Mild, Efficient, One-Pot Synthesis of Imidazolones Promoted by N,O-Bistrimethylsilylacetamide (BSA)

Article abstract of DOI:10.1055/s-0035-1562524

The formation of imidazolones by means of dehydrative cyclization was developed, using bistrimethylsilylacetamide. This highly versatile, friendly, safe, and cost-effective reagent exhibited a very large scope of starting materials, since it can promote the formation of 4-benzylidene imidazolones, 4,4-dialkyl-imidazolones, bearing alkyl, aryl, or even no substituent at C2, the latter being unavailable by classical methods. This reagent also afforded clean and high-yielding one-pot reactions in the presence of amine or imine reagents.

Full text of DOI:10.1055/s-0035-1562524

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–G
letter
A
M. Muselli et al.
Letter
Synlett
Mild, Efficient, One-Pot Synthesis of Imidazolones Promoted by
N,O-Bistrimethylsilylacetamide (BSA)
Mickaël Muselli
Ludovic Colombeau1
CH3
N
O
O
TMS
OTMS
Jonathan Hédouin
Christophe Hoarau*
Laurent Bischoff*
Ar
Ar
N
R1
O
R1-NH2
pyridine, Δ, one-pot reaction
N
N
R2
R2
synthesis of 4,4-dialkyl and 4-arylidene imidazolones:
R1 = alkyl, aryl ; R2 = H, alkyl, aryl, alkenyl
24 examples
Normandie Univ, COBRA, UMR 6014 et FR 3038, Univ Rouen,
INSA Rouen, CNRS, IRCOF, 1 Rue Tesnière, 76821 Mont Saint
Aignan Cedex, France
yields 45–99%
laurent.bischoff@univ-rouen.fr
christophe.hoarau@insa-rouen.fr
Received: 25.05.2016
Accepted after revision: 06.07.2016
Published online: 17.08.2016
lones. The authors developed a n-BuLi-promoted addition
of the amide anion onto the vicinal isonitrile, followed by
AcOH protonation at low temperature. In our hands, this
procedure worked smoothly with 4,4-dimethyl and 4,4-cy-
cloalkyl isonitriles, but proved unsuccessful in the case of 4-
benzylidene imidazolones, since the latter are more stabi-
lized by conjugation with the aromatic ring. Furthermore,
although high yields were obtained, the compatibility of
functional groups with POCl3 or n-BuLi would become a
major issue in this strategy, leading us to prepare these
compounds using N,O-bistrimethylsilylacetamide (BSA), a
mild reagent with a large tolerance for usual functional
groups.
DOI: 10.1055/s-0035-1562524; Art ID: st-2016-d0360-l
Abstract The formation of imidazolones by means of dehydrative cy-
clization was developed, using bistrimethylsilylacetamide. This highly
versatile, friendly, safe, and cost-effective reagent exhibited a very large
scope of starting materials, since it can promote the formation of 4-
benzylidene imidazolones, 4,4-dialkyl-imidazolones, bearing alkyl, aryl,
or even no substituent at C2, the latter being unavailable by classical
methods. This reagent also afforded clean and high-yielding one-pot re-
actions in the presence of amine or imine reagents.
Key words imidazolone, oxazolone, amide dehydration, bistrimethyl-
silyl acetamide, silylating agent
Concerning conjugated, 4-arylidene imidazolones, the
Erlenmeyer condensation2b remains, to date, the most
widely used synthesis. In such process, the N-acylated ami-
no acid is first condensed with an aldehyde in the presence
of acetic anhydride and sodium acetate, to yield the Erlen-
meyer oxazolone or azlactone 5. In this compound, the car-
bonyl group is sufficiently activated to allow further amidi-
fication with primary amines such as methylamine or ben-
zylamine, giving the diamide 6. Ring closure leading the
imidazolone 7 through extrusion of a water molecule has
been obtained by various methods, the most widespread
being to reflux in ethanol. Unfortunately, two major issues
rapidly appeared when we tried to use this procedure for
the preparation of our target compounds. First, the yields of
the ring-closing step were generally very low when the
amine component of the reaction was other than methyl-
amine, the reaction being highly sensitive to steric hin-
drance. On the other hand, when we attempted this proce-
dure with N-formyl glycine, the formation of the Erlenmey-
er azlactone proved unsuccessful, since the formamide had
a high propensity for dehydration in the presence of acetic
anhydride, leading to the isonitrile 4. In contrast with
Imidazolones are compounds of very high importance
in many research areas, in particular as fluorescent probes
derived from naturally occuring fluorescent proteins. Our
recent investigations2a in the field of CH arylation of 2H-im-
idazolones prompted us to find reliable sources of the latter.
