Mechanochemical preparation of hydantoins from amino esters: Application to the synthesis of the antiepileptic drug phenytoin

Article abstract of DOI:10.1021/jo5017629

The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.

Full text of DOI:10.1021/jo5017629

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Article
Mechanochemical preparation of hydantoins from amino esters.
Application to the synthesis of the anti-epileptic drug phenytoin
Laure Konnert, Benjamin Reneaud, Renata M. de Figueiredo, Jean-
Marc Campagne, Frédéric Lamaty, Jean Martinez, and Evelina Colacino
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5017629 • Publication Date (Web): 03 Oct 2014
Downloaded from http://pubs.acs.org on October 7, 2014
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Mechanochemical preparation of hydantoins from amino
esters. Application to the synthesis of the anti-epileptic
drug phenytoin
Laure Konnert,[a] Benjamin Reneaud,[a] Renata Marcia de Figueiredo,[b] Jean-Marc
Campagne,[b] Frédéric Lamaty,[a] Jean Martinez,[a] Evelina Colacino*[a]
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[a] Université Montpellier II, Institut des Biomolécules Max Mousseron
UMR 5247 CNRS – Universités Montpellier I & II - ENSCM, Place E. Bataillon, cc 1703,
34095 Montpellier (France) E-mail: evelina.colacino@univ-montp2.fr; www.greenchem.univ-
montp2.fr/
Tel. +33 (0)4 67 14 42 85; Fax +33 (0)467 14 48 66.
[b]
Institut Charles Gerhardt Montpellier (ICGM), UMR 5253 CNRS-UM2-UM1-
ENSCM, Ecole Nationale Supérieure de Chimie, 8 Rue de l
Montpellier Cedex 5 (France).
’Ecole Normale, 34296
Table of contents
R1
O
NH
HN
O
KOCN
H2O
R1
R2
OMe
Ph Ph
HCl.H2N
or
or
R3
O
O
O
HN
O
R3
NH
HCl.H2N
OMe
NH
O
HN
Planetary Ball-Mill
O
Abstract
The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester
hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-
step protocol consisted in the formation of ureido ester intermediates, followed by a base-
catalysed cyclization to hydantoins. This easy-handling mechanochemical methodology was
applied to a large variety of - and -amino esters, in smooth conditions, leading to
hydantoins in good yields and with no need of purification steps. As an example, the
methodology was applied to the “green” synthesis of the anti-epileptic drug Phenytoin, with
no use of any harmful organic solvent.
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Keywords. Amino-esters, (Iso)-cyanate, Ball-milling, Heterocycles, Anti-epileptic drugs,
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Phenytoin.
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Introduction
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2,4-Imidazolidinediones, also known as hydantoins are a class of well-known
molecules that have demonstrated a wide therapeutic interest,1 including antiepileptic,2
anticonvulsant,3 antiandrogenic,4 antidiabetic5 or anti-fungal activities.6 From the synthetic
point of view, hydantoins are precursors of choice of -amino acids,7 or provide access to
optically active polymers8 or metal complexes.9,10 A particular hydantoin, 1,3-dibromo-5,5’-
dimethylhydantoin (DBDMH), is used for bromination reactions11,12 and acts as a catalyst in a
number of organic transformations.13–15 There are three main pathways to access 1,3-
unsubstituted hydantoins,1,7,16 the choice of which depends not only on the synthetic easiness
to access the precursors, but also on the final target that includes 5-substituted or 5,5-
disubstituted hydantoins (Scheme 1).
Bucherer-Bergs conditions
(5-Substituted derivatives mainly)
O
O
R R'
N CN
R R'
H2N CN
H2N
(NH4)2CO3, KCN
Ethanol / Water
R
5
H
R'
O
KOCN
HN
or
O
or
R R'
R
R'
Reflux,
MW or neat
Organic solvent, H2O
Reflux, MW
N
Acidic or basic
medium
O
H
R R'
Y
Y
H2N
H2N
N
MW, US
or Grinding
H
O
O
O
Y = OH, OMe, OtBu,
NH2, solid support
PEG-600, H2O
or DMSO
H2N
R'
NH2
Read conditions
(5- or 5,5-di-substituted derivatives)
O
R
Biltz conditions
(5,5-di-substituted derivatives only)
O
Scheme 1. Main retrosynthetic pathways to the synthesis of 1,3-unsubstituted
hydantoins.
Under Bucherer-Bergs conditions17,18 involving a carbonyl compound, toxic potassium
cyanide and ammonium carbonate, mainly 5-substituted hydantoins were obtained. A few
examples exploited this approach to access 5,5-disubstituted derivatives,8 and very recently a
variant methodology, starting from a methylene aziridine instead of a carbonyl compound,
was also reported for the synthesis of this class of compounds.19 Reactions were mainly
performed in solution under reflux or microwaves20 (MW). Neat conditions21 were also
reported, involving Fe3O4 nanoparticles as catalyst.22 The second major pathway to obtain 1,3-
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unsubstituted hydantoins is the reaction of cyanate salts with either amino acids6 or their
ester7,23 amide or nitrile24 derivatives, known as the Read synthesis. The corresponding ureido
derivative was cyclized under acidic conditions, although the base catalysed-cyclization has
also been reported.25 This reaction has been notably used for the preparation of
spirohydantoins.26 Trimethylsilyl-isocyanate (TMS-NCO) and chlorosulfonyl-isocyanate are
alternatives to cyanate salts for the preparation of 1,3-unsubstituted hydantoins.27,28 Recently,
our group has described the solid-phase synthesis of 5-substituted hydantoins under
microwave-irradiation from supported amino acids and isocyanates.29 The condensation of
benzil and urea in excess according to Biltz reaction7,30,31 remains the main pathway to the
obtention of 5,5-disubstituted hydantoins and was historically used for the synthesis of the
anti-epileptic drug phenytoin.2,31 Several improvements were described using enabling
technologies such as ultrasonication,32,33 heating via microwave irradiation (in solution or
neat34–37), in polar solvents [water,2 poly(ethylene glycol)38 or DMSO34] or grinding the
reactants (with mortar and pestle).39 In view of the REACH (Registration, Evaluation,
Authorisation and Restriction of Chemicals) legislation,40 regulating chemical substances and
directed to both the protection of the human health and the environment from the risks of
potentially toxic chemicals, the use of certain chemicals will be phased out, affecting industries
throughout the world. Thus, the use of possible alternative substances and/or technologies,
including present and future research and development processes, will enhance innovation
and competitiveness. In this perspective, reduction or elimination of harmful chemicals
includes the possibility to perform organic synthesis in the absence of solvents, in neat
conditions41 or via mechanochemistry.42,43 Ball-milling technology has been, for the last
decade, more and more used in the field of organic chemistry.44–46 The mechanosynthesis of
heterocyclic compounds has been notably explored.47,48 However, as far as we know, no
mechanochemical procedure for the preparation of hydantoins has ever been developed. In
our ongoing work on organic mechanochemistry,49–56 investigation of a solvent-free
methodology for the synthesis of hydantoins starting from amino ester derivatives in a ball-
mill seemed promising. It is worth noting that the use of mechanochemistry for the synthesis
of heterocycles from amino acid derivatives remains a quite unexplored field, with only one
example describing the synthesis of (R)-thiazolidine from L-cysteine.57
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Herein we describe a systematic investigation and a general method for the eco-
friendly mechanochemical synthesis of 5-substituted hydantoins from a large variety of amino
acid methyl esters and potassium cyanate (Scheme 1). The ureido intermediate could be either
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isolated, or cyclized in the presence of base, to afford pure hydantoins in good to excellent
yields without purification. The methodology was also applied to the synthesis of the 5,5-
disubstituted anti-epileptic drug, phenytoin. Compared to solution synthesis, simpler reaction
conditions, better yields and easier work-up are the major benefits of this environmentally
friendly procedure.
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Results and discussions
5-Benzyl-hydantoin
2 (Table 1) served for the optimisation of the reaction conditions.
Several ball-milling parameters (type of ball-mill apparatus, material of the jars, speed)
were tested, as well as the nature of the base used in the reaction (Table 1). The
classical conditions of Read synthesis involved a two-step reaction. The hydantoic
ester, formed in the first step was cyclized by the addition of an acid in the second step
(Scheme 1). Our first objective was to perform an ‘all-in-one’ reaction, in which the
hydantoin would be directly formed from the amino ester and potassium cyanate, the
ureido intermediate being cyclized in situ in the presence of two base equivalents.
The first trials were performed in a vibrational ball-mill, using K2CO3 or NaHCO3 as
base (Table 1, entries 1 and 2). In contrast with potassium carbonate, which showed no
efficiency, NaHCO3 afforded a good conversion of the substrate into the ureido-derivative 1.
