Regioselective multicomponent sequential synthesis of hydantoins

Article abstract of DOI:10.1039/c2ob26498f

The development of new practical and green methods for the synthesis of small heterocycles is an attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the drug discovery process. Herein we report a one-pot, three-component sequential procedure for the synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions, using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which are particularly interesting bioactive compounds in medicinal chemistry. The Royal Society of Chemistry 2012.

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PAPER
Regioselective multicomponent sequential synthesis of hydantoins†
Francesca Olimpieri,a Maria Cristina Bellucci,b Tommaso Marcellia and Alessandro Volonterio*a
Received 31st July 2012, Accepted 21st September 2012
DOI: 10.1039/c2ob26498f
The development of new practical and green methods for the synthesis of small heterocycles is an
attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the
drug discovery process. Herein we report a one-pot, three-component sequential procedure for the
synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions,
using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic
carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which
are particularly interesting bioactive compounds in medicinal chemistry.
also being pursued, when possible, by implementation of classi-
cal MCRs in synthetic sequences, as well as by the invention of
Introduction
The complexity of organic target molecules is constantly increas-
ing and, consequently, novel strategies allowing the efficient for-
mation of new carbon–carbon and carbon–heteroatom bonds
between functionalized building blocks are needed. During the
past 50 years, extraordinary progress in the discovery of new
reagents, reactions, and synthetic strategies has been made.1 On
the other hand, the tools of synthetic organic chemistry are often
found inadequate when confronted with the challenge of prepar-
ing even modestly elaborate molecules in a practical and concise
fashion. A seemingly trivial but rather serious practical limitation
is set by the mere number of steps accumulating in linear
sequences and by the need for protecting-group strategies. In this
respect, step economy is an important factor, since accessibility
highly depends on the amount of steps required to reach the
desired compounds.2 Procedures that yield molecules by per-
forming multiple reaction steps in which several bonds are
formed without isolation of intermediates are commonly referred
to as tandem or domino reactions.3 Another powerful approach
toward this goal is to combine two or more distinct reactions into
a single transformation, thereby producing a sequential reaction
process.4 The intrinsic advantage of such a process is twofold:
on the one hand it provides a favorable step economy and, on the
other hand, it contributes to the implementation of the green
chemistry guidelines due to the reduced waste production and
increased atom economy. An important subclass of domino reac-
tions are multicomponent reactions (MCRs).5 Thus, efficiency is
new protocols. In particular, “one-pot” MC sequential syntheses,
in which a number (≥2) of synthetic steps involving three or
more reactants are carried out in the same flask without isolation
of any intermediate, feature a high degree of reaction mass
efficiency and are especially suitable in combinatorial chemistry
and diversity-oriented synthesis programs, thus playing a central
role in the development of modern synthetic methodology for
pharmaceutical and drug discovery research.
Traditionally, methods based on cascade and/or MC reactions
have proved quite efficient for the construction of many different
types of heterocycles.6 In fact, many small synthetic organic
molecules with biological activity contain heterocyclic rings.
Despite the tremendous advancements in the areas of synthetic
and combinatorial chemistry, suitably functionalized “privi-
leged” scaffolds are seldom easily or readily accessible. Con-
sequently, the exponentially increased cost of lead generation
and optimization has contributed to the introduction of far fewer
drugs over the past decade.7 Thus, new strategies with reduced
number of steps and purification procedures, lower costs, and
minimized chemical waste are still in high demand. Among the
“privileged” heterocyclic scaffolds, hydantoins have been widely
used in biological screenings resulting in numerous pharma-
ceutical applications.8 In fact, many functionalized hydantoins
have been identified as anti-convulsants9 and antimuscarinics,10
antiulcers and antiarrythmics,11 antivirals, antidiabetics,12 seroto-
nin and fibrinogen receptor antagonists,13 inhibitors of the
glycine binding site of the NMDA receptor,14 and antagonists of
leukocyte cell adhesion acting as allosteric inhibitors of the
protein–protein interaction.15 The observed activities usually do
not arise from the heterocycle itself but from the different substi-
tuents that have been attached to it. Indeed, by varying the nature
of peripheral substituents on this molecular framework, it is
often possible to obtain hits across a wide range of biological
targets. Moreover, substituted hydantoins are important building
aDepartment of Chemistry, Materials and Chemical Engineering
“Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milano,
Italy. E-mail: alessandro.volonterio@polimi.it; Fax: +39 0223993080;
Tel: +39 0223993139
bDipartimento di Chimica Agroalimentare, Università degli Studi di
Milano, via Celoria 2, 20133 Milano, Italy
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26498f
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blocks for the synthesis of nonnatural amino acids both in a
racemic form by alkaline degradation16 and in an enantio-
selective way by enzymatic resolution.17 For this reason, there is
high interest in developing new strategies for a straightforward
synthesis of selectively substituted hydantoins both in solution
and in the solid phase. To date, the most utilized strategy to
prepare substituted hydantoins is the strongly acidic or basic
cyclization of ureido acids obtained from the reaction of
α-amino acids or α-amino nitriles with alkyl, aryl, or chloro-
sulfonyl isocyanates, respectively, which is a multi-step sequence
and requires extended reaction time or high temperatures.18 In
this way, 3,5-di and 3,5,5-trisubstituted hydantoins are readily
accessible, while for the synthesis of 1,3,5-tri and 1,3,5,5-tetra-
substituted hydantoins it is necessary to perform a preliminary
alkylation of the amino function by reductive amination19 or
via Mitsunobu reaction.20 Various different routes/methods
for the synthesis of hydantoins have been recently developed
both in solution and in the solid phase to remove the drawbacks
associated with the above strategy.21 However, even if some
of these methods allow the synthesis of hydantoins under
milder conditions, none of them meet the modern requirements
to be “green” and “practical”, all of them being multi-step
procedures.
Very recently, we have developed an efficient three-component
sequential, domino process for the synthesis of libraries of 1,3-
disubstituted-5-arylhydantoins with a high degree of diversity
starting from simple and easily accessible reactants, such as
azides, iso(thio)cyanates and α-bromo-arylacetic acids.22 In this
paper, we provide a full account on the scope and limitations of
this new methodology, which has been studied in detail by per-
forming the reaction on many differently substituted α-bromocar-
boxylic acids. The results reported herein dramatically expand
the scope of the process and allow for the preparation of a poten-
tially very large array of structurally diverse, 1,3,5-tri and
1,3,5,5-tetrasubstituted hydantoins, including highly interesting
spiro-hydantoin scaffolds,23 in a mild (room temperature), practi-
cal and green fashion.
Scheme 1 Synthesis of hydantoins 5.
Synthesis of the starting materials
When not commercially available (like acids 1a,c,e,f,g), the start-
ing α-halo-carboxylic acids could be conveniently prepared by
two different high yielding strategies, namely α-halogenation of
the corresponding acids or esters, or substitution of the amino
moiety of the corresponding α-amino acids with bromine via a
diazonium salt (Scheme 2). The only exception to this is
α-chloro-diphenylacetic acid 1b that was efficiently prepared by
treating the corresponding α-hydroxy acid 7 with acetyl chloride
in DCM (eqn (1), Scheme 2).26 Accordingly, α-bromo-3-phenyl-
propionic acid 1d was synthesized by treating phenylalanine 8
with sodium nitrite in
a HBr/KBr solution (eqn (2),
Scheme 2),27 while bromination of acids 9 and 10 carried out
Results
Within an ongoing project aimed at the development of mild
domino processes for the synthesis of heterocycles by reacting
carbodiimides with suitable carboxylic acids,24 we envisioned
the possibility to synthesize fully substituted hydantoins by
using α-bromo-carboxylic acids as starting materials (Scheme 1).
Indeed, considering the mechanism of the coupling reaction of
carboxylic acids and nucleophiles promoted by carbodiimides,25
we envisioned that α-bromo-carboxylic acids 1 could react with
carbodiimides 2 to form a reactive intermediate O-acylisourea 4,
which, in the absence of a nucleophile, could readily cyclize to
intermediate 5 through an intramolecular nucleophilic displace-
ment of the halide. The following O → N acyl migration could
give rise to the formation of hydantoin 3. In some cases, the
O → N acyl migration could compete with the cyclization,
leading to the formation of N-acylurea 6 as a by-product or,
occasionally, as the main product. However, N-acylureas 6 can
be convergently transformed into the target hydantoins 3 by
in situ treatment with a suitable base.
Scheme 2 Synthesis of the starting α-halo carboxylic acids 1.
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with NBS in CCl4 gave rise to the formation of the corres-
ponding α-bromo acids 1h,i in high yields (eqn (3) and (4),
Scheme 2).28
formation of a complex mixture of products. However, by using
potassium tert-butoxide as the base we were able to isolate the
desired hydantoin 3i in good yields (entry 16, Table 1).
It is worth noting that the last process leads to the formation
of spiro-hydantoins, a very interesting class of compounds for
applications in medicinal chemistry.23
Reaction with symmetric carbodiimides
In order to assess the suitability of the envisioned process, we
started our study with commercially available α-Br-phenylacetic
acid 1a, which features a highly reactive electrophilic atom,
namely the benzylic carbon which bears in the α position an
excellent leaving group (the halogen atom) and another activat-
ing moiety such as the carboxy group. With respect to the carbo-
diimide component, we chose commercially available symmetric
N,N′-dialkyl carbodiimides, such as DCC and DIC. Accordingly,
by reacting 1a with DCC 2a, in the presence of 2,4,6-trimethyl-
pyridine (TMP), we obtained the formation of hydantoin 5a as
the only product. The yields of the process were dependent
on the solvent: the best result was obtained with apolar DCM
(entry 3, Table 1), while lower yields were obtained with more
polar solvents such as acetonitrile (entry 1, Table 1) and dioxane
(entry 2, Table 1). Similarly, by reacting the same acid 1a with
DIC 2b, we observed the formation of hydantoin 3b in moderate
yields when the reaction was performed in dioxane and in excel-
lent yields when performed in DCM (entries 4 and 5, respecti-
vely, Table 1). As expected, highly reactive α-chloro-
diphenylacetic acid 1b smoothly reacted with DIC 2b in DCM
giving rise to the formation of hydantoin 3c, although in lower
yields (entry 6, Table 1). Less electrophilic α-bromo-butanoic
acid 1c reacted with DCC 2a producing N-acylurea derivative 6a
in modest yields when the reaction was performed in DCM
(entry 7, Table 1). By using a more polar solvent, such as
dioxane, we increased the overall yields of the process obtaining
an almost equimolar mixture of the N-acylurea 6a and the
desired hydantoin 3d (entry 8, Table 1). Rewardingly, the in situ
addition of a suitable base (aqueous 2 N NaOH solution)
triggered the cyclization of 6a leading to the exclusive formation
of hydantoin 3d in good yields (entry 9, Table 1). Moreover, by
carrying out the reaction in highly polar DMF, which facilitates
the intramolecular nucleophilic displacement of the halide, we
were able to obtain the hydantoin 3d as the only product without
the need for a base (entry 10, Table 1). As expected, also acid 1d
reacted with DCC 2a and DIC 2b in DMF producing hydantoins
3e,f, respectively, in good yield (entries 11 and 12, Table 1).
Acid 1e, bearing the bromine atom on a quaternary carbon, is
even less reactive than 1c,d. Indeed, by reacting 1e with DCC 2a
in DMF, we obtained the formation of N-acylurea 6b along with
the desired hydantoin 3g in very good yields (entry 13, Table 1).