In the literature, several routes towards imidazolones are
described, each one having its own scope and limitations.
Besides the classical Erlenmeyer synthesis,2b more recent
advances in this field have emerged. The reaction of glycine
imidate with imines3 is also widely used, however, its main
limitation concerns the availability of the imidate, restrict-
ing the choice of substituents at C2. Other syntheses pub-
lished recently include copper-catalyzed coupling of ami-
dines4a or addition of amidines to acetylenic compounds.4b
Despite these recent achievements and already abun-
dant literature in this field (Scheme 1), a general method
compatible with all families of imidazolones is still required
and this prompted us to develop a mild and versatile proce-
dure to access these compounds. Unconjugated imidazolo-
nes, especially 4,4-dialkylated compounds, are readily avail-
able following the methodology described by Marcaccini et
al.5; the isonitrile 2 being a useful precursor of 2H-imidazo-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

B
M. Muselli et al.
Letter
Synlett
4,4′-dialkyl analogues, a similar isonitrile bearing a carbox-
amide at C1 gave no ring closure upon deprotonation and
led only to degradation products.
synthetic route first requires the preparation of the isoni-
trile 2 by POCl3-mediated dehydration of the formamide,
meaning a two-step synthesis with prior isolation of the
isonitrile. Although this reaction proceeded smoothly, we
were attracted by the possibility of carrying out direct de-
hydrative ring formation through formamide activation
with a leaving group of moderate electron-withdrawing
character. Thus, the OTMS group was chosen. We focused
our attention towards N,O-bistrimethylsilylacetamide or
BSA as a mild and easy-to-handle silylating agent.6 Since
the original report mostly concentrated on silylation of am-
ides, enols, and phenols,6b many other uses have been re-
ported for this reagent; such as transient protection of car-
boxylic acids,6c with simultaneous N-silylation to enhance
amine nucleophilicity in the case of amino acids,6d or selec-
tive acid protection of N-Boc peptides to minimize use of
TMSI used for N-Boc cleavage.6e Besides its silylating prop-
erties, this reagent was also recently employed as a building
block in oxazole synthesis.6f This reagent has several advan-
tages. Firstly, it does not require any additional base, as is
needed with TMSCl or TMSOTf which both release a strong
At this stage, we faced the requirement for mild condi-
tions that would allow the activation of N-formyl-2-amino
acid amides with a sufficiently poor leaving group to avoid
the formation of the isonitrile. In addition, we became in-
terested in a method that would allow the synthesis of both
4,4-dialkyl and 4-benzylidene imidazolones and would be
versatile enough to furnish 2H- or 2-substituted imidazolo-
nes. Therefore, we wished to develop a robust and versatile
protocol for the formation of both families of imidazolones,
avoiding substrate dependence and restrictions due to oth-
er functional groups.
Initially, we tested the literature conditions in the case
of cycloleucine derivative 1, obtained in one step by Ugi
condensation from cyclopentanone and benzyl isonitrile.