However the cyclization to hydantoin 2 did not occur, as shown by LC/MS analysis of the
crude. Speculating that more energetic conditions and longer reaction times were necessary
for a successful cyclization, the reaction was tested in a planetary ball-mill, using a stainless
steel jar under continuous milling (Table 1, entry 3). However, no improvements were
observed neither in terms of conversion of substrate nor formation of hydantoin 2. Starting
from our previous findings,53,56 cycled milling was also tested using stainless steel (Table 1,
entry 4) or tungsten carbide (entry 5) jar. In both cases, the conversion of starting material
was increased to the same extent, in favour of the ureido-derivative 1, also indicating that the
different stress phenomena provided by the nature of jar material were not important.
However, the cyclization step did not proceed even on prolonged milling, only traces of
hydantoin 2 were detected in the crude (entries 4 and 5). The physicochemical properties of
the inorganic base, under solvent-free conditions, could have been responsible for the in situ
unsuccessful cyclization. Then, K2CO3 or triethylamine (up to 4 equiv.) were added into the
jar and cycled milling was maintained at 500 rpm for 4 hours, without any success (entries 6
and 7 respectively). To better come out of this failure, the cyclization step needed to be
investigated separately starting from the ureido-derivative 1.
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Therefore, water was added to the milling jar, the phenylalanine ureido-derivative 1
precipitated and it was recovered pure by filtration. To our surprise, the TLC analysis of the
filtrate showed the presence of a new compound, which was identified by LC/MS as the
desired hydantoin 2, thus highlighting the need of water in the reaction mixture to promote
cyclization.
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Table 1. Screening of the conditions for the synthesis of 5-benzyl-hydantoin 2.
Vibrational or Planetary
Ball-milling
O
KNCO / H2O
OMe
O
OMe
+
HN
O
H2N
N
HCl.H2N
(Base)
H
NH
O
O
2
1
Ball-milling apparatusb /
Jar materialb /
Conversion
(HPLC %)
Entry
Basea
Time (h)
Rotation speed (rpm) or
Frequency (Hz)
1
0
2
1
2
3
4
5
6
7
K2CO3
VM / SS / 30 Hz
VM / SS / 30 Hz
PM / SS / 500 rpm
PM / SS / 500 rpm
PM / WC / 500 rpm
PM / SS / 500 rpm
PM / SS / 500 rpm
/
2
0
0
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
4
70
70
90
84
0
4
0
6c
6c
4c
4c
24e
6c
3c
6c
Traces
Traces
0
Et3N (excess)
0
0
8d,e Et3N/H2O
9f
10g NaHCO3 (step 1)
0
90
Et3N/H2O
PM / SS / 500 rpm
PM / SS / 300 rpm
PM / SS / 500 rpm
37
21
n.d.h
91
n.a.h
Et3N/H2O (step 2)
31
a 2 equiv. of base were used. b Typical procedure: L-phenylalanine methyl ester hydrochloride
(1 equiv), KNCO (1 equiv) and the base (2 equiv.) were milled in a vibrational ball-mill
(VM), 10 mL stainless steel (SS) jar, 2 stainless steel balls (5 mm diameter) at 30 Hz or in a
planetary ball-mill (PM), 12 mL stainless steel or 50 mL tungsten carbide (WC) jar, 25
stainless steel balls (or 50 tungsten carbide balls, 5 mm diameter) at 500 (or 300 rpm) for the
specified time. c Cycled milling of 10 minutes cycles followed by 5 minutes of standby in
d
between, with reverse rotation, for the specified time. The phenylalanyl-urea 1 was the
e
f
starting material. The reaction was performed under stirring at room temperature. The
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reaction was carried out using L-phenylalanine methyl ester hydrochloride (3.48 mmol), Et3N
g
(6.96 mmol) and H2O (200 L). Step 1: NaHCO3 (6.96 mmol); Step 2: Et3N (6.96 mmol)
and H2O (1 mL). h n.d. = not determined; n.a. = not attributed.
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Starting from this preliminary observation the cyclization step was thus investigated
in the presence of water (entry 8). The phenylalanylurea
a large excess of triethylamine was added. The homogeneous mixture was left at room
temperature, affording 5-benzyl-hydantoin with 90% conversion (entry 8). The
experiment was repeated in ball-milling conditions using a triethylamine/water mixture
(entry 9). The ureido-derivative was obtained with poor conversion, suggesting that
1 was suspended in water and
2
1
the inorganic base NaHCO3 was fundamental and necessary to drive the reaction
towards the almost quantitative formation of the ureido-intermediate. Disappointingly,
the use of a triethylamine/water mixture led to a moderate, but however better,
conversion to 5-benzyl-hydantoin 2, suggesting that instead of a one-pot procedure, a
one-pot/two-step methodology58–61 would be more appropriate (entry 10). In the first
step, the phenylalanine methyl ester hydrochloride was ball-milled with NaHCO3
(entry 10). The ureido-derivative
1 was obtained in a very good conversion, in a
shorter time (3 hours instead of 6 hours) and at a lower milling power (300 rpm instead
of 500 rpm). Then, a triethylamine/water mixture was added to the jar (entry 10, step
2). After ball-milling, the corresponding hydantoin
2 was obtained in a moderate
conversion (31%), which could be explained, in comparison with the solution-
synthesis in water, by the shorter time of the mechanochemical reaction (24 hours
against 6 hours respectively). However, our objective being to provide a simple and
rapid access to hydantoins, a prolonged time of more than 6 hours of reaction would
not be satisfying, which led us to look for better reaction conditions.
Keeping in mind from the literature that the cyclization reaction in solution was
usually carried out with diluted alcoholic HCl at reflux for 2 hours,6 we tried to perform the
cyclization step in acidic medium, starting from the ureido-phenylalanyl derivative 1 in the
presence of p-toluene sulfonic acid (PTSA, 3 equiv). The cyclization did not occur in the ball-
milling conditions, confirming the need of basic conditions also for the cyclization step.
Within this perspective, it appeared to us that since water seemed to be fundamental for the
cyclization step, it had to come into play as a proton donor in a general acid catalysis
mechanism,62–64 helping the removal of the methanolate of the ester moiety of the ureido-
derivative 1. To confirm this hypothesis, liquid-assisted grinding (LAG) was tested in the
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cyclisation step adding non-protic solvents (ethyl acetate and dichloromethane) or a protic
solvent (ethanol) to the reaction mixture (= 1.25 L/mL). In presence of AcOEt, the yield
remained comparable to the solventless conditions (81%), whereas the presence of CH2Cl2
made it drop to 48%, as the ureido derivative 1 was not fully converted as shown by LC/MS
analysis. As expected, adding EtOH enabled to get the hydantoin in a higher yield of 95%.
Not only the last result confirms the idea of a general acid catalysis of the reaction by a proton
donor species, but the tests performed in the presence of AcOEt or CH2Cl2 opened some
questioning on their specific effect in these LAG-assisted mechanosyntheses: indeed, the
divergent yields obtained for the two trials may result from the incoming solubility of the
desired cyclised product hydantoin 2 in ethyl acetate (soluble) or in dichloromethane
(insoluble). When the reaction proceeds in presence of AcOEt, the reaction may be driven by
the passage of the product in the organic layer, whereas in the presence of CH2Cl2,
insolubility would prevent the cyclization step.
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In a green chemistry perspective and considering the previous results, it was necessary
to keep at the minimum the use of (flammable) solvents and the number of reactants (as well
as their relative stoichiometry) to perform the synthesis. For this reason, instead of adding an
extra base to generate the free amino group of phenylalanine methyl ester undergoing the
nucleophilic attack on the cyanate, the base was generated in situ exploiting the degradation
of a second equivalent of potassium cyanate in water (Scheme 2). Since water seemed to be
fundamental, the reaction was explored in aqueous basic solution and the results were
compared to those obtained in the planetary ball-mill (Table 2).
KOCN
2 H2O
OMe
OMe
HCl.H2N
H2N
NH3
CO2
KCl
O
O
O
KOCN
OMe
H2N
N
H
O
KOH
1
Scheme 2. In-situ base formation via degradation of potassium cyanate with water.
Phenylalanine methylester hydrochloride was reacted with an excess of potassium
cyanate in water at room temperature (Table 2, entries 1 and 2). The corresponding
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phenylalanyl urea
1
precipitated (88% conversion) in less than 2 hours. The suspension
5
6
was kept under stirring, affording the hydantoin
2 after 7 days (entry 1). The kinetic
and yield were dependent on the equivalents of potassium cyanate introduced (entries 1
7
8
9
and 2), and so on the quantity of in situ generated base, suggesting that the synthesis
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could be accelerated with an additional amount of base. Hydantoin
2 was obtained in a
shorter reaction time when a large excess (20 equiv.; Table 2, entry 2) of KNCO was
used (i.e. more in situ generated base), but the yield was lower, due to a more
important basic hydrolysis of the methyl ester group.
