Three-step synthetic pathway to fused bicyclic hydantoins involving a selenocyclization step

Article abstract of DOI:10.1016/j.tet.2014.12.088

Sequential 5-alkenyl hydantoin and pyrrolidine ring-forming reactions have been applied in the synthesis of conformationally constrained fused bicyclic scaffold. They are assembled by a three-step reaction sequence from two variable building blocks (readily available β-ketoesters and alkenyl halides) by combining a Bucherer-Bergs reaction with a final selenium-promoted intramolecular cyclization as a key step. The chemoselectivity of this bicyclic hydantoin formation is strongly influenced by experimental factors such as the solvent and the use of additives. The reaction is regiospecific giving only five-membered fused bicyclic hydantoins in good to excellent yields stemming from the nucleophilic attack of the nitrogen atom to a cyclic seleniranium ion intermediate during the cyclization step. A separable diastereomeric mixture is obtained; the products with bridgehead substituents and phenylseleno groups in cis relationships were formed predominantly. The reaction tolerates a variety of substitution at the double bond, furthermore, the presence of substituents at C(5) and N(3) position opens up the capability of generating a broad structural diversity.

Full text of DOI:10.1016/j.tet.2014.12.088

Tetrahedron 71 (2015) 1101e1108
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Three-step synthetic pathway to fused bicyclic hydantoins involving
a selenocyclization step
ꢀ
*
ꢁ
Biljana M. Smit , Radoslav Z. Pavlovic
ꢁ
Faculty of Science, University of Kragujevac, Radoja Domanovica 12, PO Box 60, 34000 Kragujevac, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 October 2014
Received in revised form 9 December 2014
Accepted 23 December 2014
Available online 31 December 2014
Sequential 5-alkenyl hydantoin and pyrrolidine ring-forming reactions have been applied in the syn-
thesis of conformationally constrained fused bicyclic scaffold. They are assembled by a three-step re-
action sequence from two variable building blocks (readily available b-ketoesters and alkenyl halides) by
combining a BucherereBergs reaction with a final selenium-promoted intramolecular cyclization as
a key step. The chemoselectivity of this bicyclic hydantoin formation is strongly influenced by experi-
mental factors such as the solvent and the use of additives. The reaction is regiospecific giving only five-
membered fused bicyclic hydantoins in good to excellent yields stemming from the nucleophilic attack of
the nitrogen atom to a cyclic seleniranium ion intermediate during the cyclization step. A separable
diastereomeric mixture is obtained; the products with bridgehead substituents and phenylseleno groups
in cis relationships were formed predominantly. The reaction tolerates a variety of substitution at the
double bond, furthermore, the presence of substituents at C(5) and N(3) position opens up the capability
of generating a broad structural diversity.
Keywords:
Nitrogen heterocycles
Fused-ring systems
Intramolecular cyclization
Selenium
Hydantoins
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
As part of our strategy toward the preparation of hydantoin-
containing heterocycles, we sought to prepare the more con-
Imidazolidine-2,4-dione derivatives, generally called hydan-
toins,1 are important class of compounds because of their industrial
formationally constrained and varied bicyclic scaffolds, by fusing
the hydantoin ring at N(1) and C(5) positions to a functionalized
five-membered pyrrolidine ring and homologues. Furthermore, the
presence of substituents at the C(5) and N(3) positions opens up the
capability of generating broad structural diversity.
Selenocyclization proved to be a powerful and versatile tool for
the construction of heterocyclic rings.15 Although its use for the
construction of pyrrolidine rings has been well-established16 no
examples for construction of the bicyclic hydantoin system through
selenium-induced intramolecular cyclization have been reported.
