Diversified aminohydantoins from ureas and thioureas tethered to amides

Article abstract of DOI:10.1002/ejoc.201200025

Intramolecular cyclization of thioureas or ureas tethered to amides afforded 2-iminohydantoins and 2-amino-1H-imidazol-4(5H)-ones in very high yields (87-100%) regardless of the substituent (alkyls or aryls). This reaction proceeds through carbodiimides a

Full text of DOI:10.1002/ejoc.201200025

FULL PAPER
DOI: 10.1002/ejoc.201200025
Diversified Aminohydantoins from Ureas and Thioureas Tethered to Amides
Sukumar Bepary,[a] In Kwon Youn,[a] Hee-Jong Lim,[b] and Ge Hyeong Lee*[b]
Keywords: Cyclization / Amides / Hydantoins / Nitrogen heterocycles / Carbodiimides
Intramolecular cyclization of thioureas or ureas tethered to
amides afforded 2-iminohydantoins and 2-amino-1H-imid-
azol-4(5H)-ones in very high yields (87–100%) regardless of
the substituent (alkyls or aryls). This reaction proceeds
through carbodiimides and iminium ions as intermediates.
Among the reagents used to generate the carbodiimides,
CBr4/Ph3P, CCl4/Ph3P, O,OЈ-bis(2Ј-pyridyl)thiocarbonate,
and HgO were investigated.
azolin-4-one was a very attractive template for combinato-
rial synthesis due to its large number of possible substitu-
tion patterns and interesting combination of potential hy-
drogen-bond donors and acceptors on the small five-mem-
ber ring system.[2] Thus, aminohydantoin moieties are im-
posing interesting targets for future research. 2-Aminohy-
dantoin libraries have already been constructed by solid-
phase syntheses through resin-bound carbodiimides,[3]
aminoisothioureas,[4] or guanidines[5] as the key intermedi-
ates.
Though diverse carbodiimides can be generated in high
yields by the reaction of thioureas and Mukaiyama’s rea-
gent[6] or by the aza-Wittig reaction[3c] of iminophos-
phorans with isocyanates, these methods are limited to thio-
ureas with at least one aryl substituent, as aliphatic thio-
ureas were found to exhibit very low conversion[6] to the
carbodiimides. In reported studies, reaction of alkyl isocy-
anates with iminophosphorans were not found to generate
the corresponding carbodiimides, probably due to dimeriza-
tion or polymerization.[3c] Moreover, syntheses of libraries
by the cyclization–cleavage process were found to generate
Introduction
The structurally and biologically interesting 2-iminohy-
dantoin A can exist as tautomers B–I. Depending upon the
substituent, these 2-iminohydantoins have been observed to
behave as an anticancer agent,[1a] an antiproliferative,[1b]
a
BACE1 inhibitor,[1c] a serotonin receptor antagonist,[1d] an
antifungal agent,[1e] an antibacterial agent,[1e] a kinase in-
hibitor,[1f] a CHK1 inhibitor,[1g] an antihypertensive,[1h] an
anticonvulsant,[1i] an antileishmanial,[1j] a glycogen kinase-
3 inhibitor,[1k] an anti-inflammatory,[1l] and so on. Even hy-
dantoins have found therapeutic applications in drugs; for
example, the well-established phenytoin[1m] is a potent mo-
lecule for the treatment of different types of epileptic sei-
zures, nilutamide[1n] is a nonsteroidal orally active antian-
drogen in the therapy of metastatic prostate cancer, and azi-
milide[1o] is a well-known class III antiarrhythmic agent.
In addition, research has also established that among
many classes of small-molecule libraries, 2-aminoimid-
[a] Department of Chemistry, Pai Chai University,
Seo-gu, Domadong 439-6, Daejeon 302-160, Korea
[b] Korea Research Institute of Chemical Technology
P. O. Box 107, Yusung, Daejeon 305-600, Korea
E-mail: ghleee@krict.re.kr
Scheme 1. Routes for the synthesis of diversified aminohydantoin
libraries.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200025.
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Aminohydantoins from Ureas and Thioureas Tethered to Amides
isomers depending on the amines.[7] Thus, diversity of the CH2Cl2 at 0 °C for 1 h (method A), whereas the same reac-
libraries was found to be restricted. Even though an alter- tion in THF (methods B and C) afforded relatively lower
native route involving the use of a guanidine moiety has yields. The CCl4/Ph3P system (method D) required a pro-
been reported to have benefits as the key intermediate, the longed reaction time and offered a decreased yield (83%).
yields were found to be low.[5a] These limitations along with
While using DPT (methods E–G), the well-known rea-
our persistent interest in the formation of carbodiimides gent for synthesizing carbodiimides from thioureas in
and iminium-like cations as versatile intermediates for drug CH3CN with a catalytic amount of DMAP,[8c] cyclized
discovery led us to exploit this route for the synthesis of product 1c was obtained in very high yield, where the re-
diversified aminohydantoin libraries starting from diverse sulting 2-hydroxypyridine was conveniently removed from
amino amides and isocyanates or isothiocyanates the reaction mixture with a saturated solution of NaHCO3.