The addition of KOH (1 equiv.) to the solution after 2 hours from the beginning of
the reaction (Table 2, entry 3) gave similar results, confirming again that a base was
necessary for a faster kinetic in water. Then the reaction was tested in the planetary
mill, without addition of any supplementary base and increasing the relative ratio
KNCO/H2O (Table 2, entry 4). Pure phenylalanylurea
1
was obtained in high yield
could be
(97%, Table 2, entry 4) without need of purification. The ureido-derivative
1
recovered by precipitation by addition of 10% aqueous citric acid. From an
environmental point of view, regarding notably atom and solvent economy, this
procedure for the preparation of urea derivative was very advantageous.
The synthesis of urea derivatives in solution was described by Dakin from free amino acids
and potassium cyanate, using water as solvent.65 An excess of potassium cyanate and heating
were necessary to afford phenylalanylurea in 78% yield.66 Microwave irradiation was also
used to obtain urea derivatives in 78-90% yield, with heating at 80°C in this case as well.67
The synthesis from amino esters68 and especially proline methyl ester69 was also reported.
However this particular reaction was performed in chloroform to afford the urea compound in
only 69% yield. As far as we know, there is not much published in the area of
mechanochemical solvent-free or liquid assisted grinding (LAG) synthesis of (thio)urea
derivatives.70–72
Based on the observations issued from the data reported in Table 1 and with further
optimization, a mechanochemical one-pot/two-step procedure using stoichiometric amounts
of reagents (Table 2, entry 6), with a 1:2 ratio KNCO/H2O was tested. Finally, phenylalanyl
methyl ester hydrochloride was fully converted into the corresponding ureido-derivative 1,
thanks to the in situ generation of the two needed equivalents of potassium hydroxide
(Scheme 2). The cyclization reaction leading to the hydantoin 2 occurred in the second step
by adding K2CO3 (1 equiv.) (Table 2, entry 6), which was selected instead of KOH (entry 5),
because of less risk of epimerisation or ester hydrolysis.25
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Table 2. Comparison for the synthesis of hydantoin in water and in a ball-mill.
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KNCO
Base
H2O
O
(1 equiv.)
O
OMe
OMe
HN
O
HCl.H2N
H2N
N
H
In water or
Ball-milling
In water or
Ball-milling
NH
O
O
2
1
KNCO / H2O
(equiv)
Entry
Method
Base
Conditions (h)
Yield (%)
Step 1
168
18
Step 2
1
2
76
1
2
3
4
5
6
CSa
CSa
CSa
5 / 720
20 / 720
20 / 720
20 / 40
10 / 40
3 / 4
/
/
/
/
n.i.b
n.i.b
n.i.b
97
n.i.b
n.i.b
58
KOHc
2
3
77
n.o.b
BMd
BMd
BMd
/
1.5d,e
3d,e
1.5c,d
n.p.b
3e,f
1.5e,f
KOH
K2CO3
84
80
a The reaction was performed in water at room temperature under stirring and the base was
generated in situ; CS = Classical Stirring. b n.i. = not isolated, n.o. = not observed, n.p. = not
c
d
performed. The base was added after 2 hours under stirring at room temperature. BM =
Ball-milling; Typical procedure. Step 1: L-phenylalanine methyl ester hydrochloride (1 equiv)
and KNCO (equiv. as detailed in the Table) were reacted in a planetary ball-mill (12 mL
stainless steel jar, 25 stainless steel balls, 5 mm diameter) at 450 rpm for the specified time.
Cycled milling of 10 minutes cycles followed by 5 minutes of standby in between, with
e
f
reverse rotation. Step 2: The base (1 equiv.) was added and the milling was repeated in the
same conditions as Step 1 (450 rpm), with cycled milling, for the specified time.
The synthesis of phenylalanyl urea
1 could be achieved with comparable results
in terms of kinetics and yields, in both aqueous solution or planetary-mill conditions.
In the case of hydantoin, the reaction in water was slower than the mechanochemical
one and a very large excess of reactants needed to be used, which is not desirable from
the environmental point of view. Based on these findings, ball-milling was selected as
the method of choice for the synthesis of a library of 5-substituted- and 5,5-
disubstituted-hydantoins, as well as 6-membered heterocycles, starting from
-amino
methyl esters, quaternary amino methyl esters or

-amino methyl esters respectively
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(Table 3). 2- and 3-aminoisobutyric methyl ester hydrochlorides were prepared from
the corresponding amino acids by reaction with an excess of trimethylsilyl chloride
(TMSCl) in methanol, under stirring for 3 days (yields 97% and 75% respectively, see
Supporting Information). It turned out that although the substrates were very easily
converted into their urea derivatives in the first step, with a reaction time extended to
120 minutes (instead of 90 minutes as for HCl.H-Phe-OMe, Table 3, entry 1), the
conditions for the second step had to be adjusted according to the starting amino ester,
particularly concerning the nature of the base used for cyclization (Table 3). Indeed,
potassium carbonate (1 equiv) was effective for the formation of hydantoins from
phenylalanine, methionine and the sterically hindered aminoisobutyric acid methyl
esters in very good yields (Table 3, entries 1, 5 and 19 respectively). For 5,5-
dimethylhydantoin 19, the yield was doubled (92%) compared to the synthesis
performed in solution according to the Bucherer-Berger method (45%), highlighting
the performances of the ball-milling approach for recalcitrant substrates. Moreover no
synthesis of 5,5-dimethylhydantoin 19 under Read conditions was ever reported, nor of
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19
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23
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36
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38
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49
50
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60
5-[2-(methylthio)ethyl]-2,4-imidazolidinedione 5.
Table 3. Synthesis of 5-substituted-, 5,5-disubstituted hydantoins and six-membered
heterocycles.a
HCl . H-AA-OMe
R1
R2
O
R3
R3
R1
O
R2
OMe
HCl.H2N
or
OMe
HCl.H2N
O
HN
O
NH
O
or
NH
HN
O
2 KNCO / 4 H2O
450 rpm, 2 h
Cycled milling
2-12, 14-19, 22
20-21
R1 = AA side chain, R2 = H
R =
R1
1) Base, 450 rpm,
R3
R2
O
O
R2 = Me, Ph
H
N
1
OMe
2 h, Cycled milling
OMe
H2N
R3 = H, Me
or
H2N
N
H
2) Grinding with
NH4Cl / EtOAc
O
O
1, R1 = CH2Ph
R2 = H
13, R1 = CH(OtBu)Me
Entry
1b
HCl.H-AA-OMe
Compound
Yield (%)
97b
L-HCl.H-Phe-OMeb
L-HCl.H-Phe-OMec
D-HCl.H-Phe-OMe
1
2
3
2
(80)d
70 f
3
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4
5
L-HCl.H-Tyr(OtBu)-OMe
100 (53)d
(91)d
84
79 (53)d
94 (69)d
85 (53)d,e
93 (56)d
100
4
L-HCl.H-Met-OMe
L-HCl.H-Cys(Bn)-OMe
L-HCl.H-Ala-OMe
L-HCl.H-Val-OMe
L-HCl.H-Ile-OMe
D-HCl.H-Leu-OMe
L-HCl.H-Ser(OtBu)-OMe
L-HCl.H-Thr(OtBu)-OMeb
L-HCl.H-Thr(OtBu)-OMe
L-HCl.H-Phg-OMe
L-HCl.H-Asp(OMe)-OMe
L-HCl.H-Lys(Z)-OMe
L-HCl.H-Pro-OMe
5
6
6
7
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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31
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39
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59
60
8
8
9
9
10
11
12b
13
14
15
16
17
18
19
20
21
22
10
11
12
13
14
15
16
17
18
19
20
21
22
96b
96
97 f
32
91
(91)f
77g
(92)d
L-HCl.H-Trp-OMe
HCl.H-Aib-OMeh
HCl.H--Ala-OMe
HCl.H-3-Aib-OMei
47
57
84j
L-HCl.H-Gly(Ph)2-OMe
a Typical procedure. Step 1: Amino ester hydrochloride (250 mg), KNCO (3 equiv.) and H2O
(4 equiv.) were reacted in a planetary ball-mill (12 mL stainless steel jar, 25 stainless steel
balls, 5 mm diameter) at 450 rpm for 2 hours with cycled milling of 10 minutes cycles
followed by 5 minutes of standby in between, with reverse rotation; Step 2: Cs2CO3 (3 equiv)
was added and the milling was repeated in the same conditions as Step 1 (450 rpm), with
b
cycled milling, for 2 hours, except when differently stated. Only Step 1 was performed,
using 20 equiv. of KNCO and 40 equiv. of H2O. Yield referred to the ureido-derivative.
c
d
Ball-milling was performed during 90 minutes. The cyclization step was performed using
K2CO3 (1 equiv) e Based on NMR. Step 2: K2CO3 (1 equiv) and Et3N (1 equiv) were used. g
f
Step 2: The urea derivative (193 mg, 0.44 mmol), Cs2CO3 (1.31 mmol, 3 equiv) and Et3N
(0.44 mmol) were used. HCl.H-Aib-OMe (R1 = R2 = Me), 2-amino isobutyric acid methyl
h
ester hydrochloride. i HCl.H-3-Aib-OMe (R3 = Me), 3-amino-2-methylpropanoic acid methyl
j
ester hydrochloride. Trimethylsilyl isocyanate (TMS-NCO (3.60 mmol) was used (see
experimental section for more details).
