin 11k. Yield: 89% (250 mg, 887 μmol). Solvent
system for flash column chromatography: cyclohexane/EtOAc: 90/10; White solid, Mp: 101 °C;
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1H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 4.9 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.71 (t, J = 8.0 Hz,
1H), 7.53-7.45 (m, 4H), 7.43-7.38 (m, 1H), 7.10-7.05 (m, 1H), 1.93 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 175.5, 153.2, 150.7, 147.4, 138.0, 131.5, 129.2, 128.5, 126.5,
119.9, 116.2, 64.6, 23.9; IR (neat): νmax 1716, 1407, 1360, 1200, 1154, 884, 767 cm-1; ESIHRMS
m/z calcd for C16H16N3O2 [M+H]+ 282.1237, found 282.1249.
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1-(Benzofuran-2-yl)-5,5-dimethyl-3-phenylhydantoin 11l. Yield: 68% (219 mg, 684 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 95/5; Off white solid,
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Mp: 99 °C; H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 7.2 Hz, 1H), 7.55-7.47 (m, 5H),
7.47-7.39 (m, 1H), 7.35-7.25 (m, 2H), 6.83 (s, 1H), 1.80 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 174.4, 152.0, 151.6, 145.0, 131.3, 129.2, 128.6, 128.2, 126.3, 124.1, 123.5, 121.0,
111.0, 97.8, 64.0, 24.0; IR (neat): νmax 2360, 1717, 1604, 1405, 1385, 1240, 1151, 740 cm-1;
ESIHRMS m/z calcd for C19H16N2O3Na [M+Na]+ 343.1053, found 343.1072.
5,5-Dimethyl-1,3-diphenylhydantoin 11m. Yield: 96% (1.3 g, 4.67 mmol). White solid. Solvent
system for flash column chromatography: cyclohexane/EtOAc: 85/15. This compound has
been previously reported.31
1-(1,1'-Biphenyl-4-yl)-5,5-dimethyl-3-phenylhydantoin 11n. Yield: 94% (333 mg, 935 μmol).
White solid. Solvent system for flash column chromatography: cyclohexane/EtOAc: 90/10.
This compound has been previously reported.14a
5,5-Dimethyl-1-(3-methoxyphenyl)-3-phenylhydantoin 11p. Yield: 94% (292 mg, 941 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 85/15; White solid,
Mp: 95 °C; 1H NMR (400 MHz, CDCl3): δ 7.54-7.44 (m, 4H), 7.40-7.33 (t, J = 8.2 Hz 2H), 6.98-6.89
(m, 2H), 6.87 (t, J = 2.2 Hz, 1H), 3.82 (s, 3H), 1.56 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
175.2, 160.5, 159.9, 135.2, 131.9, 130.2, 129.1, 128.2, 126.2, 121.0, 114.9, 114.2, 63.6, 55.6,
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[M+H]+ 311.1390, found 311.1404.
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5,5-Dimethyl-3-phenyl-1-(4-trifluoromethylphenyl)hydantoin 11q. Yield: 96% (336 mg,
964 μmol). Solvent system for flash column chromatography: cyclohexane/EtOAc: 90/10;
Yellow solid, Mp: 100 °C; 1H NMR (400 MHz, CDCl3): δ 7.75-7.70 (d, J = 8.1 Hz, 2H), 7.54-7.45
(m, 6H), 7.42-7.35 (m, 1H), 1.59 (br. s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.7, 153.8,
137.9, 131.6, 130.1 (q, J = 32.8 Hz), 129.1, 128.4, 128.3, 126.7 (q, J = 3.6 Hz), 126.1, 123.8 (q, J
= 272.4 Hz), 63.8, 24.2; 19F NMR (376 MHz, CDCl3): δ -63.1 (s); IR (neat): νmax 1715, 1414, 1322,
1122, 1067, 753 cm-1; ESIHRMS m/z calcd for C18H16F3N2O2 [M+H]+ 349.1158, found 349.1167.