As described,5 deprotonation of the N-benzylamide with
n-BuLi at –60 °C resulted in a rapid attack on the isonitrile,
the imidazolone carbanion being subsequently reprotonat-
ed with acetic acid to yield the 2H compound. However, this
i) Ref 5:
O
O
O
R2
O
R2
R2
R1
n-BuLi,
then AcOH
N
N
H
POCl3
R1 = H
N
H
N+
N
(R = H)
C–
N
H
R1
1
2
3
this work: 2 BSA, pyridine, Δ
R1 = H, alkyl, aryl
O
O
ii) Erlenmeyer:
Ar CHO
O
Ac2O, AcONa, Δ
with R1 = H:
Ar
R1
N
CO2H
Ar
O
H
N+
C–
4
O
O
O
R2-NH2
Ar
Ar
NHR2
O
N
R2
R1 = H
N
HN
R1
N
high temperatures,
tedious reaction with
bulky or aromatic R1, R2
O
R1
R1
7
6
5
this work : R2-NH2, 2 BSA, pyridine, Δ
one-pot reaction, high yields and large scope
iii) Staudinger reaction:
O
O
O
Burgess
(Het)ArCHO
(R = Me)
PPh3
N
R2
O
N3
R1
N
R2
N
Ar
R1
N3
OMe
N
R2
R2-NH2
(R2 = Me, R1 = H, Me)
N
Ar
N3
OMe
R1
ArCHO
O
O
Baranov–Yampolsky
iv) Azide-free synthesis of 2H-imidazolones (ref. 8):
OH
O
O
O
Ar
Ar
Ar
ArCHO, NaH
ref. 8
N+
CONHR2
HN R2
H
–C
HN R2
H
N
R2
HN
O
HN
O
N
our work: 2 BSA,
pyridine, Δ
H
Scheme 1 Use of BSA in the synthesis of 4,4′-dialkyl, 4-arylidene, 2H-, 2-alkyl, 2-aryl imidazolones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

C
M. Muselli et al.
Letter
Synlett
acid. On the other hand, its moderate reactivity makes it
compatible with a wide range of functional groups. For in-
stance, we observed a selectivity of the amide towards the
tert-butyl carbamate group (vide supra). In addition, BSA is
less expensive and more stable over prolonged storage than
bis(trimethylsilyl) trifluoroacetamide or BSTFA. Finally, one
of the most important reasons for selecting this reagent
over TMSCl or HMDS lies in the formation of inert byprod-
ucts, avoiding both the nucleophilic character of ammonia
released from HMDS, or the acid arising from TMSCl or
TMSOTf.
and N-benzoyl cycloleucines were prepared from propionic
anhydride and benzoyl chloride, respectively, the acid moi-
ety being coupled with benzylamine.
Table 1 Synthesis of Cycloleucine-Derived Imidazolones
O
O
R2
R2
pyridine, BSA
100 °C, 12 h
N
N
H
O
N
N
R1
H
R1
1
3
Mechanistic considerations led us to consider both sites
of silylation. As depicted in Scheme 2, a monosilylation of
the diamide may require selectivity to lead to cyclization, or
be reversible and afford the imidazolone upon equilibrium
shift. However, we observed that the use of one single
equivalent of BSA never resulted in a complete conversion,
while quantitative cyclizations were obtained with two
equivalents of BSA. This result suggests that a disilylated in-
termediate is required, affording both electrophilic charac-
ter at C2 and a nucleophilic nitrogen at N1. Obviously, only
one TMS group is transferred from each BSA molecule,
since the NMR spectra of the crude materials exhibit the
signals expected for N-TMS acetamide.7
Entry
1
Imidazolone 3
Yield (%)
74
O
Ph
N
3a
N
H
O
N
2
3
4
5
3b
3c
3d
3e
77
83
80
63
N
N
H
O
N
N
N
H
O
N
N
Ph
Ph
R1
O
TMSO
R1
O
2 BSA
N
N
H
OTMS
N
O
N
N
N
H
R2
1 BSA
R2
Ph
TMSO
R1
O
R1
N
Both diamides were tested under the same dehydrative
conditions (2 equiv of BSA in pyridine, 0.5 M substrate con-
centration), with heating at 100 °C for 12 h. Pleasingly, 80%
and 63% yields were obtained respectively (Table 1, entries
4 and 5), demonstrating that BSA was suitable for more hin-
dered, less reactive substrates.
N
O
N
N
H
R2
R2
?
O
O
+ (TMS)2O
R1
N
HN TMS
complete conversion
H
OTMS
N
These promising results prompted us to examine
whether the method could be applied to conjugated
(4-arylidene) imidazolones, since the latter are important
in the field of fluorescent molecules with biological and
material applications.