K2CO3 was less efficient when used with a-amino esters having aliphatic side chains
[i.e. alanine (entry 7), valine (entry 8), isoleucine (entry 9) and leucine (entry 10)], leading to
only partial conversion of the corresponding ureido-precursors, even after extended reaction
times (4-6 hours). As a consequence, other bases, namely cesium carbonate (3 equiv) and
triethylamine (1 equiv) were explored. In most cases, yields were drastically increased when
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Cs2CO3 (3 equiv) was used instead of K2CO3 (entries 4, 7-10), showing its general efficiency
for the cyclization reaction, independently on the nature of amino ester side chain (Table 3,
entries 3, 4, 6-12, 14, 16 and 22). Moreover, 5-iso-propylhydantoin 8 (entry 8) and 5-iso-
butylhydantoin 10 (entry 10) were obtained with improved yields compared to solution
synthesis, from the corresponding -amino acid precursors with potassium cyanate upon
heating at 100°C for two hours (84% from HCl.H-Val-OH and 51% from HCl.H-Leu-OH
respectively).6 Triethylamine was also used in addition to carbonated bases (entries 17 and
18). It may be noticed that the liquid state of triethylamine helped the reaction to proceed, as
illustrated in the case of HCl.H-Trp-OMe (entry 18). Indeed, cyclization was not complete
when either cesium carbonate (24% yield) or triethylamine were used alone (no reaction for
step 2), while the corresponding ureido-derivative was fully converted when the bases were
used together. With L-HCl.H-Asp(OMe)-OMe (entry 15) as substrate, the hydantoin was
obtained in poor yield (32%), probably because of a side reaction between the methyl ester
side chain with the intermediate aspartyl urea. It is worth noting that, unexpectedly, the
reactivity of L- or D- phenylalanyl amino esters (entries 1 and 3 respectively) was not exactly
the same. Indeed, when the stereoisomer L afforded 5-benzyl hydantoin 2 smoothly using
K2CO3 (within 90 minutes), Et3N and longer reaction time (120 minutes) were necessary for
the cyclization step from the D-enantiomer. Six-membered heterocycles, namely
dihydrouracil (DHU) 20 and dihydrothymine (DHT) 21, were also synthesized starting from
the corresponding -aminoester precursors (entries 20 and 21), however, despite the full
conversion of the ureido-derivative, the yield remained moderate. In all cases, the final
products were recovered pure after a straightforward and simple work-up without need of
chromatographic purification or recrystallization. No by-product was formed, the only waste
being inorganic salts (KCl or CsCl), water, gases (CO2 and NH3) and MeOH (easily
eliminated by evaporation). 5-Phenylhydantoin 14 was obtained in slightly better yield (97%)
than in the Read solution synthesis (87%, heating at 100°C),6 and recrystallization was not
necessary. Except for 5-benzylhydantoin 2, 5-phenylhydantoin 14 and tryptophan derivative
18 (Table 3, entries 2, 14 and 18), hydantoins were very soluble in water, preventing their
recovery by precipitation or extraction. The final products were thus recovered by eliminating
the inorganic salts by precipitation: 10 equiv. of NH4Cl (prior to the amino ester) and 2 mL of
ethyl acetate were added to the jar (solvent-assisted grinding)73 and ball-milled for 3 cycles of
10 minutes (with a 5-minute standby between each cycle). The precipitate and the milling
balls were transferred into a round-bottom flask containing 50 mL of EtOAc and left under
stirring until the salts were completely removed from the balls. The suspension was filtered to
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eliminate the inorganic salts, with the organic phase containing the desired pure hydantoin.
This procedure also allowed elimination, as a precipitate, of any trace of residual unreacted
amino ester hydrochloride (when present).
9
Table 4. Comparison between yields obtained from the mechanochemical pathway and from
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solution synthesis.
Method
Mechanochemistry
Yield
(%)b
92
-
Compound
In Solution
Starting materialb
Yield (%)a
80
Readc,6
n.p.d
n.p.d
n.p.d
n.p.d
DBPe,74
Readc,6
Readc,6
Readc,6
n.p.d
H-Phe-OH
2
3
70
-
100
91
-
-
4
-
-
5
84
-
-
6
81
NC-NH-Ala-OMee
79
84
41
51
-
7
94
H-Val-OH
8
85
H-Ile-OH
9
93
H-Leu-OH
10
11
13
14
15
16
17
18
19
20
21
22
100
96
-
n.p.d
-
-
97
Readc,6
DBPe,74
n.p.d
DBPe,21
Readc,75
H-Phg-OH
NC-NH-Asp(OMe)-OMee
87
74
-
32
91
-
91
H-Pro-OMee
55
77
95
-
n.s.f
100
64
77
H-Trp-OH
92
Bucherer-Bergse,76 CH3COCH3
47
n.p.d
Read77
Biltz2
-
57
H-3-Aib-OH
(PhCO)2
84
W(CO)6/COg,78
H-Gly(Ph)2-NH2
a
Amino methyl ester hydrochlorides were the substrates. Reactions performed at room
57
58
59
60
b
temperature. The free amino acids were used as substrates, except where differently
specified. Reaction under reflux with HCl 10%. n.p. = not performed. DBP : N-cyano
c
d
e
amino methyl esters were used as substrates and reacted with dibutylphosphate (DBP) in
toluene or Et2O for 2 hours at 110°C. The reaction was performed under microwaves in a
e
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f
domestic oven. The yield was not specified (n.s.) in the literature.g Reaction at 45°C for 36
hours in CH2Cl2 with diazabicycloundecene (DBU) as base.
6
7
8
9
From the point of view of a benign chemistry, the above described synthetic
procedure (and work-up) presents many advantages with respect to the literature procedures:
(i) it is a very general method, particularly adapted for the synthesis of 5- and 5,5-
disubstituted hydantoins from readily available amino esters; (ii) mild reaction conditions
(room temperature) are always used; (iii) in most of the cases, yields are better, compared to
synthesis in solution; (iv) the quantity of waste is reduced – avoiding the use of an excess of
reagents or solvents (including those used to recrystallize the final product), reducing the
environmental impact (Table 4). It was surprising to notice that for all the methods described
in solution using basic conditions, the investigation of the optical purity of the 5-substituted
hydantoins has never been reported.
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22
23
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58
59
60
Indeed, to the best of our knowledge, no chiral HPLC analyses for hydantoin
syntheses have been furnished so far. L-Phenylalanyl hydantoin
benchmark, and chiral HPLC analyses were also performed on the ureido-derivative
precursor , in order to verify the preservation of the optical purity of the compounds.
In the first step (Scheme 2), the synthesis of L-phenylalanyl urea occurred in the
2 was used as
1
1
presence of in situ-generated two equivalents of KOH and gaseous NH3, which could
be responsible of the epimerization. Speculating that reactants in gas phase displayed
limited reactivity under mechanochemical conditions,79 being constantly displaced at
impact with the balls and never combining with the other reagents into the jar, while
one equivalent of KOH was involved in the reaction with the amino ester
hydrochloride, epimerization could occur in this step by action of the remaining
equivalent of KOH. However, chiral HPLC analyses (see Supporting Information)
showed that L-phenylalanyl urea
contrary, the presence of potassium carbonate used in the cyclization step led to
phenylalanyl hydantoin with 90:10 enantiomeric ratio (e.r.). Speculating that
1 was optically pure after the first step. On the
2
epimerization occurred in the second step because of KOH already present in the crude
(after the first step), the reaction was repeated and NH4Cl (1 equiv.) was added to the
jar and ball-milled for 30 min after the first step, to neutralize the extra equivalent of
KOH. However, after cyclization, the e.r. was not improved, while the yield remained
the same. When chiral HPLC analyses were performed on the alanine derivative
7
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(Table 2, entry 7), an 86:14 enantiomeric ratio was obtained. This unexpected
behaviour deserves further investigations and results will be reported in the due course.