Again, by adding aqueous soda in situ, we were able to promote
the cyclization pathway with the exclusive formation of hydan-
toins 3d,e when acid 1e was reacted with DCC 2a and DIC 2b,
respectively (entries 14 and 15, Table 1). Surprisingly, cyclic
α-bromo-carboxylic acids such as 1f were even less reactive than
1e with respect to the intramolecular nucleophilic substitution.
Thus, when 1f was reacted with DCC 2a in DMF we obtained
the formation of N-acylurea derivative 6c as the sole product in
high yields (entry 15, Table 1). The different behaviour in the
nucleophilic displacement of the bromine atom was observed
also by reacting the intermediate 6c with an aqueous solution of
NaOH which did not trigger the cyclization but led to the
Next, we studied the behaviour of less reactive symmetric
N,N′-diaryl carbodiimides (Scheme 3). Since N,N′-di-p-tolyl
carbodiimide 2c is poorly soluble in DCM, we performed
the reaction with acid 1a in dioxane as the solvent, recovering
N-acylurea derivative 6d as the only product in high yields
(eqn (1), Scheme 3). By adding a 2 N aqueous solution of
NaOH in situ, we were able to trigger the intramolecular dis-
placement of the bromine atom and to isolate the target hydantoin
3k very efficiently (eqn (2), Scheme 3). To obtain good results
with less reactive acid 1c, we had to run the reaction in even
more polar DMF. Accordingly, when 1c was reacted with N,N′-
diphenyl carbodiimide 2d we only recovered N-acylurea deriva-
tive 6e (eqn (3), Scheme 3), whereas, by adding potassium tert-
butoxide at the end of the process, we obtained the clean for-
mation of the corresponding hydantoin in high yields (eqn (4),
Scheme 3). Finally, quaternary carboxylic acids 1e,f reacted
smoothly with carbodiimide 2d giving rise to the formation of
the corresponding N-acylurea derivatives in high yields (eqn (5)
and (6), Scheme 3). However, the N-acylurea derived from acid
1e could be easily and efficiently cyclized to hydantoin 3m by
adding to the reaction mixture a 2 N NaOH aqueous solution
(eqn (5), Scheme 3), while we were not able to cyclize N-acyl-
urea 6f either by using sodium hydroxide or potassium tert-but-
oxide, confirming the fact that N-acylureas derived from cyclic
carboxylic acids are less prone to form the corresponding
hydantoins.
Reaction with asymmetric carbodiimides
In previous work,24b we have defined “strongly asymmetric”
those carbodiimides that have two very different N-substituents
in terms of electronic features, such as an aromatic and an alkyl
substituent, and “weakly asymmetric” those carbodiimides
that have two alkyl substituents at the nitrogen atoms which are
very different in terms of steric bulkiness. We have demonstrated
that both “strongly” and “weakly asymmetric” carbodiimides
react with activated α,β-unsaturated carboxylic acids giving
rise to the formation of hydantoins with mostly perfect
regioselectivity.24b
In order to assess whether the reaction of substituted α-halo-
carboxylic acids with asymmetric carbodiimides could be used
for the regioselective synthesis of fully substituted hydantoins,
we decided to use “weakly asymmetric” N-benzyl, N′-tert-butyl
carbodiimide 2e as a model compound (Scheme 4). Gratifyingly,
“weakly asymmetric” carbodiimide 2e reacted smoothly with
α-bromo-phenylacetic acid 1a under the above mentioned con-
ditions, namely TMP and DCM as solvents, giving rise to the
formation of hydantoin 3n as the only regioisomer in very good
yields (eqn (1), Scheme 4).
The reaction of the same carbodiimide with less reactive acid
1c performed in DMF was again completely regioselective even
if an almost equimolar mixture of N-acylurea 6g and hydantoin
3o was formed (eqn (2), Scheme 4). Again, by adding a 2 N
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Table 1 Reaction between differently substituted α-haloacetic acids 1 and symmetric N,N′-dialkylcarbodiimides 2
Entry
1
Acid
Carbodiimide
Solvent
CH3CN
Method
A
Base
/
Product
Yield (%)
33
2
3
Dioxane
DCM
A
A
/
/
57
>98
4
5
6
Dioxane
DCM
A
A
A
/
/
/
45
>98
68
DCM
7
DCM
A
/
46
8
Dioxane
Dioxane
DMF
A
/
35% (6a)
44% (3d)
9
A + B
NaOH (2 N)
68
65
10
A
/
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Table 1 (Contd.)
Entry
11
Acid
Carbodiimide
Solvent
DMF
Method
A
Base
/
Product
Yield (%)
71
12
DMF
A
/
65
13
14
DMF
DMF
A
/
32 (6b)
44 (3g)
A + B
NaOH (2 N)
66
15
16
DMF
DMF
A + B
NaOH (2 N)
69
84
A
/
17
DMF
A + B
tert-BuOK
63
NaOH aqueous solution to the reaction mixture we were able to
obtain the exclusive formation of hydantoin 3o, again as a single
regioisomer, in good yields (eqn (3), Scheme 4). Under the same
conditions, also unactivated quaternary acid 1e reacted with 2e
producing hydantoin 3p as the only regioisomer (eqn (4),
Scheme 4).
As expected, the process was completely regioselective also
with “strongly asymmetric” carbodiimides even if the latter were
less reactive than the “weakly asymmetric” ones. In fact, after
reacting acid 1a with N-p-MeO-benzyl, N′-p-MeO-phenyl carbo-
diimide 2f we recovered an inseparable mixture of N-acylurea 6h
and hydantoin 3q as single regioisomers (eqn (1), Scheme 5).
Also in this case, cyclization under Schotten–Bauman conditions
led to the regioselective formation of hydantoin 3q in high
yields (eqn (2), Scheme 5). By reacting acid 1c with N-benzyl,
N′-phenyl carbodiimide 2g, we obtained the formation of N-acyl-
urea 6i in better yields when the reaction was carried out in
dioxane (eqn (4), Scheme 5) as compared to DMF (eqn (3),
Scheme 5). Again, triggering the intramolecular nucleophilic dis-
placement of the bromine atom by adding a base (NaOH) to the
reaction mixture, we produced hydantoin 3r in good yields
(eqn (5), Scheme 5). Finally, also quaternary carboxylic acid 1e
reacted smoothly with “strongly asymmetric” carbodiimide 2g
giving rise to the formation of N-acylurea 6j (eqn (6), Scheme 5)
or hydantoin 3q when a 2 N NaOH aqueous solution was added
at the end of the reaction (eqn (7), Scheme 5).
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Scheme 5 Reactions with “strongly symmetric” N-benzyl, N′-phenyl
carbodiimide.
intermediates 6 are formed) cyclization triggered by adding a
suitable base to the reaction mixture (Table 2).
Scheme 3 Reactions with symmetric N,N′-diaryl carbodiimides.
Therefore, by reacting benzyl azide 12a with benzyl iso-
cyanate 13a in the presence of Ph3P in DCM, we detected the clean
formation of carbodiimide 2aa along with the Ph3PO by-product
(TLC monitoring). Next, by adding to the reacting mixture TMP
followed by acids 1a and 1h, we observed the formation of
hydantoins 3aa,ab, respectively, in good yields (entries 1 and 2,
Table 2). The process worked efficiently also with less reactive
acids 1c and 1f producing hydantoins 3ac,ad in acceptable
yields (entries 3 and 4, Table 2). In these cases, in order to be
able to run the process in an MC sequential fashion, the for-
mation of the carbodiimide 2aa through the Staudinger reaction
was achieved using DMF as a solvent. Moreover, as expected,
the reaction between quaternary acid 1f and in situ formed carbo-
diimide 2aa led to the formation of the corresponding N-acylurea
(data not shown) which was cyclized by adding potassium tert-
butoxide to the reaction mixture. “Weakly asymmetric” carbodi-
imides reacted straightforwardly also when involved in the MC
sequential process. Indeed, the reaction of azide 12b with com-
mercially available tert-butyl isocyanate 13b cleanly produced
carbodiimide 2ab in DCM which reacted with arylacetic acid 1a
leading to the formation of hydantoin 3ae as a single regioi-
somer (entry 5, Table 2). Similarly, carbodiimide 2ac, obtained
from azide 12a and isocyanate 13b, reacted with acid 1g provid-
ing hydantoin 3af, with complete regioselectivity and in good
overall yields (entry 6, Table 2). By performing the process in
DMF and adding a suitable base when the N-acylureas were
formed (TLC monitoring), we achieved the regioselective for-
mation of hydantoins 3ag,ah with acids 1c,f, respectively
Scheme 4 Reactions with “weakly symmetric” N-benzyl, N′-tert-butyl
carbodiimide.
MC sequential synthesis of hydantoins 3
With these results in hand, we turned our attention to the possi-
bility of preparing fully substituted hydantoins 3 through an MC
sequential process consisting of (1) in situ preparation of the
reacting carbodiimides 2 through the Staudinger reaction
between azides 12 and isocyanates 13, (2) reaction with the acid
1 to be added to the reaction mixture once the carbodiimide 2
is formed (TLC monitoring), and (3) (when N-acylurea
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Table 2 Three-component sequential synthesis of 1,3,5- and 1,3,5,5-substituted hydantoins
Entry
1
Azide
Iso(thio)cyanate
Carbodiimide
Acid
Solvent
DCM
Method
A
Base
/
Product
Yield (%)
61
2
DCM
A
/
63
3
4
5
DMF
DMF
DCM
A
/
56
51
55
A + B
tert-BuOK
A
/
6
7
DCM
DMF
A
/
51
60
A + B
2 N NaOH

Table 2 (Contd.)
Entry
8
Azide
Iso(thio)cyanate
Carbodiimide
Acid
Solvent
DMF
Method
A + B
Base
Product
Yield (%)
49
tert-BuOK
9
–NCS 13c
DCM
DCM
A
/
68
83
10
A + B
2 N NaOH
11
12
DCM
DCM
A + B
2 N NaOH
90
69
A
/
13
DCM
A + B
NaOH (2 N)
65

14
15
DMF
DMF
A + B
A + B
NaOH (2 N)
65
72
tert-BuOK
16
DMF
A + B
tert-BuOK
75
17
18
DCM
DCM
A + B
A + B
NaOH (2 N)
NaOH (2 N)
69
72
19
DCM
A + B
NaOH (2 N)
95
20
21
DCM
DCM
A + B
NaOH (2 N)
56
62
A
/

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(entries 7 and 8, Table 2). As expected, the reactions with
“weakly asymmetric” carbodiimide were regioselective only
when there is a substantial difference in the steric hindrance of
the two carbodiimide N-substituents. In fact, when carbodiimide
2ad, obtained by the Staudinger reaction between p-MeO-benzyl
azide 12c and methylisothiocyanate 13c, was reacted with acid
1a, we obtained an equimolar mixture of the two regioisomeric
hydantoins 3ai,ai′ (entry 9, Table 2).
Thus, we studied the behaviour of “strongly asymmetric” car-
bodiimides in the MC sequential process. As expected, in situ
formed carbodiimide 2ae reacted with highly reactive acids 1a,g
giving rise to the formation of a mixture of the corresponding
N-acyl-ureas and hydantoins (data not shown). However, by
adding a 2 N NaOH aqueous solution once the mixtures were
formed, we were able to produce hydantoins 3aj,ak, respectively,
as single regioisomers in excellent yields (entries 10 and 11,
Table 2). Even the strongly activated α-chloro-diphenylacetic
acid 1b reacted with in situ formed N-benzyl, N′-p-MeO-phenyl
carbodiimide 2af leading to the formation of regioisomeric
hydantoin 3al in DCM and without the need for a base
(entry 12, Table 2).