(Scheme 1).
In search of solvent effects for this reaction, CH2Cl2
(method E) was observed to be better than CH3CN
(method F) and THF (method G). Because DPT is ineffec-
tive in the formation of carbodiimides from ureas, this of-
fers a window for selectivity when both thiourea and urea
moieties are present in the same molecule.
Even though one example of the cyclization of thiourea
tethered to a primary amide by HgO has been reported,[9]
we decided to investigate this agent more systematically and
extensively. In our study, the cyclized adducts were obtained
quantitatively when the thioureas were stirred with HgO in
THF at room temperature for 12 h (method I), whereas at
reflux (method J) the reactions were complete within 2 h
while ensuring similar yields. Reactions were found to be
very clean, thereby permitting very convenient workup,
which involved simple filtration of the reaction mixture
through a silica gel pad. In the case of urea, cyclized prod-
uct 1c was obtained in excellent yield within 2 h (Table 1,
Entries 5 & 12), thereby constituting the first successful ex-
amples of synthesizing 2-iminohydantoin from urea.
Results and Discussion
On the basis of the assumption that the cyclization pro-
ceeds through carbodiimide intermediates, we decided to
survey the reaction of phenylurea and phenylthiourea teth-
ered to a primary amide (i.e., 1a or 1b), derived from l-
leucinamide, by using some reported dehydrothiolation rea-
gents including CCl4/Ph3P,[8a] 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDC),[8b] O,OЈ-bis(2Ј-pyridyl)thio-
carbonate (DPT),[8c] diisopropyl azodicarboxylate (DI-
AD),[8d] HgO,[8e] and CBr4/Ph3P. [8f] Because the CBr4/Ph3P
system has been reported to be successful in generating the
carbodiimide from urea but not from thiourea, we exten-
sively investigated this system for its suitability as the dehy-
drothiolation reagent for intramolecular cyclization of ureas
and thioureas tethered to amides (Table 1).
Table 1. Reaction conditions for the intramolecular cyclization of
urea and thiourea tethered to an amide.
However, on the basis of the observations during the in-
tramolecular cyclization of 1a and 1b under different condi-
tions, CBr4/Ph3P/DIPEA and HgO were selected for more
extensive investigations with thioureas, and at the same
time, only the CBr4/Ph3P/DIPEA system was selected for
the corresponding ureas (Table 2).
While using the CBr4/Ph3P/DIPEA/CH2Cl2 and HgO/
THF systems, aryl thioureas 2a and 3a derived from the
reaction of glycinamide and l-alaninamide, respectively,
with phenyl isothiocyanate offered the corresponding cy-
clized products 2c and 3c in very high yields. On the other
hand, corresponding ureas 2b and 3b, when treated with
CBr4/Ph3P/DIPEA in CH2Cl2 for 2 h, were cyclized
smoothly to afford the same cyclized products 2c and 3c,
respectively, quantitatively (Table 2, Entries 1–6). N-Benzo-
ylthiourea 4a gave cyclized product 4c in 91 and 95% yield
under similar conditions, whereas the corresponding urea
incurred relatively lower yield (Table 2, Entries 7–9), but
both alkylthiourea 5a and alkylurea 5b afforded cyclized
product 5c nearly quantitatively under the same reaction
conditions (Table 2, Entries 10–12), thus constituting the
Entry Method
Reagents
T
[°C]
Solvent
t
[h]
Yield
[%]
1
2
3
4
5
6
7
8
A
B
C
D
D
E
F
G
H
I
CBr4/Ph3P/DIPEA
CBr4/Ph3P/DIPEA
CBr4/Ph3P/DIPEA 0 to r.t.
CCl4/Ph3P/DIPEA
CCl4/Ph3P/DIPEA
DPT/cat. DMAP
DPT/cat. DMAP
DPT/cat. DMAP
DIAD/Ph3P
0
–10
CH2Cl2
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
1
2
2
4
4
3
6
6
99[a]
87[a]
78[a]
83[a]
85[b]
93[a]
53[a]
55[a]
54[a]
99[a]
97[a]
99[b]
reflux
reflux
r.t.
r.t.
r.t.
r.t.
r.t.
reflux
9
THF
THF
THF
20
12
2
10
11
12
HgO
HgO
J
K
CBr4/Ph3P/ DIPEA 0 to r.t. CH2Cl2
2
[a] Isolated yield from thiourea 1a. [b] Isolated yield from urea 1b.