Relying on the efficiency and generality of the method, successfully applied to the
sterically hindered amino ester HCl.H-Aib-OMe (Table 3, entry 19), diphenylglycine methyl
ester hydrochloride (Table 3, entry 22) was also investigated as substrate, with the objective
to prepare the anti-epileptic drug Phenytoin 22 (marketed as Phenytek® by Mylan, USA). The
methyl ester was first prepared by refluxing the amino acid with a large excess of SOCl2 in
methanol, and then engaged in the synthesis of phenytoin (See Supporting Information). The
first trials were unsuccessful, even using a large excess of reactants (20 equiv. of KNCO, 40
equiv. of H2O) and dramatic increase of milling speed (700 rpm): no conversion of the
substrate was observed. Trimethylsilyl isocyanate (TMS-NCO), a more reactive alternative to
potassium cyanate was considered (Scheme 3). To our delight, this attempt was successful.
Although the conversion of the substrate was incomplete, the formation of the ureido-
derivative from 5,5-diphenylglycine methyl ester hydrochloride was possible using 3 equiv. of
TMS-NCO. Again, the decomposition of trimethylsilyl isocyanate in presence of water80
accounts for the in-situ generation of the (liquid) base hexamethyldisilazane (HMDS) in the
presence of HCl (provided here by the amino methyl ester hydrochloride), leading also to the
formation of the amino nucleophile. Therefore, water was once again essential to the reaction
allowing the generation of the base as well as, in a second step, the hydrolysis of the N-
protected trimetylsilyl ureido-derivative A of 5,5-diphenylglycine methyl ester (Scheme 3).
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14
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18
19
20
21
22
23
24
25
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Grinding this intermediate with cesium carbonate (3 equiv), as already described
(Table 3), afforded Phenytoin 22, with full conversion of the intermediate. The limiting step
of the reaction being the nucleophilic addition of the amino group onto the isocyanate, a large
excess of a 1:1 mixture of TMS-NCO/H2O (20 equiv) was used with cycled milling, leading
to Phenytoin 22 in 84% yield after eco-friendly work-up, as previously described (Table 3,
entry 22 and Scheme 3). The residual unreacted -diphenylglycine methyl ester was
eliminated by washing the final product with water, and the volatile trimethylsilane by
evaporation.
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Ph
HN
1) TMS-NCO/H2O 1:1 (20 equiv)
450 rpm, 8 h
Ph Ph
Ph
OMe
HCl.H2N
O
2) Cs2CO3 (3 equiv)
N
H
O
O
450 rpm, 3h (cycled)
3) Grinding with NH4Cl / AcOEt
7
22, 84%
8
9
HMDS + NH3 + 2 CO2
2 TMS-NCO + 2 H2O
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14
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19
20
21
22
23
24
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O
Ph Ph
N
Ph Ph
TMS
OMe
OMe
HCl.H2N
TMS-NCO
N
H
H
O
O
A
First step:
in situ generation of the base
O
H2O
Ph Ph
N
OMe
Second step:
H2N
H
in situ hydrolysis of
TMS-ureido derivative
O
O
HN
HN
NH
NH
O
N
N
+
O
O
O
23, 3,6-diphenylglycoluril
24
Main products from mechanochemical Biltz synthesis
Scheme 3. Water-assisted mechanochemical synthesis of Phenytoin 22.
Phenytoin was historically synthesized from the condensation of benzil and urea
according to the Biltz reaction,7,31 remaining the principally used pathway to its obtention. A
few papers reported the formation of phenytoin in solution from the corresponding -amino
amide (-diphenylglycamide) via an heterogeneous tungsten-catalyzed carbonylative
cyclization78 (64% yield after column chromatography, Table 4). -Diphenylglycine ethyl
ester and aryl isocyanates81 were used for the synthesis of N-substituted phenytoin derivatives,
but no data were reported for the preparation of phenytoin from amino ester precursors. These
procedures suffered of constraining conditions (metal-mediated synthesis and handling of
gaseous CO), expensive and/or numerous reagents (e.g. the synthesis of -amino amide), and
organic solvents (for work-up and purification by column chromatography). When the Biltz
synthesis (Scheme 1) was achieved without solvent in a vibrational ball-mill at 30 Hz for two
hours, phenytoin was obtained in only 10% yield. The major products of the reaction were the
3,6-diphenylglycoluril derivative 23 and the 1,3-bis-(2-oxo-1,2-diphenylethylidene)urea 24
issued from the double condensation of benzil with urea (See Scheme 3). In solution, it was
commonly accepted that the mechanism for the formation of phenytoin 22 goes through a
pinacol rearrangement with a 1,2-shift of a phenyl group,31 while the glycoluril by-product
was formed by a double condensation of urea with benzil. It is interesting to observe that
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although the rearrangement was the favourite pathway in solution, the mechanochemical
activation switched the selectivity towards the formation of glycoluril 23 and double
condensation product 1,3-bis-(2-oxo-1,2-diphenylethylidene)urea 24 as the main products. To
compare the mechanical effects of the grinding on the outcome of the reaction,39 we also
tested the Biltz synthesis in a planetary ball-mill. At low rotation speeds (100 and 200 rpm),
the grinding was not efficient and benzil and urea remained unreacted. However, at 450 rpm
(for 30 min) partial conversion of benzil afforded phenytoin 22 in 44% yield, together with
the formation of 23 and 24, as well as other non-identified by-products (Scheme 3). Our
synthetic methodology for obtaining phenytoin under liquid assisted mechanochemical
activation was thus validated by the facts that (i) the Biltz reaction under ball-milling
conditions did not afford phenytoin in good yield, and (ii) our procedure did not generate any
undesired by-product such as 3,6-diphenylglycoluril 23 observed in the Biltz synthesis.
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19
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21
22
23
24
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60
Conclusion
A novel technological achievement for the preparation of 5- and 5,5-di-substituted hydantoins
from amino esters and potassium cyanate was described. The procedure is general and very
advantageous to prepare libraries of five- or six-membered heterocycles, including
dihydrothymine and dihydrouracile, in good to excellent yields. From an environmental point
of view, no solvent, no excess of reagents or purification steps were necessary. In particular,
the methodology was successfully applied to the preparation of the anti-epileptic drug
phenytoin in good yield, as the only cheap alternative to Biltz synthesis under
mechanochemical conditions, opening new frontiers for safe and eco-friendly synthesis of
pharmaceutically interesting drug on large scale.
Experimental Section
General Remarks and Experimental Procedures
All reagents were commercially available and used without any further purification. NMR
spectra were recorded at room temperature with the appropriate deuterated solvent (CD3CN or
d6-DMSO). Chemical shifts (δ) of 1H NMR and 13C NMR spectra are reported in ppm relative
to residual solvent signals (CHCl3 in CDCl3: δ = 7.27 ppm for 1H and CDCl3: δ = 77.04 ppm
for 13C NMR); J values are given in Hz. 1H and 13C NMR spectra were registered at 300 MHz
or 400 MHz. The identity of analytically pure final products was assessed by comparison of
1
their H NMR data previously described in the literature and by their fragmentation in
LC/MS. HRMS measurements were performed on a TOF mass analyser. Analytical high
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performance liquid chromatography (HPLC) was performed with a variable wavelength diode
detector using a CHROMOLITH RP18 column (50 x 4,6 mm), flow 5 mL/min, linear gradient
CH3CN in water 0-100% (+ 0.1% TFA) in 4.5 min. LC-MS analysis were performed with
HPLC, column Onyx C18, (25 x 4.6 mm), flow 3 mL/min linear gradient CH3CN in water 0-
100% (+ 0.1% HCO2H) in 2.5 min. The ball-milling experiments were performed in a
MM200 vibrational ball (Retsch GmbH, Haan, Germany) using 10 mL mill steel jar (2
stainless steel balls, 5 mm Ø), or PM100 planetary mill (Retsch GmbH, Haan, Germany) 12
mL steel jar (12, 24, 36 or 50 stainless steel balls, 5 mm Ø) or 50 mL tungsten carbide (WC)
jar (50 tungsten carbide balls, 5 mm Ø). For tests at 700 rpm, Fritsch Pulverisette 7 Premium
Line planetary mill (Fritsch GmbH, Idar-Oberstein, Germany) using a 20 mL stainless steel
jar (50 stainless steel balls, 5 mm Ø) was used. All compounds displayed identical spectral
data compared to literature.
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(S)-Methyl N-(aminocarbonyl)phenylalaninate 1 (Table 3, entry 1): CAS [928035-69-2].