Although less reactive than 1a, acid 1i produced regioselec-
tively hydantoin 3am in good yields upon reaction carried out in
DCM with in situ formed carbodiimide 2ag, followed by
addition of aqueous NaOH (entry 13, Table 2). As expected,
“strongly asymmetric” carbodiimides were effective also with
weakly electrophilic α-bromo acids 1c,f by carrying out the reac-
tion in DMF and triggering the cyclization of the N-acylurea
intermediates by adding a suitable base to the reaction mixture.
Indeed, acid 1c regioselectively yielded hydantoin 3an when
reacted with N-benzyl, N′-p-MeO-phenyl carbodiimide 2af and
by promoting the nucleophilic displacement of the halide by 2 N
NaOH (entry 14, Table 2). The same carbodiimide 2af as well
as N-benzyl, N′-p-NHAc-phenyl carbodiimide 2ae reacted
smoothly with acid 1f giving rise to the regioselective formation
of spiro-hydantoins 3ao,ap, respectively, in very high yields
after promoting the cyclization with potassium tert-butoxide
(entries 15 and 16, Table 2). Finally, we studied the possibility to
synthesize N,N′-diaryl hydantoins through this MC sequential
process. As expected, the Staudinger reaction between p-MeO-
phenyl azide 12e and p-MeO-phenyl isocyanate 13d worked
very efficiently both in DCM and DMF as solvents, producing
carbodiimide 2ah in almost quantitative yields. Such carbodii-
mide reacted in situ with arylacetic acids 1a,g,h leading to the
formation of hydantoins 3aq-as, respectively, after cyclization
under Schotten–Bauman conditions (entries 17–19, Table 2).
Likewise, also acid 1i was effective in producing hydantoin 3at
in acceptable yields (entry 20, Table 2). Again, more electrophi-
lic diarylacetic acid 1b yielded hydantoin 3au with no trace of
the intermediate N-acylurea (entry 21, Table 2). By shifting the
solvent to more polar DMF and triggering the cyclization of the
N-acylurea intermediates with a suitable base, we could obtain
the straightforward synthesis of hydantoins 3av,aw starting with
acids 1c and 1e, respectively (entries 22 and 23, Table 2).
Discussion
The reaction between acids 1 and carbodiimides 2 likely takes
place by the mechanism depicted in Scheme 1. As already
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observed in a related process,24d the main undesired side reaction
that could occur is the decarboxylation of the starting carboxylic
acids (leading to a complex mixture of products) that can take
place during the proton transfer-nucleophilic step leading to the
formation of the highly reactive O-acylisourea 3.24f The ease of
decarboxylation depends on the structure of the acid, namely the
more stabilized the resulting carbanion, the easier the process.
Thus, carboxylic acids having one or two phenyl rings in the
α-position, like 1a,g,h and overall 1b, are more prone to decar-
boxylation than the corresponding α-alkylacetic acids. However,
the decarboxylation pathway could be suppressed or hampered
by fine tuning the experimental conditions, mainly by choosing
a rather apolar reaction medium. The drawback in using solvents
of low polarity is the well-known slowing effect on the nucleo-
philic intramolecular displacement of the halide which generally
involves polar (SN2 mechanism) or even zwitterionic
(SN1 mechanism) intermediates.
With these considerations in mind, it becomes clear why the
reaction between highly basic N,N′-dialkyl carbodiimides, such
as 2a, and acid 1a is high yielding only when DCM is used as a
solvent, while with more polar dioxane or CH3CN the yields
are significantly lower, probably because the decarboxylation
becomes favoured (entries 1–3, Table 1). Indeed, with α-aryl-
acetic acids like 1a, the intramolecular cyclization step is very fast
because the carbon bearing the leaving group is highly electro-
philic, being in the α-position to two activating moieties such as
a phenyl ring and a carbonyl group, thus the process does not
require a highly polar solvent to take place. However, with the
exception of highly electrophilic α-chlorodiphenylacetic acid 1b,
when less nucleophilic N′-alkyl, N′-aryl carbodiimides were
reacted with α-arylacetic acids in DCM, a mixture of hydantoin
and N-acylurea derivatives is always formed, which could
be converted to the target hydantoins by using a 2 N NaOH
aqueous solution under Schotten–Baumann conditions
(Scheme 5 and Table 2). The decarboxylation process depends
also on the basicity of the carbodiimide reactants. In fact, poorly
basic N-N′-diarylcarbodiimides, such as 2c, reacted efficiently
with α-bromo-phenylacetic acid 1a also in more polar solvents,
like dioxane, producing N-acylurea 6d in high yields (eqn (1),
Scheme 3). The situation is different when α-alkylacetic acids,
such as 1c–f, are used. In this case, the decarboxylation pathway
is disfavoured (the resulting carbanion is not stabilized), thus the
use of DMF as a solvent is appropriate in order to facilitate
the challenging intramolecular nucleophilic displacement of the
halide which is not very simple (the reaction between 1c and
DCC 2a performed in dioxane led to a mixture of N-acylurea 6a
and hydantoin 3d; see entry 8, Table 2). Nevertheless, we did
not detect the formation of the N-acylurea derivative only when
mono-alkylacetic acids 1c,d reacted with highly nucleophilic
N,N′-dialkyl carbodiimides (entries 9–11, Table 1 and entry 3,
Table 2). In all the other cases, N-acylurea derivatives were
always formed as a mixture with the target hydantoins or as
single products (Schemes 3 and 5 and Table 2). Gratifyingly, we
were able to promote the cyclization by adding a suitable base to
the reaction mixture. In most cases, a 2 N aqueous NaOH solu-
tion efficiently triggered the cyclization process leading to the
formation of the target hydantoins in fair to high yields.
However, when poorly electrophilic α-Br-α-dialkylacetic
acids, including cyclic 1f, were used, the treatment of the
corresponding N-acylureas with aqueous NaOH did not promote
the cyclization, but rather the formation of a mixture of unchar-
acterized byproducts (data not shown). Probably, this occurs
because the cyclization is hampered and the nucleophilic base
can promote side reactions. In fact, by using non-nucleophilic
potassium tert-butoxide we were able to trigger the nucleophilic
displacement of the bromine atom in an efficient way (Schemes
3–5 and Table 2), with the exception of N-acylureas formed by
the reaction of cyclic α-Br-α-cyclo-hexylacetic acid 1f and N,N′-
diaryl carbodiimides (eqn (7), Scheme 3).
Concerning the reactivity of asymmetric carbodiimides,
“strongly asymmetric” N-alkyl, N′-aryl carbodiimides gave rise
to completely regioselective processes in all the cases studied
(Scheme 5 and Table 2). Indeed, the regioselectivity achieved in
the formation of the hydantoins could be ascribed to the more
nucleophilic character of the N-alkyl compared to the N′-aryl
substituent of O-acylisourea 4 in the intramolecular nucleophilic
substitution step. On the other hand, when N-acylureas are
formed the regiospecificity likely arises from the predominance
of O-acylisourea regioisomer 3′′ having the CvN bond conju-
gated with the aromatic π-system, compared to 3′ (Scheme 6).
Likewise, when the steric hindrance of the two alkylic N-sub-
stituents of “weakly asymmetric” carbodiimides is very different,
the reaction is regioselective producing hydantoins which arise
from the nucleophilic attack of the less congested N-substituent
(Scheme 4 and Table 2), while when the two substituents are
very similar, there is virtually no regioselectivity (entry 9,
Table 2).
Although with this MC sequential process we can synthesize
libraries of diversely N,N′-disubstituted hydantoins, it is worth
noting that, by choosing suitable substituents on the carbodii-
mide framework, our approach provides access to hydantoins
with orthogonal protection on the two nitrogen atoms. For
example, we have previously demonstrated that hydantoins
bearing a N-tert-butyl substituent in position 3 can be depro-
tected by treatment with methansulfonic acid, leading to the for-
mation of 1,5(,5)-substituted hydantoins,29 such as 14, while the
CAN-mediated oxidative cleavage of the N1-p-MeO-benzyl
Scheme 6 Proposed mechanism for the formation of hydantoins 3′′
and N-acylureas 6′′.
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Resonance) instrument, equipped with an ESI source, or a
standard MS instrument, equipped with an EI source.
General procedure for the synthesis of hydantoins 3 starting
from α-halo acids 1 and carbodiimides 2
To a stirred solution of 1 (1 equiv.) in an appropriate solvent
(0.1 M solution), carbodiimide 2 (1.3 equiv.) followed by TMP
(1 equiv.) were added at rt and the mixture was stirred overnight.
When needed, a 2 N NaOH aqueous solution (10% in volume)
or potassium tert-butoxide (1.3 equiv.) was added and the
mixture stirred at 0 °C until the complete formation of the
hydantoin product was detected (TLC monitoring). A 1 N HCl
aqueous solution was added until acidic pH, and the resulting
mixture extracted with DCM. The combined organic layers were
dried over anhydrous Na2SO4, filtered and concentrated under
vacuum. The crude was purified by flash chromatography.
Scheme 7 Chemoselective N-deprotection of fully substituted
hydantoins.
group of 3q leads to the formation of 3,5(,5)-substituted hydan-
toins, such as 15 (Scheme 7).
General procedure for the synthesis of hydantoins 3 under the
three-component one-pot sequential process
Conclusions
In summary, we have developed a new, general, straightforward
method for the preparation of a large array of diversely 1,3,5-
and 1,3,5,5-substituted hydantoins. We exploited a one-pot
domino sequential process starting from easily accessible
diversely substituted α-halo-acetic acids and carbodiimides. The
process works efficiently under mild conditions (room temp-
erature) and is usually totally regioselective when asymmetric
carbodiimides are used, although the nature of reactants as well
as reaction parameters such as the solvent and the presence (or
absence) of a base have strong effects on the final outcome.
Moreover, by forming in situ the reacting carbodiimide through
the Staudinger reaction between azides and iso(thio)cyanates, we
have developed a MC sequential process for the preparation of
such interesting heterocycles. We have also demonstrated that,
by choosing suitable azides or iso(thio)cyanates, we can obtain
N,N′-disubstituted hydantoins which could be chemoselectively
deprotected at one of the two nitrogen atoms, thus producing
3,5(,5)- or 1,5(,5)-di(tri)substituted hydantoins.
The operational simplicity, the good chemical yields and the
mild conditions combined with favourable atom economy
aspects and a small number of synthetic steps render this strategy
attractive and promising for the preparation of libraries of differ-
ently substituted hydantoins and spiro-hydantoins in a “green”
and “practical” fashion. Moreover, this process seems particu-
larly suitable for solid phase/combinatorial chemistry. This latter
goal is currently under investigation in our laboratories.
To a stirred solution of the azide 12 (1.3 equiv.) and isocyanate
13 (1.3 equiv.) in an appropriate solvent (0.1 M) solid PPh3
(1.3 equiv.) was added and the reaction mixture stirred until the
complete formation of the corresponding carbodiimide was
detected (TLC monitoring). Next, TMP (1 equiv.) followed by
the acid 1 (1 equiv.) were added and the solution stirred over-
night. When needed, a 2 N NaOH aqueous solution (10% in
volume) or potassium tert-butoxide (1.3 equiv.) was added and
the mixture stirred at 0 °C until the complete formation of
the hydantoin ring was detected (TLC monitoring). A 1 N HCl
aqueous solution was added and the resulting mixture extracted
with DCM. The combined organic layers were dried over an-
hydrous Na2SO4, filtered and concentrated under vacuum. The
crude was purified by flash chromatography.