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5,5-Dimethyl-1-(4-nitrophenyl)-3-phenylhydantoin 11r. Yield: 65% (213 mg, 654 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 70/30; Yellow solid,
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Mp: 131 °C; H NMR (400 MHz, CDCl3): δ 8.30-8.23 (m, 2H), 7.62-7.57 (m, 2H), 7.50-7.44
(m, 4H), 7.42-7.35 (m, 1H), 1.63 (br. s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.3, 153.5,
146.3, 140.9, 131.3, 129.1, 128.5, 127.3, 126.1, 124.8, 64.0, 24.3; IR (neat): νmax 1716, 1515,
1407, 1334, 1198, 769, 751 cm-1; ESIHRMS m/z calcd for C17H16N3O4 [M+H]+ 326.1135, found
326.1133.
5-Ethyl-5-methyl-1,3-diphenylhydantoin 11s. Yield: 73% (107 mg, 365 μmol). Solvent system
for flash column chromatography: cyclohexane/EtOAc: 90/10; White solid, Mp: 129 °C;
1H NMR (400 MHz, CDCl3): δ 7.51-7.43 (m, 6H), 7.42-7.33 (m, 4H), 2.02 (A of ABX3 syst.,
J = 14.6 and 7.4 Hz, 1H), 1.76 (B of ABX3 syst., J = 14.6 and 7.4 Hz, 1H), 1.55 (s, 3H),
1.05 (X of ABX3 syst., J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.6, 154.7, 134.4,
131.8, 129.6, 129.1, 128.3, 128.2 (2C), 126.3, 67.6, 29.9, 23.7, 8.2; IR (neat): νmax 2934, 1712,
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1494, 1412, 1374, 1190, 762, 693 cm-1; ESIHRMS m/z calcd for C18H18N2O2Na [M+Na]+
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317.1260, found 317.1275.
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1,3,5,5-Tetraphenylhydantoin 11t. Yield: 66% (265 mg, 655 μmol). White solid. Solvent
system for flash column chromatography: cyclohexane/EtOAc: 80/20. This compound has
been previously reported.32
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1,3-Diphenyl-5-methylhydantoin 11u. Yield: 91% (63 mg, 237 μmol). Off white Solid. Solvent
system for flash column chromatography: cyclohexane/EtOAc: 85/15. This compound has
been previously reported.14c
3-(2-Ethoxy-2-oxoethyl)-1-phenylhydantoin 11v. Yield: 65% (456 mg, 1.74 mmol). Solvent
system for flash column chromatography: petroleum ether/EtOAc: 80/20; Pale yellow solid,
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Mp: 155 °C; H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.5 Hz, 2H), 7.40 (t, J = 8.5 Hz, 2H),
7.18 (t, J = 7.5 Hz, 1H), 4.40 (s, 2H), 4.35 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 168.0, 166.9, 153.5, 137.5, 129.5, 124.8, 118.6, 62.2, 50.2,
39.9, 14.3; IR (neat): νmax 2982, 1710, 1445, 1383, 1216, 1017, 747 cm-1; ESIHRMS m/z calcd
for C13H14N2O4Na [M+Na]+ 285.0846, found 285.0855.
3-(1,1'-Biphenyl-4-yl)-5,5-dimethyl-1-phenylhydantoin 11w. Yield: 78% (279 mg, 782 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 85/15; White solid,
Mp: 115 °C; 1H NMR (400 MHz, CDCl3): δ 7.73-7.68 (m, 2H), 7.64-7.59 (m, 4H),
7.52-7.41 (m, 5H), 7.40-7.33 (m, 3H), 1.58 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.3,
154.0, 141.2, 140.4, 134.2, 131.0, 129.7, 129.1, 128.9, 128.7, 127.8, 127.7, 127.3, 126.4, 63.6,
24.3; IR (neat): νmax 1715, 1488, 1407, 1379, 1200, 1151, 765, 695 cm-1; ESIHRMS m/z calcd for
C23H21N2O2 [M+H]+ 357.1598, found 357.1610.