During cyclization of thiourea 1a, with the exception of first example of hydantoin ring formation from N,NЈ-di-
DIAD (method H), all reagents investigated were found to alkyl-substituted thiourea. Notably, with 5a the reaction did
afford cyclized adduct 1c in very good to excellent yields. not proceed with HgO at room temperature, but in re-
In the case of EDC, the reaction time was more than 24 h fluxing THF, however, cyclized product 5c was obtained in
even though the yield was quantitative. 2-Iminohydantoin 95% yield within 2 h. However, the use of CBr4/Ph3P/
(1c) was obtained quantitatively from N,NЈ-disubstituted DIPEA in CH2Cl2 offered excellent cyclization conditions
thiourea 1a upon treatment with CBr4/Ph3P/DIPEA in for the corresponding urea (Table 2, Entry 12).
Eur. J. Org. Chem. 2012, 2542–2548
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Bepary, I. K. Youn, H.-J. Lim, G. H. Lee
FULL PAPER
Table 2. Intramolecular cyclization of ureas and thioureas tethered in THF at room temperature, was exclusively converted into
to amides.
the corresponding urea. Similarly, when heated at reflux,
thiourea 6a was mainly converted into the corresponding
urea (90%) along with cyclized product 6c as a minor prod-
uct (7%). The observations were similar in cases of N,NЈ-
trisubstituted alkyl thiourea 7a. Thus, although HgO was
found to be an excellent reagent for the cyclization of N,NЈ-
disubstituted thioureas tethered to the primary amide, it ap-
peared ineffective for the cyclization of the corresponding
N,NЈ-trisubstituted thioureas; however, method K was still
excellent for cyclization of the corresponding urea. Similar
to 7c, cyclized product 8c was obtained in excellent yields
from N,NЈ-trisubstituted thiourea 8a and urea 8b by meth-
ods A and K, respectively (Table 2, Entries 17–20). How-
ever, cyclization (Table 2, Entries 19 & 20) through forma-
tion of urea 8b was found to be better over the cyclization
through formation of corresponding thiourea 8a, as the di-
methylthiocarbamoylation of l-alaninamide gave a complex
mixture thereby affording a very low yield of thiourea 8a,
whereas carbamoylation afforded urea 8b in high yields.
To confirm that the racemization does not occur in the
above cases, (Ϯ)-6a and (Ϯ)-7a were synthesized from (d)/
(l)-prolinamides, respectively. UV-active hydantoins (Ϯ)-6c
were analyzed by using a Chiralcel OD-H column with
0.46 cmϫ25 cm specifications and a flow rate of 1 mL/min
with n-hexane/2-propanol (70:30) as the mobile phase. GC
analyses of UV-inactive hydantoins (Ϯ)-7c were done by
using an Astek Chiral Dex B-DM with 30 m–250 μ ID–
0.12 μm df specifications (see the Supporting Information).
1
The structure of 1c was determined by H NMR, 13C
NMR, and IR spectroscopy and mass spectrometry. In all
cases we investigated, there was no epimerization, which
was confirmed by the specific rotation of 1c {[α]2D5 = –76.4
(c = 1.0, MeOH)} compared with that of the compound
synthesized by a known method.[9,10] A doublet 1-NH peak
(J = 8.1 Hz) coupled with the C-5 proton and a broad sing-
let of PhNH were observed at δ = 6.88 ppm and δ =
8.69 ppm, respectively, in the 1H NMR spectrum. In the
13C NMR spectrum, the C-2 and C-5 peaks were observed
at δ = 154.2 and δ = 120.3 ppm, respectively. The NH
stretching bands were observed at 3310 cm–1 and a strong
C=O stretching was observed at 1633 cm–1 in the IR spec-
trum. On the basis of these data, structure B looks like the
most plausible tautomer among those postulated, at least
in [D6]DMSO. When cyclized adducts 1c–8c were obtained
[a] Isolated yield. [b] Methods A–K: See Table 1; method L: CBr4/
Ph3P/DIPEA/CH2Cl2, r.t., 6 h; method M: HgO/DMF, 65 °C, 5 h.
[c] Determined by H NMR spectroscopy. [d] No reaction at room
temperature. [e] Exclusively converted into the corresponding urea.
