Synthesis of imidazolidine-2-(thi)ones via C2-selective oxidation and thionation of 2-imidazolinium halides

Article abstract of DOI:10.1055/s-0031-1290087

This article describes a scope study for the synthesis of imidazolidine-2-(thi)ones by selective oxidation or thionation of 2-imidazolinium halides, which in turn are synthesized by alkylation of 2-imidazolines obtained from an initial multicomponent reac

Full text of DOI:10.1055/s-0031-1290087

80
LETTER
Synthesis of Imidazolidine-2-(thi)ones via C2-Selective Oxidation and
Thionation of 2-Imidazolinium Halides
S
ynthesis of Imidazoli
a
dine-2-(thi)
u
ones rice Mooijman, Robin S. Bon, Nanda E. Sprenkels, Hugo N. van Oosterhout, Frans J. J. de Kanter,
Marinus B. Groen, Eelco Ruijter,* Romano V. A. Orru*
Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines and Systems (AIMMS),
VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Fax +31(20)5987488; E-mail: r.v.a.orru@vu.nl; E-mail: e.ruijter@vu.nl
Received 11 October 2011
Y
Abstract: This article describes a scope study for the synthesis of
imidazolidine-2-(thi)ones by selective oxidation or thionation of 2-
imidazolinium halides, which in turn are synthesized by alkylation
of 2-imidazolines obtained from an initial multicomponent reaction.
(R)n
CX2
NH
X
R
R
R
NCX
Y = OH, Br
NH
N
Cl
Cl
R
Key words: alkylation, cyclization, heterocycles, imines, multi-
component reactions
or
(R)n
(R)n
X
NH
R
base
N
R
N
R
X = S, O
R
In recent years, imidazolidine-2-ones (A, Figure 1) and
imidazolidine-2-thiones (B, Figure 1) have proven impor-
tant heterocyclic scaffolds. Imidazolidine-2-ones display
biological activity as NK11 or 5-HT2C receptor
antagonists2 and BACE-1 inhibitors3 and exhibit retinoi-
dal activity.4 In addition, they can be used as chiral auxil-
iaries in asymmetric synthesis.5 Imidazolidine-2-thiones
are valuable intermediates towards biologically active
compounds such as antibacterials6 and (derivatives of)
nutlins, which are promising leads for anticancer therapy.7
Furthermore, imidazolidine-2-thiones are precursors of
both cyclic guanidines8 and N-heterocyclic carbene
(NHC) ligands in coordination chemistry and homoge-
neous catalysis.9
Scheme 1 Classical synthesis of imidazolidine-2-(thi)ones
scaffolds has already been synthesized by application of
these methods, simple and efficient synthesis of structur-
ally diverse libraries proved not straightforward due to the
limited availability of substituted derivatives of these 1,2-
difunctionalized compounds.
Recently, we have reported some preliminary results on
oxidation10 and thionation12 of 2-imidazolinium halides
towards these scaffolds. The synthetic sequence was
based on an initial complexity-generating multicompo-
O
R
R
TMS
N
N
N
N
N
N
(R)n
O
S
(R)n
N
N
R
R
N
N
A
B
4a 60%a
4c 81%
Figure 1 Imidazolidine-2-ones (A) and imidazolidine-2-thiones (B)
4b 72%a
Common strategies towards the target scaffolds include
cyclization reactions of 1,2-diamines with either CO2/CS2
or (thio)phosgene under basic conditions in polar aprotic
solvents (Scheme 1). Alternatively, reaction of
iso(thio)cyanates with 2-amino alcohols, 2-bromoethyl-
amines, or aziridines also provides access to imidazoli-
dine-2-(thi)ones, although these routes might involve
multiple steps. Imidazolidine-2-thiones can also be syn-
thesized from the corresponding imidazolidine-2-ones us-
ing Lawesson’s reagent.10,11 Although a range of these
N
N
N
N
MeO
O
4e 89%
4d 39%
dr = 36:64
OMe
O
N
N
N
N
MeO
O
SYNLETT 2012, 23, 80–84
Advanced online publication: 05.12.2011
DOI: 10.1055/s-0031-1290087; Art ID: B00311ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1
4f 91%
4g 100%a
dr = 25:75
Figure 2 2-Imidazoline MCR products. a Catalyzed by addition of
AgOAc (2 mol%).