Herein, we describe a new methodology for the synthesis of
a bicyclic hydantoin scaffold and our independent efforts to exploit
intramolecular selenocyclization for fashioning molecules having
rigid, conformationally well-defined structures consistent with
attractive lead compounds for drug discovery.
relevance as intermediates in the production of a
-amino acids2 and
their frequent use in a plethora of pharmaceutical products.3
Hydantoins are a ubiquitous structural core found in a number
of natural products.4 Several derivatives exhibit diverse biological
activities, such as anticonvulsant,5 antitumor,6 anticancer,7 anti-
arrythmic,8 herbicidal,9 and others.10 The observed activities do not
arise from the hydantoin nucleus itself but from different sub-
stituents that have been appended to it.11 In particular, spi-
rohydantoins12 and fused13 bicyclic hydantoin derivatives have
recently attracted much attention in drug discovery due to their
various biological activities. However, the methods for their syn-
thesis are not numerous. Few examples have dealt with the con-
struction of six- and five-membered fused hydantoins using ring-
closing metathesis, where amino acids have been used as starting
materials to prepare the hydantoin precursors.14 Therefore, an
extensive development of new synthetic methodologies for the
preparation of new functionalized hydantoin derivatives would be
highly desirable.
2. Results and discussion
For our study, in the first step, unsaturated ketones 2aef, as
starting materials, were synthesized by carbanionic alkenylation
and subsequent decarbethoxylation of readily available b-ketoest-
ers (Scheme 1, pathway a). In the pathway b (Scheme 1) the
decarbethoxylation step was avoided in our attempt to prepare
alkenylated b-ketoesters 1aef as another set of substrates.
* Corresponding author. Fax: þ381 34 335040; e-mail address: biljam@kg.ac.rs
ꢀ
(B.M. Smit).
http://dx.doi.org/10.1016/j.tet.2014.12.088
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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B.M. Smit, R.Z. Pavlovic / Tetrahedron 71 (2015) 1101e1108
Scheme 1. Synthesis of polysubstituted alkenyl hydantoins 3aeh.
For the preparation of 5-alkenyl hydantoins, we have chosen the
group attached to carbonyl group has an influence on the whether
decarbethoxylation happens or not. The mechanism of this decar-
bethoxylation is unclear and needs further investigation.
use of the well-established BucherereBergs reaction17 because this
reaction is compatible with a large-scale production, uses non-
expensive reagents as well as mild conditions, and it proceeds in
one step starting from the appropriate unsaturated ketones. Under
these conditions (i.e., 1 equiv of ketone 2aef, 2 equiv of NaCN,
4 equiv of (NH4)2CO3, EtOH/H2O (1:1), reflux, 24 h) compounds
3aef, as crystalline solids, were obtained in good yields (61e85%)
(Scheme 1, pathway a).
The resulting 5-alkenyl hydantoins contain a double bond and
an internal nitrogen nucleophile and they can be subjected to
electrophilic cyclization. In the final step, 5-alkenyl hydantoins
were subjected to the selenium-induced cyclization reaction to
give, in an overall three-step sequence, fused bicyclic hydantoins.
We initiated our study by optimizing the reaction conditions
(Table 1). For this purpose we prepared 5-alkenyl hydantoin 3i from
commercially available unsaturated ketone 2g. The influence of
selenium reagents, bases, additives, temperature, and solvents on
the cyclization of 3i was examined. Interestingly, the chemo-
selectivity of bicyclic hydantoin formation was strongly influenced
by experimental factors such as the solvent and the use of additives.
After an initial screen of additives (Table 1) we found that the
use of silica gel afforded the highest yield of desired bicyclic
product. Concerning the solvents, the use of acetonitrile gave the
2-Alkenyl
b-ketoesters 1aef were also subjected to Bucher-
ereBergs reaction (Scheme 1, pathway b). Only 1a and 1d (R1¼Me)
afforded an expected products (with R5¼CO2Et) 3g and 3h, re-
spectively. Surprisingly, the other 2-alkenyl b-ketoesters, under the
same conditions, yielded the products 3b, 3c, 3e, and 3f (R5¼H),
which are the same as those obtained from unsaturated ketones 2b,
2c, 2e, and 2f in the pathway a. An unexpected fully decar-
bethoxylated products were obtained when the substrate had
R1¼Et or Pr. From these results it is apparent that the size of alkyl
Table 1
Optimization of the reaction conditionsa for the cyclization of 3i
Entry
X
Temperature [ꢀC]
Additive
Yieldd [%]
cis/transd
1
2
3
4
5
6
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
I
25
25
25
25
25
25
25
25
25
25
25
ꢁ5
81
25
25
None
Al2O3
AlCl3
ZnCl2
SnCl2
BF3$OEt2
SiO2
6
4
6
d
d
d
5
d
26e
35e
41e
56e
6
72:27
84:16
84:16
81:19
d
7
8b
9
SiO2
K2CO3
Et3N
Py
SiO2
SiO2
10
11
12b
13b
14b
15b,c
11
9
d
d
43e
22
4
80:20
d
SiO2
SiO2
d
68e
87:13
a
Reaction conditions: 5-methyl-5-(4-methyl-pent-3-enyl)-imidazolidine-2,4-dione (3i, 0.5 mmol), additive (0.5 mmol), acetonitrile 5 mL, PhSeX (0.55 mmol).