R2
sluggish reaction, yields 30–50%
Scheme 2 Proposed mechanism
As listed in Table 1, the synthesis of 2H-imidazolones
3a,b starting from N-formyl-cycloleucine derivatives oc-
curred with good yields with no formation of the isonitrile
(Table 1, entries 1 and 2). Dimethylglycine, a substrate prof-
iting from the Thorpe–Ingold effect gave an 83% isolated
yield of imidazolone (Table 1, entry 3). Although the BSA re-
activity is moderate, we were interested to determine
whether it exhibited a sufficient O-silylating ability for the
cyclization of amides with alkyl or aryl groups instead of
more reactive formamides. For this purpose, N-propionyl
Our starting point was the synthesis of 2H-4-ben-
zylidene imidazolones that were required as substrates for
CH arylation and vinylation at C2.8 The literature concern-
ing this particular class of compounds is sparse, presumably
due to ring closure of formamides not occurring under the
Erlenmeyer conditions. We believed that any harsh dehy-
drating reagent would lead to the isonitrile, since the ace-
tate itself can be eliminated from the O-acetylformamide
before the nucleophilic attack of the nitrogen atom of the
neighboring amide. Moreover, by analogy with cycloleucine
analogues, there is a specific route using the Staudinger re-
action, for the preparation of imidazolones having no sub-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

D
M. Muselli et al.
Letter
Synlett
stituent at C2 (R1 = H), and the latter may be considered as a
particular class of compounds with a completely different
reactivity.
To the best of our knowledge, our cyclization method
with BSA is the first example of formation of 2H-imidazolo-
nes through a dehydration process. In the literature, besides
the isonitrile/amide ring closure, the Staudinger reaction
has been described10 and extensively used by Burgess11 as a
versatile source of fluorescent imidazolones by means of a
further Knovenagel condensation. The group of Baranov
and Yampolsky also used the Staudinger reaction,10c en-
abling the synthesis of 2H-imidazolones for the first time
although with a moderate yields. Following our strategy, we
could prepare imidazolones on a multigram scale, in a very
short sequence, avoiding the use of potentially explosive
azides.
In this study, we wished to examine the reactivity of a
wide range of diamides, obtained through a one-pot proce-
dure starting from oxazolones, under similar conditions.
For over a hundred years, the Erlenmeyer procedure2b for
the preparation of imidazolones has been extensively used.
This consists of a preliminary condensation of N-acyl amino
acids with the appropriate aldehyde, heating in acetic anhy-
dride in the presence of anhydrous sodium acetate. The for-
mation of the oxazolones generally proceeds efficiently;
however, the isolated yields depend strongly on the ability
of the oxazolone to precipitate from water during workup,
while avoiding hydrolysis. In addition, the use of strictly an-
hydrous sodium acetate is preferred; generally the use of
freshly fused sodium acetate is recommended.12
The following transformation involves the reaction with
an amine; the formation of the diamide proceeding readily
due to the strongly electrophilic character of the oxazolone.
The subsequent ring closure is the most limiting step, ex-
cept when methylamine has been used, and generally pro-
ceeds by heating in ethanol in the presence of K2CO3.13 In
the case of other amines the ring closing is sluggish in most
cases. Thus, other methods have been explored, such as
heating at 220 °C,14a fusing a mixture of the oxazolone and
the amine in the presence of freshly fused sodium acetate
at 160 °C14b or heating in DMF with Cs2CO3 as a base.15 In
the case of imidazolones, however, silylation has seldom
been used as a dehydration technique. To our knowledge,
only TMSCl in DMF at 90–125 °C16a and HMDS in refluxing
DMF have described previously.16b,c As for the above-men-
tioned 4,4′-cycloalkyl imidazolones, BSA is likely to behave
as a more versatile reagent, allowing both syntheses start-
ing from either the oxazolone in the presence of an amine,
or dehydration of a preformed diamide, and would more-
over be compatible with acid-sensitive substrates and elec-
trophile-sensitive formamides.
Indeed, as presented in Scheme 3,N-formyl-dehydroam-
inoamides and their ‘aldol’ analogues can be obtained in
high yields via a [3+2] cycloaddition9 of aldehydes or ke-
tones with deprotonated isocyano acetamides such as com-
pound 8; the latter being prepared by simple amidification
of commercially available methyl isocyanoacetate. Cycload-
dition followed by acidic hydrolysis with aqueous acetic
acid led to 2-formamido-3-hydroxyamides 9. Interestingly,
when we applied this reaction, with a slight modification of
the published protocol, starting from picolylamine deriva-
tives, good diastereomeric ratios (ca. 95:5) were obtained,
whereas N-benzyl amides resulted in approximately 60:40
dr. As our target was the dehydrated form, we did not inves-
tigate the stereochemical outcome of the reaction further.