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5,5-Dimethyl-3-(3-methoxyphenyl)-1-phenylhydantoin 11x. Yield: 97% (193 mg, 622 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 70/30; White solid,
Mp: 58 °C; 1H NMR (400 MHz, CDCl3): δ 7.49-7.43 (m, 2H), 7.43-7.36 (m, 2H), 7.35-7.31 (m, 2H),
7.13-7.09 (m, 1H), 7.08 (t, J = 2.2 Hz, 1H), 6.92 (ddd, J = 8.4, 2.5 and 0.7 Hz, 1H), 3.81 (s, 3H),
1.54 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.1, 159.9, 153.8, 134.0, 132.8, 129.6, 129.5,
129.0, 128.5, 118.3, 114.3, 111.7, 63.4, 55.4, 24.0; IR (neat): νmax 2935, 1721, 1495, 1401, 1200,
773 cm-1; ESIHRMS m/z calcd for C18H19N2O3 [M+H]+ 311.1390, found 311.1404.
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5,5-Dimethyl-3-(4-nitrophenyl)-1-phenylhydantoin 11y. Yield: 49% (158 mg, 487 μmol).
Solvent system for flash column chromatography: cyclohexane/EtOAc: 80/20; Pale yellow
solid, Mp: 213 °C; 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 9.2 Hz, 2H), 7.85 (d, J = 9.2 Hz, 2H),
7.53-7.43 (m, 3H), 7.34-7.30 (m, 2H), 1.57 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.7,
153.0, 146.5, 137.8, 133.5, 129.9, 129.2 (2C), 126.0, 124.4, 63.7, 24.3; IR (neat): νmax 2936,
2362, 1716, 1517, 1411, 1342, 1201, 846, 763, 697 cm-1; ESIHRMS m/z calcd for C17H16N3O4
[M+H]+ 326.1135, found 326.1148.
5,5-Dimethyl-1-phenyl-3-(4-trifluoromethylphenyl)hydantoin 11z. Yield: 97% (338 mg,
970 μmol). Solvent system for flash column chromatography: cyclohexane/EtOAc: 90/10;
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White solid, Mp: 135 °C; H NMR (400 MHz, CDCl3): δ 7.73 (app. s, 4H), 7.51-7.40 (m, 3H),
7.35-7.30 (m, 2H), 1.56 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.9, 153.3, 135.2, 133.7,
129.8 (q, J = 35.8 Hz), 129.7, 129.1, 128.9, 126.1 (q, J = 3.7 Hz), 126.0, 123.9 (q, J = 272.3 Hz),
63.6, 24.1; 19F NMR (376 MHz, CDCl3): δ -63.1 (s); IR (neat): νmax 2357, 1716, 1406, 1325, 1127,
1066, 843 cm-1; ESIHRMS m/z calcd for C18H16F3N2O2 [M+H]+ 349.1158, found 349.1169.
3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-1-phenylhydantoin 11aa. Yield: 88% (1.1
g, 2.97 mmol). Solvent system for flash column chromatography: petroleum ether/EtOAc:
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80/20; White solid, Mp: 169 °C; H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 1.8 Hz, 1H),
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1.58 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.5, 152.6, 136.5, 135.5, 133.8 (q, JC-F = 33.1
Hz), 133.2, 130.0, 129.4, 129.2, 128.3, 123.4 (q, JC-F = 4.8 Hz), 120.7, 115.1, 108.6, 63.8, 24.2;
19F NMR (376 MHz, CDCl3): δ -62.5 (s); IR (neat): νmax 2986, 2232, 1719, 1404, 1313, 1131, 850,
691 cm-1; ESIHRMS m/z calcd for C19H15F3N3O2 [M+H]+ 374.1111, found 374.1127.
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3-(4-tert-Butylphenyl)-5,5-dimethyl-1-phenylhydantoin 11ab. Yield: 65% (219 mg,
651 μmol). Solvent system for flash column chromatography: cyclohexane/EtOAc: 90/10;
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White solid, Mp: 166 °C; H NMR (400 MHz, CDCl3): δ 7.52-7.39 (m, 7H), 7.36-7.31 (m, 2H),
1.55 (s, 6H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.4, 154.2, 151.2, 134.2, 129.6,
129.1, 129.0, 128.6, 126.1, 125.7, 63.5, 34.8, 31.4, 24.2; IR (neat): νmax 2966, 1714, 1400, 1199,
1142, 839, 763, 690 cm-1; ESIHRMS m/z calcd for C21H25N2O2 [M+H]+ 337.1911, found
337.1925.