[f] Corresponding urea was obtained in 90% yield.
from thioureas tethered to the primary amide, coupling be-
tween the N-1 and C-5 hydrogen atoms (i.e., in 1c–5c, 8c)
and coupling between NH and CαH of the 2-amino group
1
1
(i.e., in 5c and 7c) were observed in the H NMR spectra.
On the basis of these observations and the reported X-ray
1
data[11] and H NMR spectroscopic data[12] of 2-iminohy-
In the case of N,NЈ-trisubstituted phenylthiourea 6a, cy- dantoins, the structures drawn as tautomer D and tautomer
clized product 6c was obtained in 95% yield by method A, B are most reasonable when phenylamino and alkylamino
whereas similar results were obtained from cyclization of groups, respectively, are substituted at the C-2 position
the corresponding urea by using method K (Table 2, En- (Table 2).
tries 13–16). These methods, when compared with the re-
Again, in the case of N,NЈ-disubstituted phenyl thioureas
ported cyclization with HgCl2,[8c] are significantly faster 9a and 10a, as well as corresponding ureas 9b and 10b, teth-
and milder. However, thiourea 6a, when treated with HgO ered to the secondary alkyl or aryl amides were successfully
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Aminohydantoins from Ureas and Thioureas Tethered to Amides
Scheme 2. Proposed mechanism for the unwanted reaction.
cyclized when treated with CBr4/Ph3P/DIPEA in CH2Cl2 at base than DIPEA in the case of N,NЈ-dialkyl thioureas teth-
room temperature for 6 h (method L) affording the corre- ered to a secondary alkyl amide. Depending upon the sol-
sponding cyclized products 9c and 10c in very good to ex- vents, 11c was found to exist as the E-type and/or F-type
1
cellent yields (81–94%) with tautomer D resulting from tautomers (see the H NMR spectra in the Supporting In-
conjugation with the phenyl group, as the most plausible formation). Thus, on the basis of the above-mentioned ob-
form (Table 2, Entries 21–24). However, when treated with servations the reaction mechanism can be explained as that
CBr4/Ph3P/DIPEA in CH2Cl2, N,NЈ-dialkylthiourea 12a shown in Scheme 3.
tethered to a secondary alkyl amide resulted in carbodi-
imide 12aЈ, which was hydrolyzed directly to corresponding
urea 12b during workup, which was unwanted. However,
when thiourea 12a was heated at reflux with HgO in THF,
a mixture (2:1) of cyclized product 12c or 12cЈ and urea 12b
was obtained, and when heated with HgO at 65 °C in DMF,
cyclized products 12c and/or 12cЈ were produced in 87%
combined yield, as tautomers E or F, which could be equili-
brated with each other (Scheme 2).
Cyclized adduct 12c existing as the E-type tautomer was
slowly aromatized to 4-hydroxyimidazole 12d along with
unknown adducts, and accordingly in CD3OD the ABX
pattern of 12c was be changed to an AB quartet as observed
1
in the H NMR spectrum after 12 h (see Figure 1).
Scheme 3. Mechanism of cyclization of urea and thiourea.
Thiourea (R4 = H, taken as example) reacts with the tri-
halomethylphosphonium salt, resulting from the reaction of
triphenylphosphane and carbon tetrahalide, to afford II
through [a,b]. If R2 = H, II is transformed through [d,e,f]
to carbodiimide IaЈ or IbЈ, which subsequently cyclizes to
afford 2-iminohydantoin Ic or hydrolyzes to offer urea Ib
during workup when R1 and R3 are alkyl groups. If R2 ϶
Figure 1. (a) 500 MHz 1H NMR spectra of 12c/cЈ and (b) 500 MHz
1H NMR spectra of 12d in CD3OD.
The above observation was confirmed by the cyclization H, II is cyclized directly through [c,e,f] to afford cyclized
of thiourea 11a in which enolization was blocked due to the adduct V or is converted through [d,e,f] into reactive imin-
5,5-dimethyl substituents. When treated with HgO in DMF ium cation III, which undergoes subsequent cyclization
at 65 °C for 5 h, cyclized product 11c was produced in 83% through [g,h]. When HgO was used, thiourea Ia gave corre-
yield (Table 2, Entries 25–27). However, when treated under sponding urea Ib as the major adduct through concerted
the CBr4/Ph3P/DIPEA conditions, the cyclized product was steps [j,l,m] or iminium cation III, resulting from dehy-
not obtained, even after 24 h, thereby demanding a stronger drothiolation [i,j,k] of IaЈ followed by hydrolysis.