Depending on the substituent on the aromatic ring, carry-
ing out the reaction under the same conditions can lead ei-
ther to the hydroxylated form 9, or the dehydroamidoam-
ide 10, or even mixtures of both compounds. Nevertheless,
both products, either pure or as a mixture, can be cleanly
dehydrated upon heating with BSA in pyridine, leading to
2H-imidazolones 11. In our preliminary work,8 we exclu-
sively focused on 2H-imidazolones, and we initially be-
lieved that BSA was only suitable for N-formyl amino am-
ides, since the latter are the less-hindered and most reac-
tive in this series. It is worth noting that these conditions
are still compatible with formamides, although acetic anhy-
dride only led to the corresponding isonitrile. Furthermore,
the isonitrile-bearing amide cannot lead to base-promoted
ring closure as with cycloleucine, since the conjugation of
the isonitrile with the aromatic ring precludes imidazolone
formation.
–C
–
N+
O
O
N
H
NaH
THF
N
N
N
Ar
Ar
H
O
N
O
H
8
AcOH, H2O
OH
HN CHO
HN CHO
N
N
Ar
Ar
and/or
N
H
N
H
O
O
9
10
pyridine, BSA, Δ
O
Amongst recent, interesting reports dealing with the
synthesis of imidazolones, Kao and Chien et al.17 have ex-
tensively studied the synthesis of imidazolones by ring clo-
sure of previously isolated diamides obtained by the Erlen-
meyer procedure. They first examined this dehydration un-
der Mitsunobu conditions with an excess of reagent,
therefore leading to concomitant formation of substantial
Ar
N
N
N
H
11
Scheme 3 Synthesis of 2H-imidazolones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

E
M. Muselli et al.
Letter
Synlett
amounts of byproducts. They also reported very poor yields
of dehydration of the diamides under classical conditions
(K2CO3, EtOH, reflux), which led them to improve the pro-
cess by heating in dry pyridine. Good yields were generally
obtained, though necessitating long reaction times, up to
five days, and the reaction became even more sluggish with
arylamines. This work is, to our knowledge, the most com-
plete report concerning the formation of imidazolones with
substituents other than methyl, but we decided to investi-
gate the condensation in the presence of BSA of the more
challenging substrates.
Furthermore, in order to shorten the synthetic route, we
used the oxazolones as starting material, instead of isolated
diamides. Hence, when the oxazolone was allowed to react
in the presence of an amine in pyridine, the formation of
the diamide occured within a few minutes at room tem-
perature, except with less reactive aniline which required
heating at 50 °C for the amidification to reach completion.
As the oxazolone opening is presumably facilitated by pyri-
dine, there was no need for the isolation of the diamide.
Thus, upon completion of the reaction between the amine
and oxazolone, BSA was added, and the resulting solution
heated at 100 °C during 12 hours; although the reaction
was usually complete within a few hours with less-
hindered amines (Table 2).
In an initial study, heating diamide 6e (Ar = 4-MeOC6H4;
R1 = Ph, R2 = Bn) in pyridine in the presence of BSA resulted
in complete conversion (92% isolated yield) into the expect-
ed imidazolone 7e. As a result, we immediately focused on
the same reaction being run in a one-pot process starting
from the oxazolone 5 instead of isolated diamide 6.21
As expected, less-hindered substrates derived from me-
thylamine (R2 = Me) led to high isolated yields (Table 2, en-
tries 1, 3, 9, 12, 14). Furthermore, the more challenging
substrate derived from benzylamine also led to good to
very good yields (82–96%, Table 2, entries 2, 4, 5, 10, 13, 15).
Most fluorescent imidazolones bear an aromatic sub-
stituent at C2 and pleasingly, substrates derived from hip-
puric acid (R2 = Ph) also gave good yields despite the pres-
ence of the more bulky group at R2 (84–96%, Table 2, entries
4, 5, 15, 18). Not surprisingly, poorly nucleophilic aniline
gave moderate yields (Table 2, entries 6 and 11), although
entry 16 shows that this amine can also afford a good yield
of imidazolone when the arylidene group possesses a 4-di-
methylamino substituent.