5,5-Dimethyl-1-phenyl-3-(4-trifluoromethoxyphenyl)hydantoin 11ac. Yield: 80% (292 mg,
802 μmol). Solvent system for flash column chromatography: cyclohexane/EtOAc: 90/10;
White solid, Mp: 125 °C; 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 9.0 Hz, 2H), 7.52-7.41 (m, 3H),
7.35-7.29 (m, 4H), 1.55 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.1, 153.7, 148.4, 133.9,
130.4, 129.8, 129.1, 128.9, 127.5, 121.6, 120.6 (q, JC-F = 257.7 Hz), 63.7, 24.2;
19F NMR (376 MHz, CDCl3): δ -58.3 (s); IR (neat): νmax 2935, 2363, 1714, 1514, 1403, 1254,
1199, 1164, 762 cm-1; ESIHRMS m/z calcd for C18H16F3N2O3 [M+H]+ 365.1108, found 365.1120.
5,5-Dimethyl-3-(4-methoxycarbonylphenyl)-1-phenylhydantoin 11ad. Yield: 92% (119 mg,
351 μmol). Solvent system for flash column chromatography: cyclohexane/EtOAc: 80/20;
White solid, Mp: 115 °C; 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 8.7 Hz, 2H),
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7.67 (d, J = 8.7 Hz, 2H), 7.52-7.41 (m, 3H), 7.34-7.30 (m, 2H), 3.93 (s, 3H), 1.56 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 175.0, 166.5, 153.5, 136.0, 133.9, 130.4, 129.8, 129.4, 129.2,
128.9, 125.6, 63.6, 52.4, 24.3; IR (neat): νmax 2954, 2364, 1714, 1412, 1277, 1199, 1115, 767,
697 cm-1; ESIHRMS m/z calcd for C19H19N2O4 [M+H]+ 339.1339, found 339.1352.
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Multigram Scale Procedures
N3-Arylation of 4,4-dimethylhydantoin 8a. A 2 L four-necked round bottom flask equipped
with a condenser, a mechanical stirrer and a temperature probe was charged with 4-iodo-2-
trifluoromethylbenzonitrile (90.0 g, 303 mmol), copper(I) oxide (97% grade, 44.7 g, 303 mmol)
and N,N-dimethylformamide (873 mL). 5,5-Dimethylhydantoin 8a (58.2 g, 455 mmol) was
added and the flask was fitted with a glass stopper. The reaction mixture was stirred at 150 °C
for 16 hours. After cooling to room temperature, the red suspension was filtered through a
cardboard filter and washed with N,N-dimethylformamide (58 mL). The filtrate was
concentrated under reduced pressure, dissolved in N,N-dimethylformamide (58 mL) and the
green suspension was transferred into an addition funnel. A 1 L four-necked round bottom
flask equipped with a condenser, a mechanical stirrer, a temperature probe and the latter
addition funnel was charged with 233 mL of demineralized water. The green suspension was
added over 10 minutes and stirred for 30 minutes before adding a 28% aqueous ammonia
solution (111 mL) over 5 minutes. The resulting mixture was stirred for 30 minutes. The
precipitate was collected by filtration, washed with water (3x58 mL) and then dried under high
vacuum at 40 °C for 72 hours to yield 5,5-dimethyl-3-(3-trifluoromethyl-4-
cyanophenyl)hydantoin 9f as a white solid (83.6 g, 281 mmol, 93%).