1,3-Dicyclohexyl-5-phenylimidazolidine-2,4-dione, 3a. Rf
=
0.43 (hexane–AcOEt 90 : 10); FTIR (nujol) 1700,
=
ν
1684 cm−1; H NMR (400 MHz, CDCl3) δ 7.39 (m, 5H), 5.43
(s, 1H), 4.00 (m, 1H), 3.66 (m, 1H), 2.32 (m, 2H), 1.76 (m, 8H),
1.36 (m, 10H); 13C NMR (100.6 MHz, CDCl3) δ 170.7, 145.8,
134.5, 129.2, 128.9, 126.1, 79.1, 53.7, 53.1, 34.4, 34.3, 28.5,
28.4, 25.9, 25.8, 25.7, 25.1, 24.7, 24.6; ESI (m/z) 363.1
[M+ + Na, (86)], 341.1 [M+ + 1, (100)]; HRMS calcd for
[C21H28N2O2]: 340.2151, found: 340.2155.
1
1,3-Diisopropyl-5-phenylimidazolidine-2,4-dione, 3b. Rf
=
0.53 (hexane–AcOEt 80 : 20); FTIR (nujol) 1711,
=
ν
1687 cm−1; H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.44
(s, 1H), 4.41 (septet, J = 7.0 Hz, 1H), 4.00 (septet, J = 6.2 Hz,
1H), 1.45 (d, J = 7.0 Hz, 3H), 1.42 (d, J = 7.0 Hz, 3H), 1.18
(d, J = 6.2 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 170.6, 145.9, 134.3, 129.2, 128.9, 126.0,
79.1, 46.0, 45.5, 24.33, 24.31, 18.9, 18.8; ESI (m/z) 283.0
[M+ + Na, (21)], 261.0 [M+ + 1, (100)]; HRMS calcd for
[C15H20N2O2]: 260.1525, found: 260.1521.
1
Experimental section
General methods
Commercially available reagent-grade solvents were employed
without purification. 1H NMR spectra were acquired on 250, 400
or 500 MHz spectrometers. Chemical shifts are expressed in
ppm (δ), using tetramethylsilane (TMS) as an internal standard
for 1H and 13C nuclei (δH and δC = 0.00). MS spectra were
recorded with a FT-ICR (Fourier Transform Ion Cyclotron
1,3-Diisopropyl-5,5-diphenylimidazolidine-2,4-dione, 3c. Rf =
0.64 (hexane–AcOEt
= 90 : 10); FTIR (nujol) ν 1731,
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1
1687 cm−1; H NMR (400 MHz, CDCl3) δ 7.50 (m, 4H), 7.37
1H NMR (400 MHz, CDCl3) δ 3.75 (tt, J = 12.3 and 3.8 Hz,
1H), 2.75 (tt, J = 12.1 and 3.9 Hz, 1H), 2.22 (m, 2H), 2.01
(m, 4H), 1.70 (m, 5H), 1.53 (m, 12H), 1.14 (m, 7H); 13C NMR
(63 MHz, CDCl3) δ 175.9, 154.2, 62.2, 52.1, 50.7, 31.7, 30.8,
29.3, 26.3, 25.9, 25.1, 25.1, 24.6, 21.2; ESI (m/z) 333.1 [M+ +
(m, 6H), 4.42 (septet, J = 6.8 Hz, 1H), 4.10 (septet, J = 6.1 Hz,
1H), 1.43 (d, J = 6.8 Hz, 6H), 1.18 (d, J = 6.1 Hz, 6H); ESI
(m/z) 359.1 [M+ + Na, (65)], 336.1 [M+ + 1, (100)]; HRMS
calcd for [C21H24N2O2]: 336.1838, found: 336.1842.
H, (25)], 355.1 [M+
+ Na, (100)]; HRMS calcd for
[C20H32N2O2]: 332.2464, found: 332.2463.
1,3-Dicyclohexyl-5-ethylimidazolidine-2,4-dione, 3d. Rf = 0.75
(hex–AcOEt = 80 : 20); FTIR (nujol) ν 1714, 1677 cm−1
;
1H NMR (400 MHz, CDCl3) δ 4.40 (t, J = 5.0 Hz, 1H), 3.84 (m,
1H), 3.46 (m, 1H), 2.16 (m, 2H), 1.84 (m, 1H), 1.63 (m, 10H),
1.18 (m, 7H), 0.84 (t, J = 7.4 Hz, 3H); 13C NMR (63 MHz,
CDCl3) δ 172.3, 146.4, 78.7, 53.5, 52.7, 34.3, 34.1, 28.4, 28.3,
25.9, 25.7, 25.1, 24.6, 7.6; ESI (m/z) 293.2 [M+ + H, (100)],
315.1 [M+ + Na, (70)]; HRMS calcd for [C17H28N2O2]:
292.2151, found: 292.2154.
5-Phenyl-1,3-di-p-tolylimidazolidine-2,4-dione, 3k. Rf = 0.27
(hexane–AcOEt = 80 : 20); FTIR (nujol) ν 1712, 1685 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.41 (m, 7H), 7.35 (d, J = 8.5 Hz,
2H), 7.28 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 5.58 (s,
3H), 2.40 (s, 3H), 2.29 (s, 3H); 13C NMR (125.7 MHz, CDCl3)
δ 169.1, 153.8, 138.4, 134.7, 133.9, 132.2, 129.7, 129.2, 129.1,
128.9, 126.9, 126.2, 120.8, 64.7, 21.1, 20.7; ESI (m/z) 379.0
[M+ + Na, (100)], 357.0 [M+ + 1, (78)]; HRMS calcd for
[C23H20N2O2]: 356.1525, found: 356.1521.
5-Benzyl-1,3-dicyclohexylimidazolidine-2,4-dione, 3e. Rf
=
0.61 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1719, 1672 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.14 (m, 5H), 4.68 (t, J = 4.5 Hz,
1H), 3.64 (tt, J = 12.4 and 3.8 Hz, 1H), 3.47 (m, 1H), 3.07 (m,
2H), 1.95 (m, 2H), 1.66 (m, 4H), 1.51 (m, 4H), 1.14 (m, 10H);
13C NMR (63 MHz, CDCl3) δ 171.5, 145.8, 133.9, 130.1,
128.2, 127.2, 77.9, 53.5, 52.5, 37.2, 34.3, 34.1, 28.1, 27.9, 25.9,
25.7, 25.1, 24.6; ESI (m/z) 355.1 [M+ + H, (100)], 377.1 [M+ +
Na, (85)]; HRMS calcd for [C22H30N2O2]: 354.2307, found:
354.2311.
5-Ethyl-1,3-diphenylimidazolidine-2,4-dione, 3l. Rf = 0.35
(hex–AcOEt = 80 : 20); FTIR (nujol) ν 1726, 1688 cm−1; H
NMR (400 MHz, CDCl3) δ 7.37 (m, 9H), 7.17 (t, J = 6.9 Hz,
1H), 4.71 (dd, J = 5.4 and 3.0 Hz, 1H), 2.06 (m, 1H), 1.92 (m,
1H), 0.84 (t, J = 7.4 Hz, 3H); 13C NMR (63 MHz, CDCl3)
δ 170.9, 153.6, 135.5, 131.5, 129.3, 129.1, 128.3, 126.3, 125.6,
122.1, 60.4, 21.9, 7.0; ESI (m/z) 281.0 [M+ + H, (5)], 303.0
[M+ + Na, (100)]; HRMS calcd for [C17H16N2O2]: 280.1212,
found: 280.1209.
1
5-Benzyl-1,3-diisopropylimidazolidine-2,4-dione, 3f. Rf = 0.34
1
(hex–AcOEt = 80 : 20); FTIR (nujol) ν 1742, 1659 cm−1; H
5,5-Dimethyl-1,3-diphenylimidazolidine-2,4-dione, 3m. Rf
=
;
NMR (400 MHz, CDCl3) δ 7.22 (m, 3H), 7.12 (d, J = 6.5 Hz,
2H), 4.53 (dd, J = 8.7 and 6.4 Hz, 1H), 4.32 (m, 1H), 3.85 (dq,
J = 13.2 and 6.6 Hz, 1H), 3.48 (dd, J = 13.8 and 8.7 Hz, 1H),
3.16 (dd, J = 13.8 and 6.3 Hz, 1H), 1.15 (d, J = 6.8 Hz, 6H),
1.09 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 162.5, 152.8, 137.0, 129.8, 129.3, 129.1,
129.0, 128.7, 128.6, 127.3, 47.8, 45.5, 43.3, 41.4, 29.7, 22.3,
22.0, 20.5, 20.3; ESI (m/z) 275.1 [M+ + H, (30)], 297.1 [M+ +
Na, (100)]; HRMS calcd for [C16H22N2O2]: 274.1681, found:
274.1685.
0.27 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1709, 1664 cm−1
1H NMR (250 MHz, CDCl3) δ 7.49 (m, 7H), 7.41 (m, 1H), 7.35
(m, 2H), 1.57 (s, 6H); 13C NMR (63 MHz, CDCl3) δ 175.1,
153.9, 134.0, 131.7, 129.5, 128.9, 128.5, 128.0, 126.1, 63.4,
24.1; ESI (m/z) 281.0 [M+ + H, (5)], 303.0 [M+ + Na, (100)];
HRMS calcd for [C17H16N2O2]: 280.1212, found: 280.1214.
1-Benzyl-3-tert-butyl-5-phenyl-imidazolidine-2,4-dione, 3ab.
Rf = 0.23 (hexane–AcOEt 90 : 10); FTIR (nujol) ν 1740, 1712,
1
1531 cm−1; H NMR (400 MHz, CDCl3) δ 7.35 (m, 10H), 5.56
(s, 1H), 4.70 (m, 2H), 1.36 (s, 9H); 13C NMR (100.6 MHz,
CDCl3) δ 168.3, 160.6, 129.8, 129.6, 129.1, 128.9, 128.7, 128.5,
128.2, 127.9, 127.3, 126.0, 125.9, 125.9, 80.3, 53.1, 44.0, 27.8;
ESI (m/z) 345.0 [M+ + Na, (100)], 323.1 [M+ + 1, (90)]; HRMS
calcd for [C20H22N2O2]: 322.1681, found: 322.1684.
1,3-Dicyclohexyl-5,5-dimethylimidazolidine-2,4-dione, 3g. Rf
= 0.68 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1698, 1656 cm−1
;
1H NMR (250 MHz, CDCl3) δ 3.85 (tt, J = 12.3 and 3.8 Hz,
1H), 2.95 (tt, J = 12.1 and 3.7 Hz, 1H), 2.17 (m, 4H), 1.82 (m,
4H), 1.64 (m, 7H), 1.32 (s, 6H), 1.22 (m, 5H); 13C NMR
(63 MHz, CDCl3) δ 176.5, 154.1, 61.3, 53.0, 51.1, 32.6, 31.0,
29.4, 26.3, 25.9, 25.5, 25.1, 22.9; ESI (m/z) 315.2 [M+ + Na,
(100)]; HRMS calcd for [C17H28N2O2]: 292.2151, found:
292.2150.