In comparison, under similar conditions without BSA,
compound 7e was obtained with a 15% yield after two days
refluxing in pyridine,17 or 74% yield when reacting under
Mitsunobu conditions (2 equiv of Ph3P and DIAD), in the
presence of DBU (2 equiv) and catalytic DMAP, but requir-
ing time-consuming purification in order to remove large
amounts of Mitsunobu byproducts. Similarly, after three
days refluxing in pyridine, 7o was obtained in 42%; where-
as under conditions developed in this work, not only the
yields were satisfactory, but also the purification was
straightforward. Likewise, the synthesis of compound 7p
has been reported18 by refluxing the oxazolone in the pres-
ence of four molar equivalents of aniline, in glacial acetic
acid with anhydrous sodium acetate for seven hours, with a
45% yield. Finally, we prepared compounds derived from
2-furylamine, in order to compare our method to another
procedure published in the literature utilizing microwave
irradiation.19
Table 2 One-Pot Synthesis of 4-Benzylidene Imidazolones
O
O
R2-NH2
pyridine, Δ, 12 h
O
N
R2
N
N
X
X
BSA (2 equiv)
R1
R1
5
7
Entry
X
R1
R2
7
Yield (%)
1
2
OMe
OMe
OMe
Me
Me
Ph
Me
Bn
7a
98
91
99
82
90
58
84
45
85
84
52
98
92
89
96
82
94
84
7b
7c
7d
7e
7f
3
Me
4
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
NMe2
NMe2
NMe2
NMe2
NMe2
H
4-NCC6H4
Ph
Bn
Bn
Ph
5
6
Ph
For further applications, we needed to assess the com-
patibility of this method with tert-butyl protective groups
such as Boc or tert-butyl esters. Thus N-Boc-propanedi-
amine and glycine tert-butyl ester were used as the amine
component of the reaction, giving 84% and 45% yields, re-
spectively, the modest yield obtained with glycine ester be-
ing due to some degradation of the amino ester itself during
its extraction in the free amine form. This paves the way for
further applications towards fluorophores bearing a linker
for protein labeling. Noteworthy, in the field of fluorescent
imidazolones, extended conjugation at C2 gives rise to red-
shift and better quantum yields. This prompted us to exam-
ine the reaction of N-cinnamoyl glycine, and we were
pleased to observe similar yields (Table 2, entries 9 and 10),
without any noticeable degradation. With a good electron-
7
Ph
(CH2)3NHBoc
7g
7h
7i
8
Ph
CH2CO2t-Bu
9
styryl
styryl
styryl
Me
Me
10
11
12
13
14
15
16
17
18
Bn
7j
Ph
7k
7l
Me
Me
Bn
7m
7n
7o
7p
7q
7r
Ph
Me
Ph
Bn
Ph
Ph
Me
CH2-2-furyl
CH2-2-furyl
H
Ph
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

F
M. Muselli et al.
Letter
Synlett
donating groups such as 4-dimethylamino, widely used in
fluorescent molecules, we obtained even better yields than
with 4-methoxy-bearing compounds (Table 2, entries 12–
16).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562524.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
The scope of this reaction shows the excellent versatili-
ty of the one-pot synthesis under BSA activation for the de-
hydration process, and the functional-group tolerance with
tert-butyl ester, N-Boc, and conjugated alkenes.
References and Notes
(1) Present address: LRGP (équipe BioProMo), UMR-CNRS 7274,
Lorraine-Université, 1 Rue Grandville, BP451, 54001 Nancy
Cedex, France.
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Commun. 2015, 51, 745. (b) Erlenmeyer, E. Liebigs Ann. Chem.
1893, 275, 1.
(3) (a) Lehr, H.; Karlan, S.; Goldberg, M. W. J. Am. Chem. Soc. 1953,
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Bazureau, J.-P.; Hamelin, J. Tetrahedron 1995, 51, 6757.
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(7) See Supporting Information..