The reaction was conducted with 2.5 mmol of SiO2.
b
c
PhSeI was prepared by the reaction of (PhSe)2 with 1 equiv of iodine.
d
e
Diastereomeric ratios were determined from 1H NMR spectra of the crude reaction mixture.
Isolated yields.

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B.M. Smit, R.Z. Pavlovic / Tetrahedron 71 (2015) 1101e1108
1103
Table 2
best results. The use of THF, dichloromethane or pyridine gave the
Selenocyclizationa of 5-alkenyl hydantoins 3aek
desired product in a less than 10% yield. In our previous works18 we
found that the use of bases facilitates the selenoetherification, but
in this cyclization reaction the use of bases (K2CO3, triethylamine or
pyridine) did not have any influence. The effect of the reaction
temperature is also shown in Table 1 and from the results it can be
seen that the highest yield was obtained at room temperature. The
effect of halide ion of the selenylating reagent on the reaction
outcome has been observed. Although phenylselenyl bromide is the
most effective reagent for intramolecular amidoselenylations,16g,19
in our screening it was less successful than chloride and iodide
(Table 1). Phenylselenyl iodide afforded the best results in terms of
reactivity and diastereoselectivity, but we decided to use com-
mercially available PhSeCl, as it is a more convenient reagent, to use
and obtain.
Substrate
R1/R2/R3/R4/R5/R6
Product
Yieldb [%]
cis/transc
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me/H/H/H/H/H
Et/H/H/H/H/H
Pr/H/H/H/H/H
Me/Me/H/H/H/H
Et/Me/H/H/H/H
4a
4b
4c
4d
4e
4f
96
92
72
89
98
73
44
25
56
66
42
86:14
84:16
62:37
64:36
54:46
72:28
91:09
56:44
81:19
83:17
85:15
Pr/Me/H/H/H/H
Me/H/H/H/CO2Et/H
Me/Me/H/H/CO2 Et/H
Me/H/Me/Me/H/H
Me/H/Me/Me/H/Me
Me/H/Me/Me/H/Bn
4g
4h
4i
4j
4k
3j
3k
a
The reactions were conducted using 2.5 mmol of SiO2, 0.55 mmol of PhSeCl, and
0.5 mmol of alkenyl hydantoins (3aek) in acetonitrile (5 mL).
b
Isolated yield.
c
Diastereomeric ratios were determined from 1H NMR spectra of the crude re-
From the results above, optimum reaction conditions were
chosen: alkenyl hydantoin (1 equiv), PhSeCl (1.1 equiv), silica gel
(5 equiv), in acetonitrile as a solvent at room temperature.
Besides the already synthesized alkenyl hydantoins 3aei,
derivatives 3jel, substituted at N(3) and N(1) positions, were
prepared from alkenyl hydantoin 3i (Scheme 2).
action mixture.
DEPT experiments. The signals of the carbon-13 at C(7) appeared as
doublets (except in the cases of 3aed were singlets) at
70.3e75.7 ppm, while the signals of carbon-13 at C(8) appeared as
singlets or triplets at a rather lower chemical shift values (about
30e35 ppm upfield). In the case of six-membered regioisomers
chemical shift values and multiplicity of the corresponding signals
would be quite opposite.