LETTER
Synthesis of Imidazolidine-2-(thi)ones
81
R
N
oxidation
thionation
(R)n
O
S
A
B
R
R
R
R
N
N
N
R
H2N
alkylation
MCR
R
O
(R)n
(R)n
R
N
N
X
R
N
R
(R)n
EWG
NC
N
R
Scheme 2 Retrosynthetic analysis for imidazolidine-2-(thi)ones
nent reaction (MCR) which allows introduction of diver- hydes/ketones, and three isocyanides (Scheme 3), a di-
sity on five positions of the target scaffolds. However, no verse set of 2-imidazolines was synthesized in reasonable
scope study was performed since these syntheses were fo- to excellent isolated yields (39–100%; compounds 4a–g,
cused on specific target compounds. Therefore, we now Figure 2).
set out to determine the scope of these types of transfor-
mations.
Given the reduced reactivity of ketones in this MCR,
AgOAc (2 mol%) was added as catalyst for the reaction
A retrosynthetic analysis for this scope study is depicted with acetone (2a) as the carbonyl component. Under these
in Scheme 2. Imidazolidine-2-ones (A) and imidazoli- conditions, 2-imidazolines 4a and 4b were isolated in rea-
dine-2-thiones (B) can be synthesized by C2-selective ox- sonable yield.15 The moderate yield of 4d can be ex-
idation or thionation of 2-imidazolinium halides, which in plained by the relative low a-acidity of isonitrile 3b.15
turn can be synthesized by alkylation of an initial MCR AgOAc catalysis was also used in the synthesis of 4g, af-
product derived from amine, aldehyde or ketone, and a- fording the desired product in quantitative yield in this
acidic isocyanide components. This approach allows in- case.
troduction of diversity on six positions of the target scaf-
fold.
Next, the 2-imidazolinium halides 6a–j (Figure 3) were
obtained in generally excellent isolated yields either by di-
In the MCR, amines 1, aldehydes or ketones 2, and a-acid- rect alkylation with the appropriate halide 5 in CH2Cl2 or
ic isocyanides 3 are reacted to give 2-imidazolines. Prod- by application of Finkelstein conditions. The somewhat
uct formation is assumed to proceed through a Mannich- lower yield of 6g (84%) can be rationalized by the steric
type addition of the a-carbanion of an a-acidic isocyanide hindrance between the mesityl group and the spirofluore-
to the in situ formed (protonated) imine and subsequent nyl moiety, hampering facile alkylation.
cyclization.13,14 From a collection of six amines, five alde-
R1
R1
R2
R3
R2
R3
R2
R4
MCR
N
N
alkylation
R1
+
+
R3
R4
R4
H2N
R5X
5
EWG
NC
N
N
O
I
EWG
EWG
R5
1
2
3
4a–f
6a–h
amines 1
carbonyls 2
isocyanides 3
halides 5
a
a
a
a
O
NC
MeI
NH2
NH2
b
c
d
b
b
TMS
MeO
O
O
MeO
Cl
c
c
b
c
MeO
MeO
NH2
Br
O
NC
O
O
MeO
d
e
d
e
NH2
Br
O
e
f
(CH2O)n
NH2
NC
Cl
NH2
Scheme 3 Multicomponent and alkylation reactions
© Thieme Stuttgart · New York
Synlett 2012, 23, 80–84

82
M. Mooijman et al.
LETTER
O
TMS
N
N
N
N
N
N
N
N
N
I
N
I
I
I
MeO
I
Me
Me
OMe
OMe
O
OMe
6a quant.
6b quant.
6c quant.
6d 92%
6e 91%
OMe
O
O
N
N
N
N
N
N
N
N
Cl
MeO
MeO
Br
Br
N
N
I
I
O
Me
O
Me
6f 98%
6g 84%
6h 93%
6i 100%
6j 92%
Figure 3 2-Imidazolinium halides by alkylation of 2-imidazolines
O
TMS
N
N
N
N
N
N
Ph
N
N
X
S
X
X
X
N
N
MeO
Me
Me
OMe
OMe
O
OMe
7a: X = O 64%
8a: X = S 65%
8b: 70%
7c: X = O 70%
8c: X = S 71%
7d: X = O 96%
8d: X = S 60%
7e: X = O decomp.
8e: X = S 53%
OMe
O
MeO
O
N
N
N
S
N
N
N
N
X
S
S
S
MeO
N
N
N
O
O
Me
Me
Mes
8f: 89%
8g: 76%
8h: 89%
8i: 100%
7j: X = O 12%
8j: X = S 76%
Figure 4 Imidazolidine-2-(thi)ones
For the synthesis of the imidazolidine-2-ones a procedure pectedly low (12%). In this case, we were not able to pro-
was applied where oxidation is mediated by m-CPBA in vide a plausible rationalization of this result.
CH2Cl2 at 0 °C.10 For clean reactions it has proven essen-
tial to add the m-CPBA to a cooled (0 °C) solution of the
2-imidazolinium halides. To obtain the imidazolidine-2-
Spirofluorene imidazolidine-2-thiones (8a–d,f–h) were
obtained by selective C2-thionation in reasonable to ex-
cellent yield (60–89%, Figure 4). Imidazolidine-2-thione
8e, however, was obtained in only 53% yield. This can be
thiones a modified procedure of Karkhanis et al. was ap-
plied.16 In this modified procedure, 2-imidazolinium ha-
rationalized by taking into account the acidic nature of the
lides are reacted with S8 and KOt-Bu at room temperature.
R1
R1
R1
Imidazolidine-2-ones 7a,c,d were obtained in good to ex-
cellent isolated yield (64–96%, Figure 4) by selective C2
oxidation, while no product was obtained from oxidation
of substrate 6e. This is probably due to oxidation to the
corresponding imidazolium halide or oxidative cleavage
of the p-methoxybenzyl group. The yield of 7j was unex-
R2
R3
R4
R2
R3
R4
R2
R3
R4
R5X, NaI
R5X
N
N
N
acetone, r.t.
N
N
CH2Cl2, r.t.
N
I
I
EWG
EWG
EWG
R5
R5
6a–d
4a–f
6g–h
Scheme 4 Alkylation protocols of 2-imidazolines
Synlett 2012, 23, 80–84
© Thieme Stuttgart · New York