To extend this one-pot strategy, we investigated the re-
action of an imine with the oxazolone derived from hippu-
ric acid as depicted in Scheme 4. In this case, freshly fused
zinc chloride was added to activate the imine and allow the
condensation. However, the methylamine released could at-
tack either the starting oxazolone, or the oxazolone result-
ing from condensation with the imine. Only the latter will
lead to imidazolone formation, and a 55% yield was ob-
tained in this case. This yield must be compared to that ob-
tained when reacting the precondensed oxazolone with
methylamine and BSA in pyridine (99%, Table 2, entry 3),
making the previous methodology much more efficient. For
this reason, we did not examine the scope of this reaction
further.
COOH
NHCOPh
DCC, CH2Cl2
O
N
O
PMP
O
MeO
MeNH2
N
O
N
ZnCl2, BSA
Ph
pyridine, Δ
Ph
(8) Muselli, M.; Baudequin, C.; Hoarau, C.; Bischoff, L. Chem. Eur. J.
2016, 22, 5520.
O
(9) Jiang, H.; Cheng, Y.; Wang, R.; Zhang, Y.; Yu, S. Chem. Commun.
2014, 50, 6164.
N
CH3
N
MeO
Ph
(10) (a) Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45,
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Lukyanov, K. A.; Yampolsky, I. V. Chem. Commun. 2013, 49,
5778.
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the Knoevenagel condensation described therein leads to deg-
radation when starting from 2H-imidazolones.
(12) For a recent, complete review on this topic, see: Baranov, M. S.;
Lukyanov, K. A.; Yampolsky, I. V. Russ. J. Bioorg. Chem. 2013, 39,
223.
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7c (55%)
Scheme 4 One-pot reaction of imine with oxazolone
In summary, this study has demonstrated the efficiency
and versatility of BSA as a cyclocondensation reagent, for
the formation of a range of imidazolones.21 The compatibil-
ity with tert-butyl groups, activated double bonds, and for-
mamides and promoting cyclization of poorly reactive sub-
strates such as N-arylamides makes BSA a reagent of choice
for the preparation of these compounds.
Acknowledgment
This work has been partially supported by INSA Rouen, Rouen Univer-
sity, CNRS EFRD, CRUNCH network, Labex SynOrg (ANR-11-LABEX-
0029). Mickaël Muselli is grateful to the Crunch network for a grant
and Ludovic Colombeau thanks the FEDER BIOFLUORG for financial
support.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

G
M. Muselli et al.
Letter
Synlett
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(21) To a solution of (Z)-4-(4-methoxybenzylidene)-2-phenylox-
azol-5(4H)-one (5b, 280 mg, 1 mmol) in pyridine (2 mL) was
added methylamine (1 mL of a 1 M solution in THF). The reac-
tion mixture was stirred for 30 min at room temperature, then
BSA (407 mg, 2 mmol) was added and the reaction heated to
110 °C overnight. It was cooled, diluted with EtOAc, washed
with 1 M citric acid, water and brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography using PE and EtOAc pro-
vided pure (Z)-4-(4-methoxybenzylidene)-1-methyl-2-phenyl-
1H-imidazol-5(4H)-one (7c) as a yellow solid (290 mg, 99%);
mp 176 °C. 1H NMR (300 MHz, DMSO): δ = 8.29 (d, J = 8.9 Hz, 2
H), 7.93 (dd, J = 7.8, 1.7 Hz, 2 H), 7.66–7.55 (m, 3 H), 7.16 (s, 1
H), 7.05 (d, J = 8.9 Hz, 2 H), 3.82 (s, 3 H), 3.27 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 171.80, 161.59, 161.30, 137.26, 134.64,
131.40, 129.55, 129.09, 128.89, 128.70, 127.39, 114.41, 55.46,
29.14. HRMS (CI): m/z calcd for C18H17N2O2 [M + H]+: 293.1285;
found: 293.1290. IR (ATR): 3154, 2947, 1734, 1694, 1574, 1421,
1094 cm–1. Ideally, these reactions are run in a sealed tube.
When carried out in a round-bottomed flask equipped with a
reflux condenser, it is necessary to add a further molar equiva-
lent of BSA to achieve completion of the reaction, since some
BSA can be lost through evaporation.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G