1-Benzyl-3-tert-butyl-5-ethylimidazolidine-2,4-dione, 3o. Rf =
0.65 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1712, 1629 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.22 (m, 3H), 4.56
(d, J = 0.9 Hz, 2H), 4.54 (dd, J = 6.0 and 4.6 Hz, 1H), 1.90 (m,
1H), 1.73 (m, 1H), 1.21 (s, 9H), 0.82 (t, J = 7.4 Hz, 3H); 13C
NMR (63 MHz, CDCl3) δ 171.7, 144.6, 136.3, 129.0, 128.3,
127.7, 80.0, 52.5, 43.5, 30.4, 24.7, 8.0; ESI (m/z) 275.0 [M+ +
1,3-Diisopropyl-5,5-dimethylimidazolidine-2,4-dione, 3h. Rf =
0.55 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1709, 1642 cm−1
;
1H NMR (250 MHz, CDCl3) δ 4.24 (septet, J = 6.9 Hz, 1H),
3.41 (septet, J = 6.9 Hz, 1H), 1.39 (d, J = 6.9 Hz, 6H), 1.37 (d,
J = 6.9 Hz, 6H), 1.30 (s, 6H); 13C NMR (63 MHz, CDCl3)
δ 176.4, 153.9, 61.3, 44.7, 43.2, 22.7, 21.0, 19.6; ESI (m/z)
213.3 [M+ + H, (5)], 235.1 [M+ + Na, (100)]; HRMS calcd for
[C11H20N2O2]: 212.1525, found: 212.1521.
H, (80)], 297.0 [M+
+ Na, (100)]; HRMS calcd for
[C16H22N2O2]: 274.1681, found: 274.1679.
1-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-5-phenylimidazoli-
dine-2,4-dione, 3q. Rf = 0.31 (hexane–AcOEt = 70 : 30); FTIR
1
(nujol) ν 1700, 1695 cm−1; H NMR (400 MHz, CDCl3) δ 7.43
(m, 5H), 7.38 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 6.98
(d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.77 (s, 1H), 4.63
(s, 2H), 3.81 (s, 3H), 3.80 (s, 3H); 13C NMR (100.6 MHz,
1,3-Dicyclohexyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3i. Rf =
0.76 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1725, 1653 cm−1
;
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CDCl3) δ 170.0, 159.4, 158.4, 148.9, 133.4, 132.5, 129.4, 128.9,
128.6, 127.9, 127.0, 126.0, 114.4, 113.7, 80.1, 55.4, 55.2, 48.7;
ESI (m/z) 425.1 [M+ + Na, (34)], 403.1 [M+ + 1, (100)]; HRMS
calcd for [C24H22N2O4]: 402.1580, found: 402.1582.
42.4, 42.1, 32.4, 24.5, 21.3; ESI (m/z) 349.1 [M+ + H, (85)],
371.0 [M+ + Na, (100)]; HRMS calcd for [C22H24N2O2]:
348.1838, found: 348.1841.
3-tert-Butyl-1-cyclopentyl-5-phenylimidazolidine-2,4-dione, 3ae.
Rf = 0.31 (hex–AcOEt = 70 : 30); FTIR (nujol) ν 1689,
1-Benzyl-5-ethyl-3-phenylimidazolidine-2,4-dione, 3r. Rf
=
0.38 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1715, 1624 cm−1
;
1676 cm−1; H-NMR (400 MHz, CDCl3) δ 7.37–7.26 (m, 5H),
1
1H NMR (400 MHz, CDCl3) δ 7.42 (m, 6H), 7.31 (m, 3H), 7.20
(t, J = 7.0 Hz, 1H), 4.75 (s, 2H), 4.61 (dd, J = 5.5 and 3.0 Hz,
1H), 2.02 (m, 1H), 1.89 (m, 1H), 0.73 (t, J = 7.4 Hz, 3H); 13C
NMR (63 MHz, CDCl3) δ 171.7, 155.9, 135.6, 131.9, 129.2,
129.0, 128.7, 128.6, 128.3, 128.2, 128.0, 126.0, 121.7, 59.1,
44.8, 21.5, 7.1; ESI (m/z) 317.1 [M+ + Na, (100)]; HRMS calcd
for [C18H18N2O2]: 294.1368, found: 294.1364.
4.76 (s, 1H), 4.07 (quintet, J = 8.0 Hz, 1H), 1.86–1.26 (m, 8H),
1.61 (s, 9H); 13C NMR (62.9 MHz, CDCl3) δ 136.3, 129.4,
129.2, 128.6, 127.3, 126.8, 63.4, 55.5, 30.5, 29.2, 29.0, 28.8,
23.9, 23.7; ESI (m/z) 323.1 [M+ + Na, (21)], 300.1 [M+, (100)];
HRMS calcd for [C18H24N2O2]: 300.1838, found: 300.1835.
1-Benzyl-3-tert-butyl-5-(4-fluoro-phenyl)-imidazolidine-2,4-dione,
3af. Rf = 0.25 (hexane–AcOEt 90 : 10); FTIR (nujol) ν 1711,
1
1-Benzyl-5,5-dimethyl-3-phenylimidazolidine-2,4-dione, 3s. Rf
1604, 1509 cm−1; FTIR (nujol) ν 1712, 1658 cm−1; H NMR
= 0.40 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1709, 1645 cm−1
;
(400 MHz, CDCl3) δ 7.26 (m, 9H), 5.53 (s, 1H), 4.70 (d, J =
12.9 Hz, 1H), 4.66 (d, J = 12.9 Hz, 1H), 1.34 (s, 9H); 13C NMR
(100.6 MHz, CDCl3) δ 169.8, 163.1 (d, J = 248.3 Hz), 136.0,
131.6, 131.0, 130.5, 129.1, 128.5, 128.4, 127.9, 127.8, 115.9
(d, J = 22.0 Hz), 79.5, 62.0, 44.0, 30.6, 28.2, 28.0; 19F-NMR
(470.6 MHz) δ −112.1 (m, 1F); ESI (m/z) 363.0 [M+ + Na,
(100)], 341.1 [M+ + 1, (77)]; HRMS calcd for [C20H21FN2O2]:
340.1587, found: 340.1584.
1H NMR (400 MHz, CDCl3) δ 7.35 (m, 4H), 7.26 (m, 4H), 7.17
(d, J = 8.2 Hz, 2H), 4.68 (s, 2H), 1.35 (s, 6H); 1H NMR
(101 MHz, CDCl3) δ 176.0, 136.3, 129.4, 128.7, 128.5, 128.2,
127.8, 63.8, 42.6, 23.8; ESI (m/z) 295.1 [M+ + H, (5)], 317.1
[M+ + Na, (100)]; HRMS calcd for [C18H18N2O2]: 294.1368,
found: 294.1366.
1,3-Dibenzyl-5-phenylimidazolidine-2,4-dione, 3aa. Rf = 0.37
(hexane–AcOEt = 80 : 20); FTIR (nujol) ν 1701, 1690 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.34 (m, 13H), 5.63
(s, 1H), 4.84 (d, J = 14.4 Hz, 1H), 4.79 (d, J = 14.4 Hz, 1H),
4.66 (s, 2H); 13C NMR (100.6 MHz, CDCl3) δ 170.8, 148.7,
140.9, 136.1, 133.8, 129.8, 129.3, 129.2, 128.9, 128.6, 128.3,
127.7, 126.9, 126.5, 80.7, 49.4, 44.3; ESI (m/z) 379.0 [M+ + Na,
(100)], 357.1 [M+ + 1, (31)]; HRMS calcd for [C23H20N2O2]:
356.1525, found: 356.1525.
1-Benzyl-3-tert-butyl-5-ethylimidazolidine-2,4-dione, 3ag. Rf
= 0.65 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1709, 1617 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.22 (m, 3H), 4.56
(d, J = 0.9 Hz, 2H), 4.54 (dd, J = 6.0 and 4.6 Hz, 1H), 1.90 (m,
1H), 1.73 (m, 1H), 1.21 (s, 9H), 0.82 (t, J = 7.4 Hz, 3H); 13C
NMR (63 MHz, CDCl3) δ 171.7, 144.6, 136.3, 129.0, 128.3,
127.7, 80.0, 52.5, 43.5, 30.4, 24.7, 8.0; ESI (m/z) 275.0 [M+ +
H, (80)], 297.0 [M+
+ Na, (100)]; HRMS calcd for
[C16H22N2O2]: 274.1681, found: 274.1680.
1,3-Dibenzyl-5-biphenyl-4-yl-imidazolidine-2,4-dione, 3ab. Rf
1
= 0.33 (hexane–AcOEt 80 : 20); FTIR (nujol) ν 1705 cm−1; H
1-Benzyl-3-tert-butyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3ah.
Rf = 0.85 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1712,
NMR (400 MHz, CDCl3) δ 7.57 (m, 5H), 7.36 (m, 15H), 5.68
(s, 1H), 4.85 (d, J = 14.6 Hz, 1H), 4.80 (d, J = 14.6 Hz, 1H),
4.66 (s, 2H); 13C NMR (100.6 MHz, CDCl3) δ 170.4, 158.7,
129.3, 128.9, 128.8, 128.7, 128.6, 128.3, 128.0, 127.7, 127.6,
127.3, 127.2, 126.6, 126.5, 125.9, 80.2, 49.0, 44.0; ESI (m/z)
455.1 [M+ + Na, (39)], 433.1 [M+ + 1, (100)]; HRMS calcd for
[C29H24N2O2]: 432.1838, found: 432.1840.
1
1619 cm−1; H NMR (400 MHz, CDCl3) δ 7.24 (m, 2H), 7.18
(m, 3H), 4.40 (s, 2H), 1.92 (m, 2H), 1.61 (d, J = 13.4 Hz, 1H),
1.56 (s, 9H), 1.47 (m, 6H), 1.01 (m, 1H); 13C NMR (63 MHz,
CDCl3) δ 176.9, 156.8, 138.5, 128.6, 127.2, 127.1, 61.4, 57.5,
42.1, 32.5, 28.8, 24.6, 21.3; ESI (m/z) 315.1 [M+ + H, (15)],
337.1 [M+ + Na, (100)]; HRMS calcd for [C19H26N2O2]:
314.1994, found: 314.1997.
1,3-Dibenzyl-5-ethylimidazolidine-2,4-dione, 3ac. Rf = 0.56
1
(hex–AcOEt = 80 : 20); FTIR (nujol) ν 1722, 1687 cm−1; H
1-(4-Methoxybenzyl)-3-methyl-5-phenylimidazolidine-2,4-dione,
NMR (400 MHz, CDCl3) δ 7.42 (m, 2H), 7.25 (d, J = 4.5 Hz,
7H), 7.17 (m, 1H), 4.71 (d, J = 1.3 Hz, 2H), 4.62 (dd, J = 6.1,
4.7 Hz, 1H), 4.52 (s, 2H), 1.96 (m, 1H), 1.79 (m, 1H), 0.88 (t,
J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 149.0,
140.7, 135.9, 128.8, 128.5, 128.2, 127.9, 127.2, 126.4, 80.4,
48.8, 43.6, 24.7, 8.1; ESI (m/z) 309.0 [M+ + H, (100)], 331.0
[M+ + Na, (100)]; HRMS calcd for [C19H20N2O2]: 308.1525,
found: 308.1527.
3ai. Rf = 0.13 (hexane–AcOEt = 80 : 20); FTIR (nujol) ν 1704,
1691 cm−1; FTIR (nujol) ν 1706, 1665 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 7.39 (m, 5H), 7.31 (d, J = 8.4 Hz, 2H),
6.88 (d, J = 8.4 Hz, 2H), 5.63 (s, 1H), 4.59 (s, 2H), 3.80 (s, 3H),
3.13 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.6, 158.6,
149.3, 132.6, 129.4, 129.3, 128.9, 128.8, 126.0, 113.9, 80.5,
55.3, 48.6, 26.6; ESI (m/z) 311.2 [M+ + 1, (100)]; HRMS calcd
for [C18H18N2O3]: 310.1317, found: 310.1319.