Method A: L-phenylalanine methyl ester hydrochloride (500 mg, 2.32 mmol), potassium
cyanate (3.8 g, 46.4 mmol, 20 equiv.) and deionised water (92.80 mmol, 1.67 mL, 40 equiv.)
were ball-milled in a 12 mL stainless steel milling jar with 25 stainless steel milling balls (5
mm diameter). The mixture was ground at 500 rpm for 6 cycles of milling of 10 minutes, with
a 5-minute pause in between each cycle, with reverse rotation. 10% aqueous citric acid was
then added to the crude until pH = 6 and the aqueous layer extracted with ethyl acetate (3 x
8mL). The organic layer was dried over MgSO4, filtered under vacuum, concentrated and
dried over P2O5. Diethyl ether was added to the resulting oil and the product precipitated as
white cristals. (500 mg, 2.25 mmol, 97% yield). Method B: L-phenylalanine methyl ester
hydrochloride (500 mg, 2.32 mmol), potassium cyanate (941 mg, 11.6 mmol, 5 equiv. and
deionised water (9.28 mmol, 167 L, 4 equiv.) were ball-milled in a 12 mL stainless steel
milling jar with 25 stainless steel milling balls (5 mm diameter). The mixture was ground at
500 rpm for 6 cycles of milling of 10 minutes, with a 5-minute pause in between each cycle,
with reverse rotation. The crude was transferred on a sintered glass and washed with ethyl
acetate (20 mL) and the organic layer was filtered under vacuum, dried over MgSO4,
concentrated and dried over P2O5, to afford a white solid, which was dried over P2O5. (420.4
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mg, 82% yield); H NMR (300 MHz, DMSO-d6) (ppm) 2.91 (m, 2H), 4.38 (q, 1H, J = 7.9
Hz), 5.64 (s, 2H), 6.29 (d, 1H, J = 8.1 Hz), 7.15-7.31 (m, 5H);66 13C{1H} NMR (300 MHz,
DMSO-d6) (ppm): 7. ESI-(+) m/z:
223 [M+H]+, 245 [M+Na]+, 180.
(5S)-(Phenylmethyl)-2,4-imidazolidinedione 2 (Table 3, entry 2): CAS [3530-82-3]. Step
1: L-phenylalanine methyl ester hydrochloride (250 mg, 1.16 mmol) and potassium cyanate
(282 mg, 3.48 mmol, 3 equiv.) and deionised water (84 L, 4.64 mmol, 4 equiv.) were ball-
milled in a 12 mL stainless steel milling jar with 25 stainless steel milling balls (5 mm
diameter). The mixture was ground at 450 rpm for 6 cycles of milling of 10 minutes, with a 5-
minute pause in between each cycle, with reverse rotation. Step 2: K2CO3 (160 mg, 1.16
mmol, 1 equiv.) was added to the jar and the mixture was ground again for a series of 6 cycles
of milling of 10 minutes, with a 5-minute pause in between each cycle, with reverse rotation.
10% aqueous citric acid is then added to the crude until pH=5 and the aqueous layer was
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extracted with ethyl acetate (3 x 5 mL). The organic layer was dried over MgSO4, filtered,
concentrated and dried over P2O5, affording the title compound as a white solid (173.9 mg,
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80% yield, e.r. 90:10 in favour of the L-isomer); H NMR (300 MHz, DMSO-d6) (ppm)
2.92 (d, 2H, J = 5.1 Hz), 4.33 (t, 1H, J = 6.1 Hz), 7.16-7.28 (m, 5H), 7.94 (s, 1H), 10.44 (s,
1H); 13C{1H} NMR (300 MHz, DMSO-d6) (ppm)36.458.4126.7, 128.1, 129.3, 129.8,
135.6, 157.1; ESI-(+) m/z: 191 [M+H]+.
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Typical procedure for the synthesis of compounds 3-21 (Table 3, entries 3-12 and 14-21).
Step 1: amino methyl ester hydrochloride (250 mg, 1 equiv.), potassium cyanate (3 equiv.)
and deionised water (4 equiv.) were added to a 12 mL stainless steel milling jar with 25
stainless steel milling balls (5 mm diameter). The mixture was ground at 450 rpm for 8 cycles
of milling of 10 minutes, with a 5-minute pause in between each cycle, with reverse rotation.
Step 2: the base (K2CO3, Cs2CO3, triethylamine or a mixture of them, as reported in Table 3)
was added to the jar and the mixture was ground again at 450 rpm for 8 cycles of milling of
10 minutes, with a 5-minute pause in between each cycle, with reverse rotation. Work-up:
NH4Cl (10 equiv) were added to the crude with ethyl acetate (2 mL) and the medium was
ground at 450 rpm for 3 cycles of 10 minutes, with a 5-minute pause in between each cycle,
with reverse rotation. The precipitate, the organic layer and the milling balls were transferred
into a round-bottom flask containing AcOEt (50 mL) and left under stirring until no solid left
on the balls. The organic layer was filtered and concentrated to afford the products as white
solids.
(5R)-(Phenylmethyl)-2,4-imidazolidinedione 3 (Table 3, entry 3). CAS [3530-82-3]: (154.3
mg, 70% yield, e.r. 90:10 in favour of the D-isomer); Step 2: The cyclization was performed
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using K2CO3 (160 mg, 1.16 mmol, 1 equiv.) and Et3N (162 L, 1.16 mmol, 1 equiv.); H
NMR (300 MHz, DMSO-d6) (ppm): 2.91-2.94 (m, 2H), 4.33 (t, 1H, J = 4.1 Hz), 7.17-7.31
(m, 5H), 7.91 (s, 1H), 10.40 (s, 1H);6 13C{1H} NMR (300 MHz, DMSO-d6)  (ppm): 36.4,
58.2, 126.7, 128.1, 129.7, 135.6, 157.0, 175.1; ESI-(+) m/z: 191 [M+H]+.
5-p-(Tert-butyloxyphenyl)methyl-2,4-imidazolidinedione 4 (Table 3, entry 4). (227.6 mg,
quant.). Step 2: The cyclization was performed using Cs2CO3 (849 mg, 2.61 mmol, 3 equiv.).
1H NMR (300 MHz, DMSO-d6) (ppm): 1.26 (s, 9H), 2.88 (m, 2H), 4.28 (t, 1H, J = 5.1 Hz),
13
6.85 (d, 2H, J = 8.5 Hz), 7.09 (d, 2H, J = 8.5 Hz), 7.89 (s, 1H), 10.43 (s, 1H); C{1H} NMR
(300 MHz, DMSO-d6) ppm): 38.6, 35.8, 58.5, 77.7, 123.3, 130.19, 130.23, 153.8, 157.2,
175.3; ESI-(+) m/z: 263 [M+H]+, 248, 207; HRMS ESI-(+): calcd. for C14H18N2O3 [M+H]+
263.1396, found 263.1394.
5-[2-(Methylthio)ethyl]-2,4-imidazolidinedione 5 (Table 3, entry 5). CAS [13253-44-6].
(198.2 mg, 91% yield). Step 2: The cyclization was performed using K2CO3 (173 mg, 1.25
1
mmol, 1 equiv). H NMR (300 MHz, DMSO-d6) ppm):m, 1H), 1.86-1.97 (m,
1H), 2.53 (m, 2H), 4.08 (qd, 1H, J = 1.1 Hz, J = 4.5 Hz), 7.99 (s, 1H), 10.63 (s, 1H);82
13C{1H} NMR (300 MHz, DMSO-d6) ppm):14.9, 29.3, 31.5, 56.9, 157.8, 176.3; ESI-(+)
m/z: 175 [M+H]+, 147, 103.
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3-Methyl-5-[[(phenylmethyl)thio]methyl]-2,4-imidazolidinedione 6 (Table 3, entry 6).
CAS [20210-01-9]. (186.9 mg, 84% yield). Step 2: The cyclization was performed using
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Cs2CO3 (938 mg, 2.88 mmol, 3 equiv). H NMR (300 MHz, DMSO-d6) ppm):2.72 (m,
2H), 3.78 (s, 2H), 4.32 (t, 1H, J = 3.8 Hz), 7.27 (m, 5H), 8.01 (s, 1H), 10.74 (s, 1H); 13C{1H}
NMR (300 MHz, DMSO-d6) ppm):32.0, 35.9, 57.7, 126.9, 128.4, 128.9, 138.3, 157.6,
174.8;83 ESI-(+) m/z: 237 [M+H]+.
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5-Methyl-2,4-imidazolidinedione 7 (Table 3, entry 7). CAS [616-03-5]. (165.0 mg, 81%
yield). Step 2: The cyclization was performed using Cs2CO3 (1.75 g, 5.37 mmol, 3 equiv). 1H
NMR (300 MHz, DMSO-d6) ppm):1.21 (d, 3H, J = 6.9 Hz), 4.02 (qd, 1H, J = 6.9 Hz), 7.87
(s, 1H), 10.57 (s, 1H); 13C{1H} NMR (300 MHz, DMSO-d6) (ppm): 17.5, 55.0, 157.8,
177.1;74 ESI-(+) m/z: 115 [M+H]+, 133 [M+H2O]+.
