DPT-mediated synthesis of 2-aminoimidazolidin-4-ones from thioureas tethered to amides

Article abstract of DOI:10.1080/00397911.2013.827724

2-Aminoimidazolidin-4-ones have been synthesized by using di-2-pyridyl thiocarbonate (DPT), taking the thioureas tethered to amides as the starting materials. Both the primary amides and secondary amides have been subjected to this cyclization method and

Full text of DOI:10.1080/00397911.2013.827724

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DPT-Mediated Synthesis of 2-
Aminoimidazolidin-4-ones from
Thioureas Tethered to Amides
Sukumar Bepary a , In Kwon Youn a , Hee-Jong Lim b & Ge Hyeong
Lee b
a Department of Chemistry , Pai Chai University , Daejeon , Korea
b Korea Research Institute of Chemical Technology , Daejeon , Korea
Accepted author version posted online: 16 Apr 2014.Published
online: 29 May 2014.
To cite this article: Sukumar Bepary , In Kwon Youn , Hee-Jong Lim & Ge Hyeong Lee (2014) DPT-
Mediated Synthesis of 2-Aminoimidazolidin-4-ones from Thioureas Tethered to Amides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:13, 1876-1880, DOI: 10.1080/00397911.2013.827724
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Synthetic Communications1, 44: 1876–1880, 2014
Copyright # Korea Research Institute of Chemical Technology
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.827724
DPT-MEDIATED SYNTHESIS OF
2-AMINOIMIDAZOLIDIN-4-ONES FROM THIOUREAS
TETHERED TO AMIDES
Sukumar Bepary,1 In Kwon Youn,1 Hee-Jong Lim,2 and
Ge Hyeong Lee2
1Department of Chemistry, Pai Chai University, Daejeon, Korea
2Korea Research Institute of Chemical Technology, Daejeon, Korea
GRAPHICAL ABSTRACT
Abstract 2-Aminoimidazolidin-4-ones have been synthesized by using di-2-pyridyl
thiocarbonate (DPT), taking the thioureas tethered to amides as the starting materials.
Both the primary amides and secondary amides have been subjected to this cyclization
method and in general this simple and convenient method was found to ensure good to
excellent yields (81–99%).
Keywords Aminohydantoin; aminoimidazolidinone; cyclization; synthesis
INTRODUCTION
In combinatorial synthesis, 2-amino-imidazolidin-4-one is a very attractive
template because of its large number of possible substitution patterns and interesting
combination of potential hydrogen bond donors and acceptors on a small five-
membered ring system. This conformationally constrained single ring structure, with
its guanidine- and imidazole-like moieties, can be exploited for achieving chemical
diversity and also for generating a broad drug-like screening library. Thus a number
of reports have been published mentioning the synthesis of diversified 2-aminoimida-
zolidin-4-ones, most of which are in the area of solid-supported synthesis[1–5] with
few in solution-phase approaches.[6–9] These reported approaches studies have been
observed to bear some common limitations, because they require use of relatively
Received June 16, 2013.
Address correspondence to In Kwon Youn, Department of Chemistry, Pai Chai University, Seo-Gu,
Doma-dong 439-6, Daejeon 302-160, Korea, and Ge Hyeong Lee, Korea Research Institute of Chemical
Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Korea. E-mail: yink@pcu.ac.kr, ghlee@krict.re.kr
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1876