Eur. J. Org. Chem. 2012, 2542–2548
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2545

S. Bepary, I. K. Youn, H.-J. Lim, G. H. Lee
FULL PAPER
The organic layer was washed with saturated NaHCO3 solution
and brine, dried with MgSO4, filtered, and concentrated in vacuo
to give the crude product, which was purified by flash column
Conclusions
In conclusion, we have developed novel methods for the
synthesis of distinct 2-iminohydantoins from ureas and chromatography (20–40% ethyl acetate in n-hexane) to give the
pure product.
thioureas, thereby imposing an excellent approach for gen-
erating a diversified 2-iminohydantoin library. Further ex-
amination of the scope and mechanism of the reaction are
currently underway in our laboratory.
General Procedure for the Cyclization of Ureas/Thioureas with
DIAD/Ph3P (Method H): A mixed solution of substituted urea/
thiourea (1.0 mmol), DIAD (1.2 mmol), and Ph3P (1.2 mmol) in
dry THF (6 mL) was stirred for 20 h. The reaction mixture was
filtered through a pad of Celite and concentrated in vacuo to afford
the crude product, which was purified by flash column chromatog-
raphy (20–40% ethyl acetate in n-hexane) to give the pure product.
Experimental Section
General: 1H NMR spectra were recorded at 300 MHz, unless other-
wise specified, in CDCl3 solution by using tetramethylsilane as an
internal standard. Analytical thin-layer chromatography was per-
formed on precoated silica gel plates (0.25 mm 60 F-254 E. Merck).
The products were purified by flash column chromatography on
silica gel 60 (Merck, 230–400 mesh). GC analyses of the UV-inac-
tive hydantoins were done by using Astek Chiral Dex B-DM with
30 m–250 μ ID–0.12 μm df specifications, whereas those of UV-
active hydantoins were accomplished by using a Chiralcel OD-H
column with 0.46 cmϫ25 cm specifications with a flow rate of
1 mL/min with hexane/2-propanol (70:30) as the mobile phase.
Commercially available compounds and solvents were used without
previous purification.
General Procedure for the Cyclization of Ureas/Thioureas with HgO
(Methods I, J, and M): A mixed solution of substituted urea/thio-
urea (1.0 mmol) and HgO (3.0 mmol) in dry solvent (4 mL) was
stirred at the optimized temperature. After the reaction was com-
plete, the reaction mixture was filtered through a pad of Celite
and concentrated in vacuo to afford the crude product, which was
purified by flash column chromatography (20–100% ethyl acetate
in n-hexane) to give the pure product.
(S)-5-Isobutyl-2-(phenylimino)imidazolidin-4-one (1c): White solid,
m.p. 99–100 °C. [α]2D5 = –76.4 (c = 1.0, MeOH). 1H NMR
(300 MHz, [D6]DMSO): δ = 0.90 (t, J = 7.8 Hz, 6 H), 1.80–1.65
(m, 3 H), 4.64 (m, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.94 (m, 1 H),
7.25 (m, 2 H), 7.42 (m, 2 H), 8.69 (br. s, 1 H) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 21.9, 22.3, 25.0, 40.5, 41.5, 119.7, 121.1,
General Procedure for the Reaction of Isothiocyanates/Isocyanates
with Aminoamide Hydrochloride: To a stirred solution of amino-
amide hydrochloride (10.1 mmol) and triethylamine (30 mmol) in
MeOH (30 mL) was added dropwise phenyl (or isopropyl) isothio-
cyanate/isocyanate (10 mmol) over a few minutes at 0 °C. For free
aminoamides, the isothiocyanate (1 equiv.) was used in dry CH2Cl2.
After an additional 0.5 h of stirring, the cooling bath was removed,
and the reaction mixture was warmed to room temperature. After
the reaction was complete, as indicated by TLC, the reaction mix-
ture was concentrated in vacuo to afford the crude product, which
was purified by flash column chromatography (40–100% ethyl acet-
ate in n-hexane) to give pure products 1a–7a, 1b–7b, 9a–12a and
9b–12b. For 8a, products were obtained from the reaction of l-
alaninamide with N,N-dimethylcarbamoyl chloride in dry CH2Cl2
in the presence of triethylamine at 0 °C.
124.5, 129.4, 137.8, 155.2 ppm. IR (solid): ν = 3310, 2944, 1633
˜
(C=O), 1595, 1548, 1445, 1231 cm–1. MS: m/z (%) = 232 (3) [M +
1]+, 231 (4) [M]+, 188 (29), 175 (100), 146 (16). HRMS (EI): calcd.
for C13H17N3O [M]+ 231.1372; found 231.1359.