5-Isopropyl-2,4-imidazolidinedione 8 (Table 3, entry 8). CAS [16935-34-5]. (200.1 mg,
94% yield). Step 2: The cyclization was performed using Cs2CO3 (1.46 g, 4.47 mmol, 3
equiv). 1H NMR (300 MHz, DMSO-d6) ppm): 0.79 (d, 3H, J = 6.8 Hz), 0.93 (d, 3H, J = 6.9
Hz), 1.98 (m, 2H), 3.90 (dd, 1H, J = 1.3 Hz, J = 3.5 Hz), 7.91 (s, 1H), 10.57 (s, 1H);6 13C{1H}
NMR (300 MHz, DMSO-d6) ppm):15.8, 18.6, 29.5, 62.1, 157.8, 175.4; ESI-(+) m/z: 143
[M+H]+, 161 [M+H2O]+.
5-(1-Methylpropyl)-2,4-imidazolidinedione 9 (Table 3, entry 9). CAS [62540-98-1]. (183.6
mg, 85% yield). Step 2: The cyclization was performed using Cs2CO3 (1.35 g, 4.13 mmol, 3
equiv). 1H NMR (300 MHz, DMSO-d6) ppm):0.82-0.91 (m, 6H), 1.16-1.22 (m, 1H), 1.28-
1.33 (m, 1H), 3.94 (dd, 1H, J = 1.1 Hz, J = 3.5 Hz), 7.90 (s, 1H), 10.57 (s, 1H);6 13C{1H}
NMR (300 MHz, DMSO-d6) ppm): 11.6, 15.0, 23.3, 36.3, 62.2, 157.7, 175.4; ESI-(+) m/z:
157 [M+H]+.
5-(2-Methylpropyl)-2,4-imidazolidinedione 10 (Table 3, entry 10). CAS [67337-73-9].
(200.0 mg, 93% yield). Step 2: The cyclization was performed using Cs2CO3 (1.35 g, 4.13
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mmol, 3 equiv). H NMR (300 MHz, DMSO-d6) ppm): 0.85-0.89 (m, 6H), 1.37-1.48 (m,
2H), 1.70-1.77 (m, 1H), 3.97-4.02 (m, 1H), 8.00 (s, 1H);6 13C{1H} NMR (300 MHz, DMSO-
d6) ppm):21.4, 23.1, 24.1, 41.3, 56.1, 157.4, 176.5; ESI-(+) m/z: 157 [M+H]+.
5-Tert-butoxymethyl-2,4-imidazolidinedione 11 (Table 3, entry 11) (218.8 mg, quant.).
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Step 2: The cyclization was performed using Cs2CO3 (1.15 g, 3.54 mmol, 3 equiv). H NMR
(300 MHz, DMSO-d6) ppm):1.10 (s, 9H), 3.49 (m, 2H), 4.07 (pseudo-s, 1H), 7.80 (s, 1H),
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10.49 (s, 1H); C{1H} NMR (300 MHz, DMSO-d6) ppm):27.2, 58.7, 60.5, 72.8, 157.8,
174.3; ESI-(+) m/z: 187 [M+H]+, 205 [M+H2O]+; HRMS ESI-(+): calcd. for C8H14N2O3
[M+H]+ 187.1083, found 187.1083.
5-(1-Tert-butoxyethyl)-2,4-imidazolidinedione 12 (Table 3, entry 12). (139.2 mg, 96%
yield). Step 2: The cyclization was performed using Cs2CO3 (715 mg, 2.20 mmol, 3 equiv).
1H NMR (300 MHz, DMSO-d6) ppm):1.07 (s, 9H), 1.15 (d, 3H, J = 6.3 Hz), 3.83-3.92 (m,
1H), 7.87 (s, 1H); 13C{1H} NMR (300 MHz, DMSO-d6) ppm):20.4, 28.4, 63.9, 65.8, 73.1,
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157.9, 174.5; ESI-(+) m/z: 201 [M+H]+, 145; HRMS ESI-(+): calcd. for C9H16N2O3 [M+H]+
201.1239, found 201.1232.
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Methyl N-(aminocarbonyl)-(tert-butyl)threoninate 13 (Table 3, entry 13). The synthesis
was performed as for compound 2 using Method B (247.7 mg, 96% yield). H NMR (300
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MHz, DMSO-d6) (ppm): 1.07 (pseudo-s, 12H), 3.61 (s, 3H), 4.08-4.18 (m, 1H), 5.84 (s,
2H), 5.98 (d, 1H, J = 9.4 Hz); 13C{1H} NMR (300 MHz, DMSO-d6) (ppm):20.5, 28.1, 51.5,
57.9, 67.3, 73.3, 158.6, 172.1; ESI-(+) m/z: 233 [M+H]+, 255 [M+Na]+, 177, 134; HRMS
ESI-(+): calcd. for C10H20N2O4 [M+H]+ 233.1501, found 233.1501.
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5-Phenyl-2,4-imidazolidinedione 14 (Table 3, entry 14). CAS [89-24-7]. (210.8 mg, 97%
yield). Step 2: The cyclization was performed using Cs2CO3 (1.20 g, 3.69 mmol, 3 equiv) and
Et3N (171 L, 1.23 mmol, 1 equiv.). Work-up: Treatment with NH4Cl followed by washing
with 10% aq. citric acid and drying over P2O5. 1H NMR (300 MHz, DMSO-d6) ppm): 5.16
(s, 1H), 7.32-7.41 (m, 5H), 8.39 (s, 1H), 10.78 (s, 1H);6 13C{1H} NMR (300 MHz, DMSO-d6)
ppm):61.2, 126.7, 128.2, 128.7, 136.1, 157.5, 174.2; ESI-(+) m/z: 177 [M+H]+.
2,5-Dioxo-4-Imidazolidine acetic acid methyl ester 15 (Table 3, entry 15). CAS [78212-
20-1]. (70.6 mg, 32% yield). Step 2: The cyclization was performed using Cs2CO3 (1.24 g,
3.80 mmol, 3 equiv). 1H NMR (300 MHz, DMSO-d6) ppm): 2.71 (d, 2H, J = 5.4 Hz), 4.25
(t, 1H, J = 5.5 Hz), 7.89 (s, 1H), 10.67 (s, 1H); 13C{1H} NMR (300 MHz, DMSO-d6)
ppm):35.3, 51.7, 54.2, 157.6, 159.6, 169.9, 175.1;74 ESI-(+) m/z: 173 [M+H]+, 159, 141,
103.
Benzyl 4-(2,5-dioxoimidazolidin-4-yl)-butylcarbamate 16 (Table 3, entry 16). CAS
[67320-75-6]. (212.7 mg, 91% yield). Step 2: The cyclization was performed using Cs2CO3
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(740 mg, 2.27 mmol, 3 equiv). H NMR (300 MHz, DMSO-d6) ppm):1.08-1.71 (m, 6H),
2.98 (q, 2H, J = 6.3 Hz), 3.98 (t, 1H, J = 4.9 Hz), 5.04 (s, 2H), 7.22-7.41 (m, 5H), 7.93 (s,
1H), 10.59 (s, 1H); 13C{1H} NMR (300 MHz, DMSO-d6) ppm):21.5, 29.0, 30.9, 57.5,
65.1, 74.3, 127.7, 128.3, 137.3, 156.1, 157.5, 176.1; ESI-(+) m/z: 306 [M+H]+, 328 [M+Na]+,
262; HRMS ESI-(+): calcd. for C15H19N3O4 [M+H]+ 306.1454, found 306.1451.
Tetrahydro-1H-Pyrrolo(1,2-c)-imidazole-1,3(2H)-dione 17 (Table 3, entry 17). CAS
[5768-79-6]. (191.7 mg, 91%). Step 2: The cyclization was performed using K2CO3 (492 mg,
1.51 mmol, 1 equiv) and Et3N (211 L, 1.51 mmol, 1 equiv). 1H NMR (300 MHz, DMSO-d6)
ppm):1.58-1.71 (m, 1H), 1.91-2.08 (m, 3H), 2.97-3.08 (m, 1H), 3.42-3.50 (m, 1H), 4.08-
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4.14 (m, 1H), 10.74 (s, 1H); C{1H} NMR (300 MHz, DMSO-d6) ppm):26.6, 26.7, 44.9,
63.9, 160.9, 175.4;21 ESI-(+) m/z: 141 [M+H]+.
5-(1H-Indol-3-ylmethyl)-2,4-imidazolidinedione 18 (Table 3, entry 18) CAS [21753-16-2].