N1-Arylation of 5,5-dimethyl-3-(3-trifluoromethyl-4-cyanophenyl)hydantoin 9f. A 1 L four-
necked round bottom flask equipped with a condenser, a mechanical stirrer and a
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cyanophenyl)hydantoin 9f (50.0 g, 168 mmol), copper iodide (6.40 g, 33.6 mmol) potassium
carbonate (46.5 g, 336 mmol) and toluene (240 mL). The flask was fitted with a glass stopper
and was then flushed with nitrogen at 22 +/- 3 °C before trans-N,N’-dimethylcyclohexane-1,2-
diamine (9.60 g, 67.3 mmol) was added over ca. 2 minutes. The reaction mixture turned blue
and a slight exotherm (up to 26 °C) was observed (Picture 1, Supporting Information).
Iodobenzene (48.0 g, 235 mmol) was added over 5 minutes (Picture 2, Supporting
Information) and the mixture was then heated to reflux (110 °C, Picture 3, Supporting
Information) and stirred for 24 hours (the mixture turns green upon heating, Picture 4,
Supporting Information). TLC (heptane/ethyl acetate: 60/40) showed complete consumption
of the starting material (Picture 5, Supporting Information). The temperature was adjusted to
22 +/- 3 °C and ethyl acetate (340 mL) was added followed by silica (50.0 g) and Clarcel® (50.0
g). The mixture was stirred for 15 min and filtered through a Büchner (Picture 6, Supporting
Information). The cake was copiously washed with ethyl acetate (1650 mL). The filtrate was
concentrated to low volume at 40 °C under vacuum to yield a brown residue (117 g). Toluene
(340 mL) and heptane (200 mL) were added and the resulting suspension was stirred for 1 h
at 22 +/- 3 °C and then for 1 hour at 2 +/- 3 °C (Picture 7, Supporting Information). The cake
was washed twice with a cold mixture of toluene (30 mL) and heptane (20 mL) (Picture 8,
Supporting Information). The wet product (98.7 g) was dried under vacuum at 50 °C for 18
hours to yield 5,5-dimethyl-1-phenyl-3-(3-trifluoromethyl-4-cyanophenyl)hydantoin 11z as an
off-white solid (51.3 g, 137 mmol, 82%).
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C4-Selective Thionation of 5,5-Dimethyl-1,3-diphenylhydantoin
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5,5-Dimethyl-1,3-diphenyl-4-thiohydantoin 15. In a pressure tube, 5,5-dimethyl-1,3-
diphenylhydantoin 11l (140 mg, 0.50 mmol) was dissolved in toluene (2 mL) before adding
phosphorus pentasulfide (111 mg, 0.50 mmol). The pressure tube was flushed with argon and
closed with a Teflon-coated screw cap before heating the reaction mixture at 120 °C for 18
hours. The mixture was then cooled to room temperature, quenched with a 1M aqueous
solution of hydrochloric acid and extracted with EtOAc. The combined organic layers were
washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude
residue was purified by flash column chromatography over silica gel (cyclohexane/EtOAc:
gradient from 90/10 to 80/20) to give the desired 5,5-dimethyl-1,3-diphenyl-4-thiohydantoin,
obtained as a white solid and as a single regioisomer (85 mg, 0.29 mmol, 57%). The
regioselectivity of the thionation and the structure of this compound have been assigned on
the basis of 13C NMR chemical shifts (C2, C4 and C5) as well as by comparison of the 13C NMR
chemical shifts reported for enzalutamide.33 The two regioisomers have been reported in 1983
but had been misassigned.19 Mp: 138 °C; 1H NMR (400 MHz, CDCl3): δ 7.57-7.43 (m, 8H), 7.38-
7.35 (m, 2H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 208.9, 154.2, 134.5, 134.3, 129.6,
129.2 (3C), 128.9, 127.7, 72.3, 28.1 IR (neat): νmax 1751, 1495, 1408, 1371, 1297, 1194, 1169,
1102, 753, 695, 664 cm-1; ESIHRMS m/z calcd for C17H16N2OSNa [M+Na]+ 319.0876, found
319.0884.
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Author Contributions. ‡ These authors contributed equally.
Supporting Information Available. Pictures of the different stages of the multigram scale N1-
arylation and copies of NMR spectra (PDF), Primary NMR data files (ZIP). This material is
available free of charge on the ACS Publication Website.