2-(Phenylimino)imidazolidin-4-one (2c): Needle-type white solid,
m.p. 160–162 °C (n-hexane/iPrOH). 1H NMR (300 MHz, [D6]-
DMSO). δ = 4.12 (d, J = 6.0 Hz, 2 H), 6.69 (br. t, J = 6.0 Hz, 1
H), 6.94 (m, 1 H), 7.25 (m, 2 H), 7.41 (m, 2 H), 8.92 (br. s, 1
H) ppm. 13C NMR (75.4 MHz, [D6]DMSO). δ = 28.3, 118.1, 118.5,
121.7, 128.7, 139.7, 154.7 ppm. IR (solid): ν = 3330, 3304, 1640
˜
(C=O), 1597, 1560, 1442, 1312, 1231, 1134 cm–1. MS: m/z (%) =
176 (6) [M + 1]+, 175 (38) [M]+, 174 (100), 131 (20), 119 (87), 91
(22), 77 (17). HRMS (EI): calcd. for C9H9N3O [M]+ 175.0746;
found 175.0761.
General Procedure for the Cyclization of Ureas/Thioureas with CBr4/
Ph3P (Methods A–C and K): To a stirred solution of substituted
urea/thiourea (1.0 mmol), Ph3P (1.3 mmol), and DIPEA
(3.0 mmol) in dry solvent (4 mL) was added dropwise a solution of
CBr4 (1.2 mmol) in dry solvent (1 mL) at 0 °C over 1 min. After
the reaction was complete, the reaction mixture was warmed to
room temperature and concentrated in vacuo to afford the crude
product, which was purified by flash column chromatography (20–
100% ethyl acetate in n-hexane) to give the pure product.
(S)-5-Methyl-2-(phenylimino)imidazolidin-4-one (3c): White solid,
m.p. 158–160 °C. [α]2D5 = –110.6 (c = 1.0, MeOH). 1H NMR
(300 MHz, [D6]DMSO). δ = 1.47 (d, J = 7.2 Hz, 3 H), 4.68 (m, 1
H), 6.88 (d, J = 7.5 Hz, 1 H), 6.94 (m, 1 H), 7.33 (m, 2 H), 7.47
(m, 2 H), 8.68 (br. s, 1 H) ppm. 13C NMR (75.4 MHz, [D6]DMSO).
δ = 18.5, 36.6, 118.1, 120.9, 121.8, 128.7, 139.6, 154.1 ppm. IR
(solid): ν = 3310, 1633 (C=O), 1595, 1548, 1445, 1231 cm–1. MS:
˜
m/z (%) = 190 (6) [M + 1]+, 189 (46) [M]+, 188 (100), 145 (32), 119
(91), 93 (27), 77 (14). HRMS (EI): calcd. for C10H11N3O
[M]+ 189.0902; found 189.0907.
General Procedure for the Cyclization of Ureas/Thioureas with CCl4/
Ph3P in CH2Cl2 (Method D): A stirred solution of substituted urea/
thiourea (1.0 mmol), CCl4 (0.5 mL), Ph3P (1.3 mmol), and DIPEA
(3.0 mmol) in dry CH2Cl2 (6 mL) was heated at reflux for 4 h. The
reaction mixture was allowed to cool to room temperature and con-
centrated in vacuo to afford the crude product, which was purified
by flash column chromatography (20–40% ethyl acetate in n-hex-
ane) to give the pure product.
(S)-5-Methyl-2-(benzoylimino)imidazolidin-4-one (4c): White solid,
m.p. 186–188 °C. [α]2D5 = –74.8 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.70 (d, J = 7.2 Hz, 3 H), 4.82 (m, 1 H),
7.50–7.70 (m, 3 H), 7.95–8.03 (m, 2 H), 9.24 (br. d, J = 6.9 Hz, 1
H), 9.76 (br. s, 1 H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 19.1,
36.9, 118.9, 128.1, 129.2, 131.7, 133.8, 154.2, 168.7 ppm. IR (solid):
ν = 3328, 3273, 1694 (C=O), 1663 (C=O), 1522, 1457, 1271,
˜
1219 cm–1. MS: m/z (%) = 218 (0.8) [M + 1]+, 217 (4) [M]+, 105
(100), 77 (81), 50 (24). HRMS (EI): calcd. for C11H11N3O2 [M]+
217.0851; found 217.0845.
General Procedure for the Cyclization of Ureas/Thioureas with DPT
(Methods E–G): A mixed solution of substituted urea/thiourea
(1.0 mmol) and DPT (1.1 mmol) in dry solvent (6 mL) was stirred
at room temperature. The reaction mixture was concentrated in
vacuo, and the residue was diluted with water and ethyl acetate.