(131.2 mg, 77% yield). Step 2: The cyclization was performed upon urea derivative (193 mg,
0.44 mmol) using Cs2CO3 (426 mg, 1.30 mmol, 3 equiv) and Et3N (61 L, 0.44 mmol, 1
equiv). Work-up: Treatment with NH4Cl followed by washing with 10% aq. citric acid and
drying over P2O5. 1H NMR (300 MHz, DMSO-d6) ppm): 3.06 (d, 2H, J = 4.8 Hz), 4.30 (t,
1H, J = 4.0 Hz), 6.94 (t, 1H, J = 6.9 Hz), 6.99 (t, 1H, J = 7.0 Hz), 7.12 (d, 1H, J = 2.3 Hz),
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7.31 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 7.8 Hz), 7.88 (s, 1H), 10.35 (s, 1H), 10.89 (s, 1H);
13C{1H} NMR (300 MHz, DMSO-d6) ppm):26.5, 58.3, 107.9, 111.2, 118.3, 118.6, 120.8,
124.1, 127.5, 135.9, 157.4, 175.8; ESI-(+) m/z: 230 [M+H]+, 130.
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Methyl 2-amino-2-methylpropanoate hydrochloride. CAS [15028-41-8]. To a suspension
of 2-aminoisobutyric acid (2.34 g, 22.70 mmol) in anhydrous methanol (15 mL) was slowly
added trimethylsilyl chloride (12.70 mL, 100.00 mmol, 4.4 equiv) at 0°C under N2. The
mixture was left under stirring for 48h at room temperature. The solvent was then evaporated
and the white solid was recrystallized in diethyl ether. The white crystals were dried over
P2O5. (3.38 g, 97% yield); 1H NMR (300 MHz, DMSO-d6) ppm): 1.48 (s, 6H), 3.73 (s, 3H),
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8.80 (broad s, 3H); C{1H} NMR (300 MHz, DMSO-d6) ppm):23.2, 53.1, 55.7, 171.9;84
ESI-(+) m/z: 118 [M+H]+.
5,5’-Dimethyl-2,4-imidazolidinedione 19 (Table 3, entry 19). CAS [77-71-4]. (192.2 mg,
92% yield). Step 2: The cyclization was performed using K2CO3 (225 mg, 1.63 mmol, 1
1
equiv). H NMR (300 MHz, DMSO-d6) ppm): 1.24 (s, 6H), 7.94 (s, 1H), 10.54 (s, 1H);
13C{1H} NMR (300 MHz, DMSO-d6) ppm):24.6, 58.8, 155.9, 179.1;85 ESI-(+) m/z: 129
[M+H]+.
Dihydrouracil 20 (Table 3, entry 20). CAS [504-07-4]. (96.2 mg, 47% yield). Step 2: The
cyclization was performed using Cs2CO3 (1.75 g, 5.37 mmol, 3 equiv). Work-up: Filtration of
the salts on silica with pure ethyl acetate was performed to recover the product. 1H NMR (300
MHz, DMSO-d6) ppm): 2.43 (t, 2H, J = 6.8 Hz), 3.19 (td, J = 2.7 Hz, J = 6.8 Hz), 7.47 (s,
13
1H), 9.93 (s, 1H); C{1H} NMR (300 MHz, DMSO-d6) ppm):30.4, 35.4, 154.0, 171.1;86
ESI-(+) m/z: 133 [M+H]+.
Methyl 3-amino-2-methylpropanoate hydrochloride. To a suspension of 3-aminoisobutyric
acid (5.00 g, 56.12 mmol) in anhydrous methanol (25 mL) was slowly added trimethylsilyl
chloride (35.61 mL, 280.62 mmol) at 0°C under N2. The mixture was left under stirring for
48h at room temperature. The solvent was then evaporated and the white solid was
recrystallized in diethyl ether. The white crystals were dried over P2O5. (1.14 g, 75% yield);
CAS [137132-12-8]. 1H NMR (300 MHz, DMSO-d6) ppm): 1.16 (d, 3H, J = 6.6 Hz), 2.86
(m, 2H), 3.03 (m, 1H), 3.64 (s, 3H), 8.26 (broad s, 3H); 13C{1H} NMR (300 MHz, DMSO-d6)
ppm):14.7, 40.7, 52.0, 173.7; ESI-(+) m/z: 118 [M+H]+; HRMS ESI-(+): calcd. for
C5H11NO2 [M+H]+ 118.0868, found 118.0868.
Dihydrothymine 21 (Table 3, entry 21). CAS [696-04-8]; (118.9 mg, 57% yield); Step 2:
The cyclization was performed using Cs2CO3 (1.59 g, 4.88 mmol, 3 equiv). Work-up: Same as
1
compound 20. H NMR (300 MHz, DMSO-d6) ppm): 1.04 (d, 3H, J = 7.0 Hz), 2.52-2.59
(m, 1H), 2.93 (t, 1H, J = 11.0 Hz), 3.20-3.27 (m, 1H), 7.48 (s, 1H), 9.89 (s, 1H); 13C{1H}
NMR (300 MHz, DMSO-d6) ppm): 12.6, 34.5, 42.2, 154.2, 174.0; ESI-(+) m/z: 129
[M+H]+.
Methyl 2-amino-2,2-phenylacetate. To a suspension of -diphenylglycine (2.00 g, 8.80
mmol) in methanol (25 mL) was added thionyl chloride (0.64 mL, 8.80 mmol) at 0°C and the
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mixture was left under stirring overnight at room temperature. Thionyl chloride (2.56 mL,
36.20 mmol) was added slowly at 0°C and the reaction medium was refluxed for 8 h, then,
left under stirring overnight at room temperature. This operation was repeated twice again,
adding 5 equiv. of SOCl2 each time. The solvent was evaporated and an aqueous solution of
NaHCO3 5% aq. (10 mL) was added to the crude, followed by extraction with ethyl acetate (3
x 5 mL). The organic layer was dried over MgSO4 and concentrated. The crude was
solubilized in methanol (25 mL) and HCl 1N (4.5 mL) was added. The mixture was left under
stirring for 1 hour. The solvent was then evaporated and the white solid was recrystallized in
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diethyl ether and dried over P2O5. (1.06 g, 43% yield). CAS [93504-24-6]; H NMR (300
MHz, DMSO-d6) ppm): 3.86 (s, 3H), 7.31-7.49 (m, 10H), 9.74 (broad s, 3H); 13C{1H}
NMR (300 MHz, DMSO-d6) ppm): 54.1, 68.4, 127.8, 128.7, 129.3, 136.8, 169.6; ESI-(+)
m/z: 242 [M+H]+, 225, 197, 165; HRMS ESI-(+): calcd. for C15H15NO2 [M+H]+ 242.1181,
found 242.1181.
5,5-Diphenyl-2,4-imidazolidinedione (or Phenytoin) 22 (Table 3, entry 22). Step 1.
diphenylglycine methyl ester hydrochloride (125 mg, 0.45 mmol) trimethylsilyl
isocyanate (488 L, 3.60 mmol, 8 equiv.) and deionised water (81 L, 4.50 mmol, 10 equiv.)
were added in a 12 mL stainless steel milling jar with 25 stainless steel milling balls (5 mm
diameter). The mixture was ground continuously at 450 rpm for 3 hours. Trimethylsilyl
isocyanate (488 L, 3.60 mmol, 8 equiv.) and deionised water (81 L, 4.50 mmol, 10 equiv.)
were added and the mixture was ground again for 3 hours at 450 rpm. A last portion of
trimethylsilyl isocyanate (244 L, 1.80 mmol, 4 equiv.) was added with no additional water
and the reaction mixture was ground at 450 rpm for 2 hours. Step 2. Cs2CO3 (440 mg, 1.35
mmol, 3 equiv.) was added to the jar and the mixture was ground for a series of 12 cycles of
milling (10 minutes milling followed by 5-minute pause in between each cycle, with reverse
rotation). Work-up. NH4Cl (481 mg, 9.0 mol, 20 equiv.) and ethyl acetate (2 mL) were added
to the crude and the mixture was ground at 450 rpm for 3 cycles of 10 minutes followed by 5-
minute pause in between each cycle, with reverse rotation. The precipitate, the organic layer
and the milling balls were transferred into a round-bottom flask containing AcOEt (50 mL)
and left under stirring until no solid was left on the balls. The organic layer was filtered and
concentrated in vacuo to afford the product as a white solid (95.6 mg, 84% yield); CAS [57-
1
41-0]; H NMR (300 MHz, DMSO-d6) ppm):7.26-7.40 (m, 10H), 9.31 (s, 1H), 11.10 (s,
13
1H); C{1H} NMR (300 MHz, DMSO-d6) ppm): 70.2, 126.6, 128.0, 128.5, 139.9, 155.9,
174.6;87 ESI-(+) m/z: 253 [M+H]+, 225.
Acknowledgements
The authors are grateful to Mr. Julien Fullenwarth (Institut Charles Gerhardt, Montpellier) for
the access to the Planetary Mill Pulverisette 7 Premium (Fritsch) for some experiments.
Supporting Information. 1H and 13C spectral data of all compounds. Chiral HPLC analyses
of compounds
1
,
2
and
7
.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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