The exclusively cis fusion of the bicyclic system was established
on the basis of the chemical shifts of the carbon-13 signals at the
C(7a) position. The signals appeared at 58.0e68.1 ppm, which is
consistent with chemical shifts reported for analogous cis-5,5-
fused bicyclic systems.16d,21 Reported chemical shift values for
trans-fused bicyclic systems are higher.
These reactions proceeded in stereoselective manner obtaining
the separable diastereomeric mixture. The products with bridge-
head substituent and CH2SePh group in cis relationship were
formed predominantly. The stereochemistry of CH2SePh group was
assigned by the values of chemical shifts and coupling constants of
the proton at C(7) position. The observed diastereomeric ratios and
chemical yields are summarized in Table 2.
The reaction tolerates a variety of substitution at the double
bond. Precursors with allyl (3aec) and metallyl substitutes (3def)
afforded bicyclic products in high yield. In the case of the analogues
with terminally disubstituted double bond (3i) the yield was lower
probably due to steric hindrance. The size of the alkyl substituent
at C(5) position in precursors decreased the yield of the products
(4c and 4f).
Scheme 2. Preparation of N(3) and N(1) substituted derivatives 3jel.
Using the optimized conditions, we next explored the scope and
generality of this intramolecular cyclization with a variety of
5-alkenyl hydantoins 3aek. The clean formation of fused bicyclic
hydantoins 4aek was observed in all cases (Scheme 3). From the
results summarized in Table 2, it is apparent that good to excellent
yields of fused bicyclic hydantoins are generally obtained.
The reaction is regiospecific giving only five-membered fused
bicyclic hydantoins stemming from the nucleophilic attack of the
nitrogen atom to cyclic seleniranium ion intermediate during the
cyclization step. The formation of this single regioisomer proceeds
via a favorable 5-exo-trig ring closure process.20 Structural eluci-
dations were made on the basis of chemical shift values and mul-
tiplicity of the carbon-13 at C(7) and C(8) positions obtained from
We alsotested the reactivityof N(3)-alkylatedalkenyl hydantoins
3j and 3k. The cyclization proceeded well, which opens up the
possibility topreparea great numberof products with highdiversity.
Scheme 3. Selenocyclization of 5-alkenyl hydantoins 3aek to fused bicyclic hydantoins 4aek.

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1104
Finally we tried to obtain the bridged bicyclic hydantoin by
was isolated by extraction of the aqueous solution with diethyl
ether (4ꢂ20 mL). The combined organic layers were dried (Na2SO4)
and evaporated. A residue was distilled under reduced pressure to
involving N(3) nitrogen atom in the ring closure reaction. For that
purpose we used hydantoin precursor 3l (Scheme 2) with sub-
stitution at N(1) and being unsubstituted at N(3), but this attempt
failed.
give 2-alkenyl
b
-ketoester as transparent oil. Compounds 1a,22a
1b,22b 1c,22c 1d,22d and 1e22e were known.
Thus, we have an easy access to azabicyclic compounds bearing
nitrogen at the fusion of five-membered rings, which are key
building blocks in many multistep alkaloids and drug syntheses.
Due to the presence of the carbonyl and phenylselenium groups,
these products can be employed for further interesting trans-
formations.19 Furthermore, substituted proline derivatives could be
obtained by hydrolytic opening of hydantoin ring.13b
4.2.1. Ethyl 2-acetylpent-4-enoate (1a). Yield 6.43 g, 63%, liquid; IR
(ATR) nmax: 3082, 2983, 1739, 1715, 1643, 1149, 919 cmꢁ1 1H NMR
;
(200 MHz, CDCl3)
d
1.22 (t, J¼7.1 Hz, 3H), 2.28 (s, 3H), 2.64 (ddt,
J¼7.3, 7.0, 1.4 Hz, 2H), 3.57 (dd, J¼7.3, 7.2 Hz, 1H), 4.25 (q, J¼7.1 Hz,
2H), 5.07e5.18 (m, 2H), 5.72e5.86 (m, 1H); 13C NMR (50 MHz,
CDCl3)
d 14.4, 29.4, 32.4, 59.5, 61.7, 117.7, 134.5, 169.5, 202.8. Anal.
Calcd for C9H14O3: C: 63.51, H: 8.29%. Found: C: 63.53, H: 8.27%.