1,3-Dibenzyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3ad. Rf
=
;
3-(4-Methoxybenzyl)-1-methyl-5-phenylimidazolidine-2,4-
0.36 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1709, 1685 cm−1
dione, 3ai′. Rf = 0.24 (hexane–AcOEt = 80 : 20); FTIR (nujol)
1H NMR (400 MHz, CDCl3) δ 7.32 (m, 2H), 7.22 (m, 8H), 4.62
(s, 2H), 4.45 (s, 2H), 1.94 (m, 2H), 1.65 (m, 1H), 1.51 (m, 6H),
1.00 (m, 1H); 13C NMR (63 MHz, CDCl3) δ 175.5, 156.0,
138.2, 136.5, 128.7, 128.6, 128.3, 127.7, 127.4, 127.4, 63.5,
ν 1709, 1697 cm−1; H NMR (400 MHz, CDCl3) δ 7.39 (m,
1
7H), 6.84 (d, J = 8.8 Hz, 2H), 5.57 (s, 1H), 4.71 (d, J = 14.1 Hz,
1H), 4.65 (d, J = 14.1 Hz, 1H), 3.87 (s, 3H), 3.1 (s, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 170.5, 159.4, 148.7, 133.6, 130.1,
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1-Benzyl-3-(4-methoxyphenyl)-1,3-diazaspiro[4.5]decane-2,4-
129.4, 128.9, 128.0, 126.2, 114.0, 80.1, 55.2, 43.3, 32.4; ESI
(m/z) 333.1 [M+ + Na, (44)], 311.1 [M+ + 1, (100)]; HRMS
calcd for [C18H18N2O3]: 310.1317, found: 310.1315.
dione, 3ao. Rf = 0.26 (hex–AcOEt = 80 : 20); FTIR (nujol)
1
ν 1696, 1632 cm−1; H NMR (400 MHz, CDCl3) δ 7.33 (m,
5H), 7.09 (dd, J = 7.7, 1.5 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H),
4.59 (s, 2H), 3.72 (s, 3H), 2.00 (m, 2H), 1.79 (d, J = 13.9 Hz,
2H), 1.54 (m, 5H), 0.90 (qt, J = 12.6, 3.3 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 175.2, 159.2, 155.2, 133.7, 130.6, 130.0,
129.3, 128.8, 128.7, 114.0, 64.6, 55.2, 41.6, 33.0, 24.3,
21.4; ESI (m/z) 364.2 [M+ + H, (100)]; HRMS calcd for
[C22H24N2O3]: 364.1787, found: 364.1788.
[4-(3-Benzyl-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-phenyl]-
carbamic acid benzyl ester, 3aj. Rf = 0.27 (hexane–AcOEt
70 : 30); FTIR (nujol) ν 1709.40, 1519; 1H NMR (400 MHz,
CDCl3) δ 7.32 (m, 19H), 6.83 (s, 1H), 5.68 (s, 1H), 5.12 (s, 2H),
4.60 (s, 2H); 13C NMR (62.3 MHz, CDCl3) δ 170.2, 169.9,
155.6, 153.1, 148.8, 140.1, 138.6, 138.1, 137.8, 135.9, 135.1,
133.2, 132.4, 129.8, 129.9, 129.3, 129.1, 129.0, 128.9, 128.8,
128.6, 128.3, 128.2, 127.8, 127.6, 127.4, 127.2, 126.8, 126.6,
126.3, 126.0, 121.5, 120.9, 118.9, 80.1, 79.9, 67.0, 62.9, 49.3,
44.8, 29.6; ESI (m/z) 514.1 [M+ + Na, (100)], 492.1 [M+ + 1,
(25)]; ESI (m/z) 333.1 [M+ + Na, (44)], 311.1 [M+ + 1, (100)];
HRMS calcd for [C30H25N3O4]: 491.1845, found: 491.1849.
Benzyl 4-(1-benzyl-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)-
phenylcarbamate, 3ap. Rf = 0.35 (hex–AcOEt = 70 : 30); FTIR
1
(nujol) ν 1675, 1632, 1611 cm−1; H NMR (400 MHz, CDCl3)
δ 9.09 (br s, 1H), 7.28 (m, 9H), 5.11 (s, 2H), 4.38 (d, J = 3.8
Hz, 2H), 1.78 (m, 4H), 1.52–1.35 (m, 6H); 13C NMR
(101 MHz, CDCl3) δ 173.7, 155.9, 153.2, 138.9, 137.9, 136.1,
131.3, 128.6, 128.3, 127.5, 118.1, 67.0, 45.1, 39.6, 24.6, 24.3;
{4-[3-Benzyl-4-(4-fluoro-phenyl)-2,5-dioxo-imidazolidin-1-yl]-
phenyl}-carbamic acid benzyl ester, 3ak. Rf = 0.30 (hexane–
ESI (m/z) 483.1 [M+
+ H, (100)]; HRMS calcd for
[C29H29N3O4]: 483.2158, found: 483.2155.
AcOEt 70 : 30); FTIR (nujol)
ν
1704, 1516; 1H NMR
(400 MHz, CDCl3) δ 7.35 (m, 16H), 7.11 (m, 2H), 7.03 (s, 1H),
5.72 (s, 1H), 5.19 (s, 2H), 4.67 (s, 2H); 13C NMR (100.6 MHz,
CDCl3) δ 169.7, 163.5 (d, J = 249.2 Hz), 153.1, 140.0, 138.1,
135.9, 128.6, 128.3, 128.2, 127.9 (d, J = 8.5 Hz), 127.4, 127.2,
126.6, 118.9, 116.1 (d, J = 22.0 Hz), 79.4, 67.1, 49.3; 19F NMR
(470.6 MHz) δ −112.5 (m, 1F); ESI (m/z) 532.0 [M+ + Na,
(100)], 510.0 [M+ + 1, (22)]; HRMS calcd for [C30H24FN3O4]:
509.1751, found: 509.1748.
1,3-Bis-(4-methoxy-phenyl)-5-phenyl-imidazolidine-2,4-dione,
3aq. Rf
=
0.30 (hexane–AcOEt 70 : 30); FTIR (nujol)
ν 1717.22, 1644.61, 1509.81 cm−1
;
1H NMR (400 MHz,
CDCl3) δ 7.34 (m, 5H), 6.95 (d, J = 8.9 Hz, 2H), 6.83 (d, J =
8.9 Hz, 2H), 5.52 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H); 13C-NMR
(100.6 MHz, CDCl3) δ 159.4, 157.1, 133.2, 129.3, 129.2, 127.7,
127.1, 124.3, 123.0, 114.4, 64.8, 55.5, 55.4; ESI (m/z) 411.0
[M+ + Na, (100)], 389.1 [M+ + 1, (1)]; HRMS calcd for
[C23H20N2O4]: 388.1423, found: 388.1425.
1-Benzyl-3-(4-methoxy-phenyl)-5,5-diphenyl-imidazolidine-2,4-
5-(4-Fluoro-phenyl)-1,3-bis-(4-methoxy-phenyl)-imidazolidine-
dione, 3al. Rf = 0.40 (hexane–AcOEt 80 : 20); FTIR (nujol)
1
ν 1709, 1514 cm−1; H NMR (400 MHz, CDCl3) δ 7.55 (m,
2,4-dione, 3ar. Rf = 0.20 (hexane–AcOEt 70 : 30); FTIR (nujol)
1
ν 1774, 1717, 1509 cm−1; H NMR (400 MHz, CDCl3) δ 7.36
4H), 7.36 (m, 12H), 7.26 (m, 1H), 6.99 (d, J = 8.6 Hz, 2H), 4.78
(s, 2H), 3.83 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 171.3,
159.9, 148.5, 140.9, 138.3, 129.3, 129.1, 128.7, 128.4, 127.8,
126.9, 126.7, 125.3, 88.1, 55.9, 50.0; ESI (m/z) 471.0 [M+ + Na,
(100)], 449.1 [M+ + 1, (50)]; HRMS calcd for [C29H24N2O3]:
448.1787, found: 448.1786.
(m, 6H), 7.07 (m, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.84 (d, J =
8.9 Hz, 2H), 5.51 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 169.2, 164.4, 160.5 (d, J = 242.4 Hz),
157.2, 153.9, 128.8 (d, J = 8.5 Hz), 127.61, 124.14, 123.09,
116.3 (d, J = 22.0 Hz), 114.50, 114.47, 64.05, 55.49, 55.40;
19F-NMR (470.6 MHz) δ −112.9 (m, 1F); ESI (m/z) 428.9
[M+ + Na, (100)], 407.0 [M+ + 1, (28)]; HRMS calcd for
[C23H19FN2O4]: 406.1329, found: 406.1326.
1-(4-Methoxy-benzyl)-3-(4-methoxy-phenyl)-5-methyl-5-phenyl-
imidazolidine-2,4-dione, 3am. Rf
=
0.30 (hexane–AcOEt
80 : 20); FTIR (nujol) ν 1706, 1611, 1514 cm−1
;
1H NMR
5-Biphenyl-4-yl-1,3-bis-(4-methoxy-phenyl)-imidazolidine-2,4-
(400 MHz, CDCl3) δ 7.55 (d, J = 8.5 Hz, 2H), 7.37 (m, 5H),
7.29 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.88 (d, J =
8.5 Hz, 2H), 4.66 (s, 2H), 3.81 (s, 6H), 1.97 (s, 3H); 13C NMR
(62.3 MHz, CDCl3) δ 172.8, 159.3, 158.4, 148.1, 138.2, 132.7,
128.7, 128.5, 127.8, 124.5, 114.3, 113.7, 84.7, 55.4, 55.2, 48.8,
25.5; ESI (m/z) 439.0 [M+ + Na, (100)]; HRMS calcd for
[C25H24N2O4]: 416.1736, found: 416.1736.
dione, 3as. Rf = 0.15 (hexane–AcOEt 80 : 20); FTIR (nujol)
1
ν 1717, 1510 cm−1; H NMR (400 MHz, CDCl3) δ 7.60 (d, J =
7.9 Hz, 2H), 7.55 (d, J = 7.9 Hz, 2H), 7.41 (m, 9H), 6.99 (d, J =
8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.57 (s, 1H), 3.83 (s, 3H),
3.76 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 168.7, 162.1,
140.2, 132.1, 128.8, 128.0, 127.7, 127.5, 127.1, 123.0, 114.5,
64.5, 55.5, 55.4; ESI (m/z) 487.1 [M+ + Na, (100)]; HRMS
calcd for [C29H24N2O4]: 464.1736, found: 464.1733.
1-Benzyl-5-ethyl-3-(4-methoxyphenyl)imidazolidine-2,4-dione,
3an. Rf = 0.43 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1709,
1,3-Bis-(4-methoxy-phenyl)-5-methyl-5-phenyl-imidazolidine-
1
1611 cm−1; H NMR (400 MHz, CDCl3) δ 7.39 (m, 3H), 7.21
2,4-dione, 3at. Rf = 0.42 (hexane–AcOEt 80 : 20); FTIR (nujol)
1
(m, 4H), 6.80 (d, J = 8.4 Hz, 2H), 4.36 (s, 2H), 3.88 (t, J = 7.2
Hz, 1H), 3.73 (s, 3H), 2.03 (m, 1H), 1.84 (m, 1H), 0.82 (t, J =
7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 172.6, 159.1, 154.2,
137.4, 129.9, 129.6, 129.3, 129.2, 129.1, 114.1, 55.3, 47.2, 44.3,
28.1, 11.9; ESI (m/z) 324.3 [M+ + H, (100)]; HRMS calcd for
[C19H20N2O3]: 324.1474, found: 324.1471.