LETTER
Synthesis of Imidazolidine-2-(thi)ones
83
General Procedure for the Synthesis of Imidazolidine-2-ones 7
by C2-Oxidation (Scheme 5)
To a solution of an imidazolinium salt 6 (0.05 M) in freshly distilled
CH2Cl2, m-CPBA (3 equiv) was added at 0 °C. The reaction mixture
was stirred at r.t. for 18 h and subsequently washed with Na2CO3
(2×), concentrated in vacuo, and purified by flash chromatography
to afford the imidazolidin-2-one.
R1
R1
R1
R2
R3
R4
R2
R3
R4
R2
R3
R4
N
N
N
KOt-Bu, S8
m-CPBA
O
S
THF
r.t., 3 h
CH2Cl2
0 °C to r.t.
18 h
N
N
R5
N
R5
I
EWG
R5
EWG
EWG
7a–d
6a–d
8a–d
Scheme 5 Oxidation and thionation of 2-imidazolinium halides
General Procedure for the Synthesis of Imidazolidine-2-thiones
8 by C2-Thionation (Scheme 5)
backbone protons, where, considering the basic condi-
tions, deprotonation can lead to various competing side
reactions, leading to scrambling of products. On the other
hand, the other ester-functionalized imidazolidine-2-
thiones 8j and 8i were obtained in good (76%) and quan-
titative yield, respectively. In the latter case, 8i was syn-
thesized in 94% yield over three steps starting from 3c.
Reactions were carried out under an inert atmosphere of dry argon
at a 0.04 M concentration of an imidazolinium salt 6 in freshly dis-
tilled THF. The reaction vessel was charged with imidazoline salt,
KOt-Bu (1.0 equiv), and S8 (1.0 equiv) and flushed twice with ar-
gon. THF was added, and the reaction mixture was stirred at r.t. for
2 h, after which H2O was added. The mixture was subsequently ex-
tracted with Et2O (2×), EtOAc (2×), and CH2Cl2 (2×). The com-
bined organic layers were subsequently dried with Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography to afford the imidazolidin-2-thione.
In summary, we have presented a short and resource-effi-
cient three-step synthetic strategy towards imidazolidine-
2-ones 7 and imidazolidine-2-thiones 8 by C2-selective
oxidation and thionation of 2-imidazolinium halides. This
methodology allows facile introduction of six points of di-
versity in the target scaffolds by a diversity-generating
MCR and subsequent alkylation reaction. The target het-
erocycles were obtained in up to 70% and 94% overall
yields, respectively, over three steps. With these results in
hand, follow-up chemistry towards the synthesis of sever-
al of bioactive compounds is currently under investiga-
tion.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was performed with financial support from the Nether-
lands Organization for Scientific Research (NWO, VICI Grant). Dr.
M. T. Smoluch (VU University Amsterdam) is kindly acknowl-
edged for conducting HRMS measurements.
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General Procedure for the Synthesis of 2-Imidazolinium Salts 6
by N-Alkylation (Scheme 4)
For Iodides
Reactions were carried out at a concentration of 0.15–0.25 M of a
2-imidazoline 4 in dry CH2Cl2, unless noted otherwise. The alkyl io-
dide (1.0 equiv) was added to a stirred solution of the 2-imidazoline,
and the reaction mixture was stirred at r.t. for 18 h. Then, the reac-
tion mixture was concentrated in vacuo. The crude product was
washed with pentane or Et2O to afford the pure imidazolinium salt.
For Bromides and Chlorides
Reactions were carried out at a concentration of 1 M of a 2-imida-
zoline 4 in acetone. The alkyl halide (1.0 equiv) was added to a
stirred solution of the 2-imidazoline and KI (1.0 equiv). The reac-
tion mixture was stirred at r.t. for 18 h and concentrated in vacuo.
Then the reaction mixture was taken up in CH2Cl2 and subsequently
filtered over Celite and concentrated in vacuo to afford the pure im-
idazolinium salt.
© Thieme Stuttgart · New York
Synlett 2012, 23, 80–84

84
M. Mooijman et al.
LETTER
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Synlett 2012, 23, 80–84
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