3. Conclusions
4.2.2. Ethyl 2-propionylpent-4-enoate (1b). Yield 8.79 g, 74%, liquid;
IR (ATR) nmax: 3081, 2982, 2941, 1741, 1716, 1644, 1462, 1369, 1182,
In conclusion, we have demonstrated a short and convenient
method for the preparation of fused bicyclic hydantoins, in good to
excellent yields, starting from simple commercially available mate-
rials in an only three-step reaction sequence, including an intra-
molecular electrophilic amidoselenylation of 5-alkenyl hydantoins.
The excellent chemo- and regioselectivity are important advantages
ofthismethod, whichfurnishesmoleculeswithsixpointsofdiversity.
920 cmꢁ1
;
1H NMR (200 MHz, CDCl3)
d
1.07 (t, J¼7.2 Hz, 3H), 1.26
(t, J¼7.2 Hz, 3H), 2.38e2.73 (m, 4H), 3.54 (t, J¼7.4 Hz, 1H), 4.19
(q, J¼7.2 Hz, 2H), 5.00e5.15 (m, 2H), 5.63e5.85 (m, 1H); 13C NMR
(50 MHz, CDCl3)
d 7.6, 14.1, 32.3, 35.4, 58.4, 61.3, 117.3, 134.4, 169.3,
205.1. Anal. Calcd for C10H16O3: C: 65.19, H: 8.75%. Found: C: 65.24,
H: 8.79%.
4. Experimental section
4.1. General
4.2.3. Ethyl 2-allyl-3-oxohexanoate (1c). Yield 6.18 g, 52%, liquid; IR
(ATR) nmax: 3078, 2959, 2934, 2875, 1742, 1715, 1642, 1454, 1237,
1185, 1033, 919 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
0.88 (t, J¼7.4 Hz,
3H), 1.24 (t, J¼7.1 Hz, 3H), 1.51e1.68 (m, 2H), 2.51 (q, J¼7.4 Hz, 2H),
2.59 (ddt, J¼7.4, 6.8, 1.3 Hz, 2H), 3.53 (t, J¼7.4 Hz, 1H), 4.19
(q, J¼7.1 Hz, 2H), 4.49e5.09 (m, 2H), 5.64e5.78 (m, 1H); 13C NMR
All commercials, 6-methylhept-5-en-2-one (2g), allyl chloride,
methallyl chloride, deuterochloroform, metallic sodium, magne-
sium turnings, diphenyldiselenide, phenylselenyl chloride, phe-
nylselenyl bromide, 3-oxo-butyric acid ethyl ester, 3-oxo-pentanoic
acid ethyl ester and 3-oxo-hexanoic acid ethyl ester, iodine, am-
monium carbonate, and sodium cyanide were used as received
without further purification. Solvents were purified by distillation
prior use. Anhydrous ethanol was prepared by standard drying
procedure.
Reaction products were purified by fractional distillation
(semimicro and micro Vigreux columns), column chromatography
or recrystallization. For column chromatography E. Merck silica gel
(60, particle size 0.063e0.200 mm) was used. Thin-layer chroma-
tography (TLC) was performed on silica gel 60 on Al plates, layer
thickness 0.2 mm. IR spectra were recorded on a PerkineElmer
FT-IR spectrometer model Spectrum One. 1H NMR spectra were
recorded on Varian 2000 NMR spectrometer (at 200 MHz) in CDCl3
as a solvent. Obtained data were reported as follows: chemical shift
(50 MHz, CDCl3)
d 13.5, 14.0, 16.8, 32.1, 44.0, 58.5, 61.3, 117.3, 134.3,
169.2, 204.5. Anal. Calcd for C11H18O3: C: 66.64, H: 9.15%. Found: C:
66.71, H: 9.09%.