ν 1697, 1648, 1508 cm−1; H NMR (400 MHz, CDCl3) δ 7.63
(d, J = 8.9 Hz, 2H), 7.41 (m, 5H), 7.19 (d, J = 8.9 Hz, 2H), 6.98
(d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 3.80
(s, 3H), 1.98 (s, 3H); 13C NMR (62.3 MHz, CDCl3) δ 172.5,
159.4, 156.2, 146.3, 137.9, 137.4, 128.8, 128.0, 124.7, 124.5,
114.3, 113.9, 85.3, 55.4, 55.3, 28.3, 25.5; ESI (m/z) 425.0
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[M+ + Na, (100)], 403.0 [M+ + 1, (30)]; HRMS calcd for
[C24H22N2O4]: 402.1580, found: 402.1581.
2.21 (m, 2H), 2.09 (m, 2H), 1.89 (m, 2H), 1.72 (t, J = 13.6 Hz,
4H), 1.61 (m, 5H), 1.49 (m, 4H), 1.28 (m, 9H); 13C NMR
(63 MHz, CDCl3) δ 168.3, 153.3, 67.3, 56.8, 50.3, 39.3, 32.3,
30.5, 26.0, 25.4, 25.3, 24.8, 24.6, 24.2; ESI (m/z) 413.1 [M+ + H,
(5)], 415.1 [(M + 2)+ + H, (5)], 435.0 [M+ + Na, (90)], 437.0
[(M + 2)+ + Na, (100)]; HRMS calcd for [C20H33BrN2O2]:
412.1725, found: 412.1722.
1,3-Bis-(4-methoxy-phenyl)-5,5-diphenyl-imidazolidine-2,4-
dione, 3au. Rf = 0.50 (hexane–AcOEt 70 : 30); FTIR (nujol)
1
ν 1701, 1513, 1508 cm−1; H NMR (400 MHz, CDCl3) δ 7.60
(d, J = 8.9 Hz, 4H), 7.42 (m, 8H), 7.22 (d, J = 8.9 Hz, 2H), 7.01
(d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 3.82
(s, 3H); 13C NMR (62.3 MHz, CDCl3) δ 170.6, 159.6, 156.3,
145.9, 137.7, 137.3, 129.0, 128.7, 128.2, 126.3, 124.7, 114.4,
114.0, 88.2, 55.5, 55.4; ESI (m/z) 487.0 [M+ + Na, (100)], 465.0
[M+ + 1, (19)]; HRMS calcd for [C29H24N2O4]: 464.1736,
found: 464.1739.
2-Bromo-2-phenyl-N-p-tolyl-N-(p-tolylcarbamoyl)acetamide,
6d. Rf = 0.30 (hexane–AcOEt = 90 : 10); FTIR (nujol) ν 2917,
1
1696, 1682 cm−1; H NMR (400 MHz, CDCl3) δ 11.1 (br s,
1H), 7.44 (d, J = 8.4 Hz, 2H), 7.34 (m, 9H), 7.12 (d, J = 8.9 Hz,
2H), 5.42 (s, 1H), 2.46 (s, 3H), 2.32 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 171.5, 151.4, 139.9, 135.0, 134.8, 134.4,
133.9, 130.4, 129.5, 129.1, 128.9, 128.8, 120.2, 47.4, 21.3,
20.8; ESI (m/z) 438.0 [M+ + 3, (87)], 437.0 [M+ + 1, (87)],
457.0 [M+ − HBr, (100)]; HRMS calcd for [C23H21BrN2O2]:
436.0786, found: 436.0785.
5-Ethyl-1,3-bis(4-methoxyphenyl)imidazolidine-2,4-dione, 3av.
Rf = 0.36 (hex–AcOEt = 70 : 30); FTIR (nujol) ν 1721,
1635 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 11.4 Hz,
2H), 7.27 (d, J = 11.4 Hz, 2H), 6.90 (d, J = 11.6 Hz, 2H), 6.88
(d, J = 11.6 Hz, 2H), 4.57 (dd, J = 5.3 and 3.2 Hz, 1H), 3.75 (s,
3H), 3.74 (s, 3H), 2.01 (m, 1H), 1.84 (m, 1H), 0.84 (t, J = 7.4
Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 171.4, 159.3, 157.6,
154.1, 128.3, 127.6, 124.4, 124.3, 114.8, 114.6, 114.4, 114.2,
61.1, 55.5, 21.9, 7.1; ESI (m/z) 341.0 [M+ + H, (5)], 363.0 [M+
+ Na, (100)]; HRMS calcd for [C19H20N2O4]: 340.1423, found:
340.1420.
2-Bromo-N-phenyl-N-(phenylcarbamoyl)butanamide, 6e. Rf
= 0.44 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 2916, 1696,
1
1665 cm−1; H NMR (400 MHz, CDCl3) δ 11.22 (bs, 1H), 7.48
(m, 5H), 7.26 (m, 4H), 7.04 (t, J = 7.4 Hz, 1H), 3.91 (t, J = 7.4
Hz, 1H), 2.12 (m, 1H), 1.89 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H);
13C NMR (63 MHz, CDCl3) δ 173.2, 151.5, 137.4, 137.0,
129.8, 129.6, 129.2, 129.0, 124.4, 120.2, 47.0, 28.2, 12.0; ESI
(m/z) 281.0 [(M − HBr)+ + H, (10)], 361.0 [M+ + H, (5)], 363.0
[(M + 2)+ + H, (5)], 383.0 [M+ + Na, (100)], 385.0 [(M + 2)+ +
Na, (95)]; HRMS calcd for [C17H17BrN2O2]: 360.0473, found:
360.0478.
1,3-Bis(4-methoxyphenyl)-5,5-dimethylimidazolidine-2,4-dione,
3aw. Rf = 0.16 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1707,
1
1633 cm−1; H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 9.1 Hz,
2H), 7.14 (d, J = 9.1 Hz, 2H), 6.91 (d, J = 7.4 Hz, 2H), 6.88 (d,
J = 7.4 Hz, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 1.43 (s, 6H); 13C
NMR (63 MHz, CDCl3) δ 175.5, 159.6, 159.1, 154.4, 130.5,
127.5, 126.3, 124.5, 114.8, 114.3, 63.3, 55.5, 23.9; ESI (m/z)
341.0 [M+ + H, (100)], 363.0 [M+ + Na, (100)]; HRMS calcd
for [C19H20N2O4]: 340.1423, found: 340.1422.
1-Bromo-N-phenyl-N-(phenylcarbamoyl)cyclohexanecarbox-
amide, 6f. Rf = 0.43 (hex–AcOEt = 80 : 20); FTIR (nujol) ν
1
1722, 1611 cm−1; H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H),
7.48 (m, 2H), 7.44 (m, 2H), 7.38 (m, 3H), 7.24 (t, J = 8.0 Hz,
2H), 7.03 (t, J = 8.0 Hz, 1H), 1.81 (m, 2H), 1.72 (m, 2H), 1.52
(m, 2H), 2.76 (m, 4H); 13C NMR (63 MHz, CDCl3) δ 173.9,
152.8, 137.6, 136.9, 130.9, 129.5, 129.0, 128.6, 124.7, 124.3,
120.3, 120.1, 67.0, 53.4, 39.7, 38.1, 24.7, 24.7, 24.5, 22.8; ESI
(m/z) 343.0 [(M − HBr)+ + Na, (100)], 422.9 [M+ + Na, (80)];
HRMS calcd for [C20H21BrN2O2]: 400.0786, found: 400.0788.
2-Bromo-N-cyclohexyl-N-(cyclohexylcarbamoyl)butanamide,
6a. Rf = 0.65 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1717,
1
1612 cm−1; H NMR (400 MHz, CDCl3) δ 6.08 (bs, 1H), 4.30
(t, J = 7.1 Hz, 1H), 4.08 (t, J = 11.4 Hz, 1H), 3.70 (m, 1H), 2.15
(m, 1H), 2.01 (m, 3H), 1.73 (m, 11H), 1.31 (m, 7H), 0.97 (t, J =
7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 167.9, 153.1, 55.4,
50.3, 47.9, 32.7, 32.1, 30.9, 30.5, 28.6, 25.9, 25.3, 25.3, 24.6,
12.0; ESI (m/z) 293.3 [(M − HBr)+ + H, (100)], 395.1 [M+ +
Na, (40)], 397.1 [(M + 2)+ + Na, (40)]; HRMS calcd for
[C17H29BrN2O2]: 372.1412, found: 372.1415.
N-(Benzylcarbamoyl)-2-bromo-N-tert-butylbutanamide, 6g.
Rf = 0.40 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1734,
1
1627 cm−1; H NMR (400 MHz, CDCl3) δ 7.27 (m, 5H), 6.04
(bs, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.97 (t, J = 7.2 Hz, 1H), 1.99
(m, 1H), 1.83 (m, 1H), 1.39 (s, 9H), 0.80 (t, J = 7.3 Hz, 3H);
13C NMR (63 MHz, CDCl3) δ 171.7, 144.6, 136.3, 129.0,
128.3, 127.7, 80.0, 52.5, 43.5, 30.4, 24.7, 8.0; ESI (m/z) 275.0
[(M − HBr)+ + H, (20)], 355.0 [M+ + H, (5)], 357.0 [(M + 2)+ +
H, (5)], 376.9 [M+ + Na, (100)], 378.9 [(M + 2)+ + Na, (100)];
HRMS calcd for [C16H23BrN2O2]: 354.0943, found: 354.0944.
2-Bromo-N-cyclohexyl-N-(cyclohexylcarbamoyl)-2-methylpro-
panamide, 6b. Rf = 0.55 (hex–AcOEt = 80 : 20); FTIR (nujol)
1
ν 1725, 1663 cm−1; H NMR (250 MHz, CDCl3) δ 6.33 (d, J =
7.4 Hz, 1H), 4.23 (m, 1H), 3.69 (m, 1H), 2.00 (s, 6H), 1.74 (m,
10H), 1.27 (m, 10H); 13C NMR (63 MHz, CDCl3) δ 170.3,
153.5, 59.6, 57.3, 50.3, 32.6, 32.4, 30.7, 26.1, 25.5, 25.4, 24.6;
ESI (m/z) 293.2 [(M − HBr)+ + H, (100)], 395.1 [M+ + Na,
(70)], 397.1 [(M + 2)+ + Na, (70)]; HRMS calcd for
[C17H29BrN2O2]: 372.1412, found: 372.1411.
N-(Benzylcarbamoyl)-2-bromo-N-phenylbutanamide, 6i. Rf =
0.41 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1753, 1646 cm−1
;
1H NMR (400 MHz, CDCl3) δ 9.22 (bs, 1H), 7.41 (d, J = 6.5
Hz, 4H), 7.29 (m, 3H), 7.24 (m, 3H), 4.45 (dd, J = 5.5 and 2.7
Hz, 2H), 3.90 (t, J = 7.3 Hz, 1H), 2.05 (m, 1H), 1.85 (m, 1H),
0.83 (t, J = 7.3 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 172.6,
154.3, 137.8, 137.4, 129.6, 129.3, 129.2, 128.7, 127.8, 127.5,
47.1, 44.8, 28.1, 11.9; ESI (m/z) 295.1 [(M − HBr)+ + H, (20)],
1-Bromo-N-cyclohexyl-N-(cyclohexylcarbamoyl)cyclohexane-
carboxamide, 6c. Rf = 0.61 (hex–AcOEt = 80 : 20); FTIR
1
(nujol) ν 1709, 1627 cm−1; H NMR (400 MHz, CDCl3) δ 6.14
(d, J = 6.9 Hz, 1H), 4.17 (t, J = 11.7 Hz, 1H), 3.58 (m, 1H),
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375.0 [M+ + H, (25)], 377.0 [(M + 2)+ + H, (30)], 397.0
[M+ + Na, (90)], 399.0 [(M + 2)+ + Na, (100)]; HRMS calcd for
[C18H19BrN2O2]: 374.0630, found: 374.0633.