SYNTHESIS OF AMINOIMIDAZOLIDINONES
1877
costly resin and use of protection and deprotection steps, with the related costs.
Most of these methods require guanylation[2,4] by addition of secondary amine before
the cyclization step, thereby generating 2-dialkylamino derivatives only, whereas the
use of primary amines generated regeoisomers.[4,5] Some approaches required harsh
reaction conditions,[2,3] extended reaction time,[1,2] or the use of heavy metals.[4] In
some cases there were lower overall yields,[6] thereby imposing some more limitations.
In the case of solution-phase synthesis, the aza-Wittig-type reactions[7,8] were also found
to be limited to use of only the secondary amines just before cyclization, thereby gener-
ating 2-dialkylamino derivatives. Use of primary amines generated regeoisomers,[9]
depending on the nucleophilicities and steric properties of the amines used.
RESULTS AND DISCUSSION
We have focused on the synthesis of 2-aminoimidazolidin-4-ones by a comp-
lementary approach to further diversify this attractive library using readily available
starting materials. Our objective was to find a novel approach that offers greater
yields while ensuring neutral reaction conditions; minimizes reaction steps, reaction
time, and related costs; and minimizes racemization or regeoisomerization. Accord-
ingly, commercially available L-amino acid amides and isothiocyanates were first
converted to N,N0-disubstituted aryl (or alkyl) thioureas tethered to the primary
(or secondary) amides, which were then treated with di-2-pyridylthionocarbonate
(DPT) using a catalytic amount of DMAP to get the cyclized product 2 or 3
(Scheme 1).
While searching for the optimum reaction condition, cyclized product (2a) was
obtained in 53% yield when run in CH3CN for 6 h at room temperature (Table 1).
Though a similar result has been observed from tetrahydrofuran (THF), greater
yield (93%) was attained when the reaction was run in CH2Cl2 and the reaction
was found to be completed within 3 hs. This ensured a short two-step process for
getting the 2-aminoimidazolidin-4-one. Thus, relatively nonpolar solvent CH2Cl2
appeared as the most suitable (entries 1–3) one and accordingly was selected as
the solvent for the next studies.
In reported studies[7] done using triphenylphosphine (as in aza-Wittig-type
reactions) as the reagent in intermediate step(s), there was a need for recrystallization
to remove the hazardous triphenylphosphine oxide. In our previous research work[10]
for generating the 2-iminohydantoins using triphenylphosphine as the reagent, we
faced similar hazards in some cases. In another aza-Wittig-type study, it was
reported[9] that the generated iminophophorane was too labile to be isolated either
by crystallization or by flash column chromatography and was observed to be hydro-
lized to the corresponding alpha-amino esters and triphenylphosphine oxides. In that
Scheme 1. DPT-mediated synthesis of 2-aminoimidazolidin-4-ones from thioureas tethered to amides.

1878
S. BEPARY ET AL.
Table 1. DPT-mediated synthesis of 2-aminoimidazolidin-4-ones by thioureas tethered to amides
Entry
Substrate
R1
R2
R3
Reaction time (h)
Productsa
Yield (%)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1c
1d
1e
1f
iso-Butyl
iso-Butyl
iso-Butyl
H
Ph
Ph
Ph
Ph
Ph
Ph
n-Pr
Ph
Ph
H
H
3
6
2a
2a
2a
2b
2c
2d
—
3f
93
55c
53d
81
H
6
H
3
CH3
Bn
H
3
89
91
H
3
iso-Butyl
iso-Butyl
iso-Butyl
H
12
1.5
1.5
NR
99
Ph
n-Pr
1g
3g
96
aCompounds are known, and the spectral data are available in Refs. 10 and 11.
bIsolated yields.
cTHF was used as solvent.
dCH3CN was used as solvent.
case, they were to run the next step without further purification to get the necessary
carbodiimide. In another aza-Witting approach[7] to synthesize the 2-aminoimidazolidin-
4-one from alpha-azidoesters, the stability of some carbodiimide intermediates were very
uncertain, thereby demanding very careful control of the reaction and storage conditions.
In our approach, the reaction was very clean, permitting smooth thin-layer chromato-
graphic (TLC) monitoring. At the same time DPT gave acidic 2-hydroxypyridine as
the by-product (Scheme 1), offering very convenient workup process (simple washing
with saturated NaHCO3 solution offered the desired product).
As can be shown in entries 4–6 (Table 1), the N,N0-disubstituted phenyl thiour-
eas (1b–1d) were smoothly cyclized to the corresponding cyclized products (2b–2d)
within 3 h in excellent yields (81–91%), thus indicating satisfactory conversion to
the corresponding carbodiimide intermediates, which spontaneously cyclized to the
desired 2-aminoimizazolidin-4-ones. These represent the excellent scope of generat-
ing the 2,5-disubstituted 2-aminoimidazolidin-4-one libraries by exploitting DPT-
mediated cyclization of thioureas tethered to amides.
However, in the case of simple N,N0-dialkyl substituted thioureas (1e), disap-
pointingly, there was no reaction (entry 7, Table 1) even after running the reaction
for 12 h. This indicates that if both the R1 and R2 are alkyl substituents, then
DPT cannot generate the intermediate carbodiimide and thus is not capable of
inducing the subsequent cyclization. This can be further justified by entries 8 and
9, where the presence of aromatic rings favored the carbodiimide generation, thereby
ensuring nearly quantitative yields (99% and 96%). These approaches offered a better
method when compared to the cyclization of similar thioureas by using CBr4=Ph3P=
DIPEA=CH2Cl2.[10] Besides, DPT-mediated cyclization demanded much shorter