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Acknowledgement. Our work was supported by the Université libre de Bruxelles (ULB) and
Minakem. P.T., P.G. and C.D. acknowledge the Fonds pour la formation à la Recherche dans
l’Industrie et dans l’Agriculture (F.R.I.A.) for graduate fellowships.
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References
1 Baeyer, A. Vorläufige Notiz über das Hydantoïn. Justus Liebigs Ann. Chem. 1861, 117, 178.
2 For recent reviews on the chemistry of hydantoins, see: (a) Konnert, L.; Lamaty, F.; Martinez,
J.; Colacino, E. Recent advances in the synthesis of hydantoins: the state of the art of a
valuable scaffold. Chem. Rev. 2017, 117, 13757. (b) Meusel, M.; Gütschow, M. Recent
developments in hydantoin chemistry. A review. Org. Prep. Proced. Int. 2004, 36, 391.
3 For representative recent examples of hydantoin natural products, see: (a) Tian, X.; Peng, X.;
Yu, M.; Huang, Y.; Wang, X.; Zhou, L.; Qiu, M. Hydantoin and thioamide analogues from
Lepidium meyenii. Phytochem. Lett. 2018, 25, 70. (b) Geng, H.-C.; Yang, D.-S.; Chen, X.-L.;
Wang, L.-X.; Zhou, M.; Mei, W.-Q. Meyeniihydantoins A–C, three novel hydantoin
derivatives from the roots of Lepidium meyenii Walp. Phytochem. Lett. 2018, 26, 208. (c)
Wang, Q.; Tang, X.; Luo, X.; De Voogd, N. J.; Li, P.; Li, G. (+)- and (−)-Spiroreticulatine, A Pair
of Unusual Spiro Bisheterocyclic Quinoline-imidazole Alkaloids from the South China Sea
Sponge Fascaplysinopsis reticulata. Org. Lett. 2015, 17, 3458. (d) Yasuda, T.; Araki, A.;
Kubota, T.; Ito, J.; Mikami, Y.; Fromont, J.; Kobayashi, J.’i. Bromopyrrole Alkaloids from
Marine Sponges of the Genus Agelas. J. Nat. Prod. 2009, 72, 488. (e) Cachet, N.; Genta-
Jouve, G.; Regalado, E. L.; Mokrini, R.; Amade, P.; Culioli, G.; Thomas, O. P. Parazoanthines
A−E, Hydantoin Alkaloids from the Mediterranean Sea Anemone Parazoanthus axinellae.
J. Nat. Prod. 2009, 72, 1612.
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4 For representative examples, see: (a) Leitch, J. A.; Cook, H. P.; Bhonoah, Y.; Frost, C. G. Use of
the Hydantoin Directing Group in Ruthenium (II)-Catalyzed C–H Functionalization. J. Org.
Chem. 2016, 81, 10081. (b) Kondoh, A.; Ota, Y.; Komuro, T.; Egawa, F.; Kanomata, K.;
Terada, M. Chiral Brønsted acid-catalyzed enantioselective Friedel–Crafts reaction of 2-
methoxyfuran with aliphatic ketimines generated in situ. Chem. Sci. 2016, 7, 1057. (c)
Etxabe, J.; Izquierdo, J.; Landa, A.; Oiarbide, M.; Palomo, C. Catalytic Enantioselective
Synthesis of N,Cα,Cα-Trisubstituted α-Amino Acid Derivatives Using 1H-Imidazol-4(5H)-
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5 For a representative example, see: Oyaizu, K.; Ohtani, Y.; Shiozawa, A.; Sugawara, K.; Saito, T.;
Yuasa, M. Highly stable gold (III) complex with a hydantoin ligand in alkaline media. Inorg.
Chem. 2005, 44, 6915.
6 For a representative example, see: Raia, R. K.; Jayakrishnan, A. Synthesis and Polymerization
of a New Hydantoin Monomer With Three Halogen Binding Sites for Developing Highly
Antibacterial Surfaces. New J. Chem. 2018, 42, 12152.
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