3 (a) L. F. Tieze, Chem. Rev., 1996, 96, 115; (b) A. Domling and I. Ugi,
Angew. Chem., Int. Ed., 2000, 39, 3169; (c) A. Domling, Chem. Rev.,
2006, 106, 17.
4 (a) J. Andraos, Org. Process Res. Dev., 2005, 9, 149;
(b) D. B. Ramachary and S. Jain, Org. Biomol. Chem., 2011, 9, 1277.
5 For some reviews on MC reaction see: (a) R. M. Armstrong,
A. P. Combs, P. A. Brown and T. A. Keating, Acc. Chem. Res., 1996, 29,
123; (b) H. Bienaymé, C. Hulme, G. Oddon and P. Schmitt, Chem.–Eur.
J., 2000, 6, 3321; (c) A. Dömling and I. Ugi, Angew. Chem., Int. Ed.,
2000, 39, 3169; (d) A. Dömling, Curr. Opin. Chem. Biol., 2000, 4, 318;
(e) B. Ganem, Acc. Chem. Res., 2009, 42, 463; (f) E. Ruijter,
R. Scheffelaar and R. V. Orru, Angew. Chem., Int. Ed., 2011, 50, 6234;
(g) A. Dömling, W. Wang and K. Wang, Chem. Rev., 2012, 112, 3083.
6 (a) R. V. A. Orru and M. de Greef, Synthesis, 2003, 1471;
(b) J. D. Sunderhaus and S. F. Martin, Chem.–Eur. J., 2009, 15, 1300;
(c) L.-Q. Lu, J.-R. Chen and W.-J. Xiao, Acc. Chem. Res., 2012, 45,
1278–1293.
N-(Benzylcarbamoyl)-2-bromo-2-methyl-N-phenylpropanamide,
6j. Rf = 0.29 (hex–AcOEt = 80 : 20); FTIR (nujol) ν 1754,
1
1629 cm−1; H NMR (250 MHz, CDCl3) δ 9.00 (bs, 1H), 7.45
(m, 5H), 7.36 (m, 5H), 4.52 (d, J = 5.5 Hz, 2H), 1.68 (s, 6H);
13C NMR (63 MHz, CDCl3) δ 173.8, 155.3, 137.8, 137.4,
131.1, 129.5, 129.2, 128.9, 128.6, 128.5, 127.8, 127.4, 127.1,
126.7, 126.1, 59.6, 45.0, 33.1; ESI (m/z) 295.1 [(M − HBr)+ +
H, (30)], 396.9 [M+ + Na, (98)], 398.9 [(M + 2)+ + Na, (100)];
HRMS calcd for [C18H19BrN2O2]: 374.0630, found: 374.0627.
7 (a) B. Hileman, Chem. Eng. News, 2002, 80, 58; (b) N. Singh, R. Guha,
M. A. Giulianotti, C. Pinilla, R. A. Houghten and J. L. Median-Franco,
J. Chem. Inf. Model., 2009, 49, 1010.
General procedure for the N3-tert-butyl deprotection
8 G. Gerona-Navarro, R. Gonzalez-Muñiz, A. Fernandez-Carvajal,
J. M. Gonzalez-Ros, A. Ferrer-Montiel, C. Carreño, F. Albericio and
M. Royo, ACS Comb. Sci., 2011, 13, 458.
9 J. C. Thenmozhiyal, P. T. H. Wong and W. K. Chui, J. Med. Chem., 2004,
47, 1527.
10 (a) C. W. Bazil and T. A. Pedley, Annu. Rev. Med., 1998, 49, 135;
(b) M. S. Luer, Neurol. Res., 1998, 20, 178.
11 (a) M. Matsukura, Y. Daiku, K. Ueda, S. Tanaka, T. Igarashi and
N. Minami, Chem. Pharm. Bull., 1992, 40, 1823; (b) J. Knabe, J. Baldauf
and A. Ahlhelm, Pharmazie, 1997, 52, 912.
A stirred solution of hydantoin 3 (1 equiv.) and CH3SO3H (10%
in volume) in DCM (0.5 M solution) was heated at 60 °C in a
sealed tube for 3 h. The solution was cooled to r.t., diluted with
a 5% NaHCO3 aqueous solution until basic and extracted with
DCM. The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated under vacuum. When necess-
ary, the crude was purified by flash chromatography.
12 L. Somsák, L. Kovács, M. Tóth, E. Ösz, L. Szilágyi, Z. Györgydeák,
Z. Dinya, T. Docsa, B. Tóth and P. Gergely, J. Med. Chem., 2001, 44,
2843.
1-cyclo-Pentyl-5-phenylimidazolidine-2,4-dione, 14. Rf = 0.34
1
(hex–AcOEt = 50 : 50); FTIR (nujol) ν 1685, 1623 cm−1; H
NMR (400 MHz, CDCl3) δ 7.57 (br s, 1H), 7.41 (m, 5H), 4.94
(s, 1H), 4.01 (quintet, J = 8.9 Hz, 1H), 1.88–1.29 (m, 8H);
13C-NMR (100.6 MHz, CDCl3) δ 171.2, 155.4, 134.4, 129.3,
128.3, 127.2, 65.3, 55.4, 30.1, 29.1, 23.5, 23.3; ESI (m/z) 245.2
[M+ + H, (9)], 267.2 [M+ + Na, (100)]; HRMS calcd for
[C14H16N2O2]: 244.1212, found: 244.1214.
13 (a) G. P. Moloney, A. D. Robertson, G. R. Martin, S. MacLennan,
N. Mathews, S. Dosworth, P. Y. Sang, C. Knight and R. Glen, J. Med.
Chem., 1997, 40, 2347; (b) G. P. Moloney, G. R. Martin, N. Mathews,
A. Milne, H. Hobbs, S. Dosworth, P. Y. Sang, C. Knight, M. Williams,
M. Maxwell and R. Glen, J. Med. Chem., 1999, 42, 2504.
14 M. Jansen, H. Potschka, C. Brandt, W. Löscher and G. Dannhardt,
J. Med. Chem., 2003, 46, 64.
15 K. Last-Barney, W. Davidson, M. Cardozo, L. L. Frye, C. A. Grygon,
J. L. Hopkins, D. D. Jeanfavre, S. Pav, C. Qian, J. M. Stevenson,
L. Tong, R. Zindell and T. A. Kelly, J. Am. Chem. Soc., 2001, 123, 5643.
16 J. C. Sutherland and G. P. Hess, Nat. Prod. Rep., 2000, 621.
17 (a) C. Syldatk, R. Müller, M. Siemann, K. Krohn and F. Wagner, in Bio-
catalytic Production of Amino Acids and Derivatives, ed. J. D. Rozzell
and F. Wagner, Hanser, München, 1992, p. 75; (b) K. Drauz and
H. Waldmann, Enzyme Catalysis in Organic Synthesis, VCH, Weinheim,
1995, p. 409.
18 C. A. López and G. G. Trigo, Adv. Heterocycl. Chem., 1985, 38,
177.
19 (a) S. W. Kim, S. Y. Ahn, J. S. Koh, J. H. Lee, S. Ro and H. Y. Cho,
Tetrahedron Lett., 1997, 38, 4603; (b) J. Matthews and R. A. Rivero,
J. Org. Chem., 1997, 62, 6090; (c) M. M. Sim and A. J. Ganesan, Org.
Chem., 1997, 62, 3230.
General procedure for the N1-p-benzyl deprotection
To a solution of the hydantoin 3 (1 equiv.) in CH3CN (0.1 M
solution) a solution of CAN (4 equiv.) in water (0.8 M solution)
was added dropwise at 0 °C. The temperature was raised to rt
and when the starting material disappeared (TLC monitoring)
the mixture was diluted with water and extracted with AcOEt.
The combined organic layers were dried over anhydrous
Na2SO4, filtered, concentrated under vacuum and the crude
purified by flash chromatography.
20 A. Boeijen, J. A. W. Kruijtzer and R. M. J. Liskamp, Bioorg. Med. Chem.
Lett., 1998, 8, 2375.
3-(4-Methoxyphenyl)-5-phenylimidazolidine-2,4-dione, 15. Rf
= 0.24 (hex–AcOEt = 50 : 50); FTIR (nujol) ν 1708, 1663 cm−1
;
21 Some very recent papers dealing with the synthesis of hydantoins:
(a) T. Miura, Y. Mikano and M. Murakami, Org. Lett., 2011, 13, 3560;
(b) G. Baccolini, C. Boga, C. Delpivo and G. Micheletti, Tetrahedron
Lett., 2011, 52, 1713; (c) O. A. Attanasi, L. De Crescentini, G. Favi,
S. Nicolini, F. R. Perrulli and S. Santeusanio, Org. Lett., 2011, 13, 353;
(d) I. A. Hashmi, A. Aslam, K. Ali Syed, A. Vigar-uddin and
I. A. Firdous, Synth. Commun., 2010, 40, 2869; (e) M. Gao, Y. Yang,
Y.-D. Wu, C. Deng, W.-M. Shu, D.-X. Zhang, L.-P. Cao, N.-F. She and
A.-X. Wu, Org. Lett., 2010, 12, 4026; (f) S. M. Dumbris, D. J. Diaz and
L. McElwee-White, J. Org. Chem., 2009, 74, 8862.
1H-NMR (400 MHz, CDCl3) δ 7.45 (m, 5H), 7.34 (d, J =
9.4 Hz, 2H), 6.98 (d, J = 9.4 Hz, 2H), 5.87 (s, 1H), 3.83 (s, 3H);
13C-NMR (100.6 MHz, CDCl3) δ 170.2, 159.9, 131.6, 129.8,
129.2, 127.0, 126.1, 123.4, 79.9, 55.5; ESI (m/z) 283.2 [M+ + H,
(72)], 305.2 [M+ + Na, (100)]; HRMS calcd for [C16H14N2O3]:
282.1004, found: 282.1001.
22 F. Olimpieri, A. Volonterio and M. Zanda, Synlett, 2008, 3016.
23 (a) E. Naydenova, N. Pencheva, J. Popova, N. Stoyanov, M. Lazarova
and B. Aleksiev, Farmaco, 2002, 57, 189; (b) H. Byrtus, M. Pawlowski,
B. Duszynska, A. Wesolowska, E. Chojnaka-Wojcik and A. Bojarski,
Polym. J. Pharm., 2001, 53, 395; (c) R. M. Schelkum, P. Yuen, K. Serpa,
K. L. T. Meltzer, L. D. Wise, E. R. Whittemore and R. M. Woodward,
J. Med. Chem., 2000, 43, 1892; (d) H. U. Stilz, W. Guba, B. Jablonka,
M. Just, O. Klinger, W. König, V. Wehner and G. Zoller, J. Med. Chem.,
Notes and references
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2 P. A. Wender and B. L. Miller, Nature, 2009, 460, 197.
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28 K. Scwarzkopf, M. Blumenstein, A. Hayen and J. O. Matzger,
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