SYNTHESIS OF AMINOIMIDAZOLIDINONES
1879
Scheme 2. Plausible mechanism of DPT-mediated synthesis of 2-aminoimidazolidin-4-ones from thioureas
tethered to amides.
reaction time (1.5 h) as compared to that needed (6 h) for cyclization by CBr4=Ph3P=
DIPEA=CH2Cl2. Thus these DPT-mediated cyclization represents an additional
rapid and convenient approach for generation of diversified 2,3,5-trisubstituted
2-aminoimdazolidin-4-one libraries from thioureas tethered to secondary amides.
In cases where there are both the thiourea and urea groups in the same mol-
ecule, some reported[10] agents such as CBr4=Ph3P=DIPEA=CH2Cl2 or CCl4=Ph3P=
DIPEA=CH2Cl2 cannot be used to induce the selective cyclization as they can offer
the cyclized products by exploiting either of these functional groups, thereby offering
regeoisomers or simply undesired products. However, DPT-mediated cyclization
ensures the expected selectivity as it can exploit only the thiourea moieties because
it cannot generate the carbodiimides but not from the ureas.
Because all the reactions were run at room temperature, this DPT-mediated
approach may be a good replacement for the those procedures where the methods
were not suitable to generate the desired 2-aminoimidazolidin-4-ones simply because
of the harsh reaction conditions. At the same time, this neutral reaction condition
might be an excellent option for cases where the reacting intermediates or products
might have acid-sensitive or base-sensitive functional groups or moieties.
While predicting the mechanism of this cyclization, the thiourea 1 is first
converted (Scheme 2) to the conjugate 10 through [a,b,c,d] releasing one molecule
of 2-hydroxypyridine. This intermediate is again passed through [e,f,g,h] to generate
the carbodiimide, thus releasing one more 2-hydroxypyridine molecule and
additionally one molecule of carbondisulfide. This carbodiimide is then spon-
taneously undergone through [i,j,k] to generate the 2-iminoimidazolidin-4-one 3.
Finally if the thiourea used was a primary amide (i.e., R3 is H), this final compound
again undergoes the favoured tautomerism through [l,m] to generate the desired
2-aminoimidazolidin-4-one 2.
EXPERIMENTAL
General Procedure for Synthesizing 2-Aminoimidazolidin-4-ones
from Thioureas
The DPT (1.1 mmol) and a catalytic amont of DMAP were added to the thio-
urea (1.0 mmol) in dry CH2Cl2 (2 mL). The mixture was then stirred for 1.5–6 h at
room temperature and concentrated in vacuo. The residue was diluted with water
and EtOAc, and the organic layer was washed with saturated NaHCO3 solution
and brine, dried over MgSO4, filtered, and concentrated in vacuo to get the crude

1880
S. BEPARY ET AL.
product, which was purified by flash column chromatography using increasing
polarity gradients of hexane=EtOAc=CH2Cl2. Spectral data are available in
Refs. 10 and 11.
CONCLUSION
We have developed a simple and convenient approach for the synthesis of
2-aminoimidazolidin-4-ones from thioureas with DPT under neutral reaction con-
ditions, thereby imposing an excellent complementary approach for generating
diversified 2-aminoimidazolidin-4-one libraries. Further examinations of the scope of
this method for the synthesis of library are currently under way in our laboratories.
FUNDING
We thank the Korea Research Institute of Chemical Technology (KK-
1203-C0) and Ministry of Education, Science and Technology (KN-1236) for the
financial support.
SUPPLEMENTARY DATA
Full experimental detail of cyclization of the thioureas tethered to amide,
1H NMR spectral data of the thioureas, analytical and spectral data, along with
1H NMR and 13C NMR spectra of the cyclized products for this article can be
accessed on the publisher’s website.
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