(S)-5-Isobutyl-2-(propylamino)-1H-imidazol-4(5H)-one (5c): Pale-
yellow oil. [α]2D5 = –66.0 (c = 1.0, MeOH). 1H NMR (300 MHz,
2546
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2542–2548

Aminohydantoins from Ureas and Thioureas Tethered to Amides
[D6]DMSO). δ = 0.94–0.78 (m, 9 H), 1.38 (m, 2 H), 1.76–1.52 (m, 77 (81). HRMS (EI): calcd. for C19H21N3O [M]+ 307.1685; found
3 H), 2.96 (m, 2 H), 4.55 (m, 1 H), 6.13 (t, J = 5.7 Hz, 1 H), 6.56
(d, J = 8.4 Hz, 1 H) ppm. 13C NMR (75.4 MHz, [D6]DMSO). δ =
11.2, 21.7, 21.8, 23.0, 24.3, 39.6, 40.8, 41.1, 120.7, 156.7 ppm. IR
307.1691.
(S)-2-(Benzylimino)-3,5,5-trimethylimidazolidin-4-one (11c): White
solid, m.p. 118–120 °C. H NMR (CDCl3, 300 MHz): δ = 1.36 (s,
1
(neat): ν = 3347, 2961, 2934, 2874, 1642 (C=O), 1563, 1557, 1469,
˜
6 H), 3.05 (s, 3 H), 4.45 (s, 2 H), 7.20–7.45 (m, 5 H + NH) ppm.
1275 cm–1. MS: m/z (%) = 198 (12) [M + 1]+, 197 (7) [M]+, 156
(21), 154 (60), 141 (100), 87 (24), 86 (30), 73 (21), 70 (36), 69 (64),
56 (66), 55 (87). HRMS (EI): calcd. for C10H19N3O [M]+ 197.1528;
found 197.1519.
13C NMR (75.4 MHz, CDCl3): δ = 25.5, 25.7, 127.4, 127.7,
128.8 ppm. IR (solid): ν = 3339, 2983, 1668 (C=O), 1540, 1478,
˜
1453, 1406, 1374, 1337, 1299, 1237, 1171, 1066, 1046, 1028,
1003 cm–1. MS: m/z (%) = 232 (6) [M + 1]+, 231 (38) [M]+, 154
(12), 145 (25), 91 (100), 83 (13), 69 (22), 65 (28), 58 (90). HRMS
(EI): calcd. for C13H17N3O [M]+ 231.1372; found 231.1379.
(S)-3-(Phenylimino)hexahydropyrrolo[1,2-e]imidazol-1-one
(6c):
White solid, m.p. 136–138 °C. [α]2D5 = –157.3 (c = 1.0, MeOH). H
NMR (300 MHz, [D6]DMSO). δ = 2.30–1.95 (m, 4 H), 3.42 (m, 1
H), 3.61 (m, 1 H), 4.79 (dd, J = 7.5, 3.3 Hz, 1 H), 6.98 (m, 1 H),
7.26 (m, 2 H), 7.51 (m, 2 H), 8.47 (br. s, 1 H) ppm. 13C NMR
(75.4 MHz, [D6]DMSO). δ = 24.6, 30.0, 45.8, 47.0, 119.9, 120.1,
1
Supporting Information (see footnote on the first page of this arti-
cle): General information on the synthesis conditions and experi-
mental protocols for the synthesis of starting materials 1a–12a and
1b–12b as well as conditions and experimental protocols for the
cyclization of these compounds; 1H NMR spectra of starting mate-
rials 1a–12a and 1b–12b; 1H and 13C NMR spectra of the products
1c–12c; graphs showing the retention time comparison as observed
by the chiral HPLC and GC analysis.
122.3, 128.3, 139.7, 153.4 ppm. IR (solid): ν = 3372, 3278, 2953,
˜
2872, 1646 (C=O), 1592, 1530, 1442, 1364, 1240 cm–1. MS: m/z (%)
= 216 (6) [M + 1]+, 215 (37) [M]+, 188 (29), 123 (30), 119 (100),
80 (25). HRMS (EI): calcd. for C12H13N3O [M]+ 315.1059; found
315.1051.
(S)-3-(Propylamino)-5,6,7,7a-tetrahydropyrrolo[1,2-e]imidazol-1-one
(7c): White solid, m.p. 61–63 °C. [α]2D5 = –109.8 (c = 1.0, MeOH).
1H NMR (300 MHz, [D6]DMSO). δ = 0.84 (t, J = 7.5 Hz, 3 H),
1.43 (m, 2 H), 1.90–2.20 (m, 4 H), 3.00 (m, 2 H), 3.19 (m, 1 H),
3.25–3.43 (m, 1 H), 4.67 (dd, J = 7.2, 3.0 Hz, 1 H), 6.50 (br. t, 1
H) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 11.4, 23.5, 25.1, 30.8,
Acknowledgments
We thank the Ministry of Education, Science and Technology and
the Korea Research Institute of Chemical Technology (KRICT) for
financial support.
42.6, 45.3, 47.3, 119.5, 155.9 ppm. IR (solid): ν = 3350, 2964, 2934,
˜
2874, 1626 (C=O), 1535, 1458, 1384, 1350, 1244, 1194, 1145 cm–1.
MS: m/z (%) = 182 (8) [M + 1]+, 181 (21) [M]+, 152 (11), 141 (17),
123 (89), 112 (22), 96 (72), 86 (14), 80 (25), 68 (100). HRMS (EI):
calcd. for C9H15N3O [M]+ 181.1215; found 181.1220.
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(S)-5-Methyl-2-(dimethylamino)-1H-imidazol-4(5H)-one (8c): White
solid, m.p. 127–129 °C. [α]2D5 = –82.4 (c = 1.0, MeOH). H NMR
1
(300 MHz, [D6]DMSO). δ = 1.42 (d, J = 7.2 Hz, 3 H), 2.80 (s, 6
H), 4.61 (m, 1 H), 6.94 (br. d, J = 7.8 Hz, 1 H) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 19.9, 36.3, 37.8, 120.8, 156.8 ppm. IR (so-
lid): ν = 3262, 2943, 1619 (C=O), 1508, 1453, 1388, 1219,
˜
1063 cm–1. MS: m/z (%) = 142 (18) [M + 1]+, 141 (92) [M]+, 97
(14), 88 (15), 72 (100). HRMS (EI): calcd. for C6H11N3O [M]+
141.0902; found 141.0911.
(S)-5-Isobutyl-2-(phenylimino)-3-propylimidazolidin-4-one
(9c):
White solid, m.p. 81–83 °C. [α]2D5 = +26.3 (c = 1.0, MeOH). 1H
NMR (300 MHz, [D6]DMSO). δ = 0.80–0.9 = 2 (m, 9 H), 1.35–
1.68 (m, 4 H), 1.78 (m, 1 H), 3.48 (t, J = 7.2 Hz, 2 H), 3.97 (m, 1
H), 6.90 (m, 2 H), 6.96 (m, 1 H), 7.24–7.29 (m, 2 H + NH) ppm.
13C NMR (75.4 MHz, CDCl3): δ = 11.4, 21.2, 21.9, 23.3, 25.1, 40.9,
41.6, 56.1, 122.5, 123.2, 129.6, 148.0, 149.8, 174.3 ppm. IR (solid):
ν = 3332, 3278, 2959, 2933, 2872, 1666 (C=O), 1591, 1490, 1450,
˜
1371, 1317, 1212, 1114, 1097, 1019 cm–1. MS: m/z (%) = 274 (15)
[M + 1]+, 273 (55) [M]+, 244 (14), 230 (18), 188 (100), 175 (71),
156 (80), 145 (73), 119 (31), 86 (30), 77 (39). HRMS (EI): calcd.
for C16H23N3O [M]+ 273.1841; found 273.1849.
(S)-5-Isobutyl-2-(phenylimino)-3-phenylimidazolidin-4-one
(10c):
1
White solid, m.p. 104–106 °C. [α]2D5 = +38.7 (c = 1.0, MeOH). H
NMR (300 MHz, [D6]DMSO). δ = 0.91 (d, J = 6.6 Hz, 6 H), 1.50–
1.70 (m, 2 H), 1.87 (m, 1 H), 4.19 (m, 1 H), 6.88 (m, 2 H), 6.95
(m, 1 H), 7.25 (m, 2 H), 7.31–7.58 (m, 5 H + NH) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 22.0, 23.3, 25.1, 56.2, 122.4, 123.3, 127.4,
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˜
3313, 2959, 2928, 2870, 1659 (C=O), 1589, 1498, 1412, 1323, 1185,
1167, 1129, 1094, 1070 cm–1. MS: m/z (%) = 308 (22) [M + 1]+, 307
(91) [M]+, 264 (77), 251 (44), 194 (55), 131 (30), 119 (100), 92 (39),
Eur. J. Org. Chem. 2012, 2542–2548
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Received: January 10, 2012
Published Online: March 16, 2012
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Eur. J. Org. Chem. 2012, 2542–2548