4.2.4. Ethyl 2-acetyl-4-methylpent-4-enoate (1d). Yield 6.41 g, 58%,
liquid; IR (ATR) nmax: 3080, 2982, 2938, 1739, 1715, 1650, 1243,
1147 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
1.28 (t, J¼7.2 Hz, 3H), 1.73
(s, 3H), 2.23 (s, 3H), 2.56 (d, J¼7.6 Hz, 2H), 3.66 (t, 1H, J¼7.6 Hz, 1H),
4.18 (q, J¼7.2 Hz, 2H), 4.57e4.62 (m, 1H), 4.68e4.73 (m, 1H); 13C
NMR (50 MHz, CDCl3) d 14.0, 22.3, 28.8, 35.8, 58.2, 61.3, 112.2, 141.8,
169.4, 202.6. Anal. Calcd for C10H16O3: C: 65.19, H: 8.75%. Found: C:
65.22, H: 8.69%.
4.2.5. Ethyl 4-methyl-2-propionylpent-4-enoate (1e). Yield 8.44 g,
71%, liquid; IR (ATR) nmax: 3080, 2980, 2941, 2909, 1740, 1714, 1651,
1449, 1158, 894 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
1.06 (t, J¼7.2 Hz,
d
(ppm) from internal tetramethylsilane (
d
¼0.0 ppm), multiplicity,
3H), 1.26 (t, J¼7.2 Hz, 3H), 1.74 (s, 3H), 2.39e2.74 (m, 4H), 3.69
(t, J¼7.8 Hz, 1H), 4.18 (q, J¼7.2 Hz, 2H), 4.66e4.70 (m, 1H),
coupling constant J (Hz), and number of protons. 13C NMR spectra
were measured at 50 MHz in CDCl3 as a solvent. The solvent res-
4.75e4.80 (m, 1H); 13C NMR (50 MHz, CDCl3)
d 7.6, 14.1, 22.4, 35.2,
onance (
d
¼77.0 ppm) was used as internal reference and chemical
35.9, 57.3, 61.3,112.1, 142.0,169.5, 205.3. Anal. Calcd for C11H18O3: C:
66.64, H: 9.15%. Found: C: 66.63, H: 9.11%.
shifts are reported to the nearest 0.1 ppm. The elemental analyses
were performed by standard micro-methods using an Elemental
Vario ELIII CHNSO analyzer by Microanalytical laboratory, Faculty of
chemistry, University of Belgrade. Melting points were performed
on a Mel-Temp capillary melting points apparatus, model 1001 and
are uncorrected.
4.2.6. Ethyl 2-methallyl-3-oxohexanoate (1f). Yield 8.40 g, 66%,
liquid; IR (ATR) nmax: 3080, 2967, 2937, 2877, 1740, 1714, 1652, 1447,
1368, 1158, 1024, 894 cmꢁ1 1H NMR (200 MHz, CDCl3)
; d 0.93
(t, J¼7.4 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H), 1.64 (sex, J¼7.4 Hz, 2H), 1.76
(s, 3H), 2.40e2.68 (m, 4H), 3.70 (t, J¼7.6 Hz, 1H), 4.20 (q, J¼7.2 Hz,
2H), 4.69e4.73 (m, 1H), 4.77e4.82 (m, 1H); 13C NMR (50 MHz,
4.2. General procedure for alkenylation of
b-ketoesters.
Preparation of 2-alkenyl -ketoesters (1aef)
b
CDCl3) d 13.5, 14.0, 16.8, 22.4, 35.7, 43.7, 57.5, 61.3, 112.1, 142.0, 169.5,
204.6. Anal. Calcd for C12H20O3: C: 67.89, H: 9.50%. Found: C: 67.81,
H: 9.54%.
To a stirred solution of sodium ethoxide (metallic sodium
(1.38 g, 60 mmol), in anhydrous ethanol (40 mL)), -ketoester
b
(60 mmol) was added at room temperature. The mixture was stir-
red for 1 h before alkenyl chloride (60 mmol) was added dropwise
over a period of 30 min. The mixture was heated to reflux until the
litmus test showed a neutral reaction (3e5 h), cooled to room
temperature, and poured into water (25 mL). The crude product
4.3. General procedure for decarbethoxylation of 2-alkenyl
b-ketoesters. Preparation of ketones 2aef
b
-Ketoester 1aef (20 mmol) in aqueous NaOH (2.40 g in 30 mL
deionized water) was heated to reflux for 2 h. The crude product

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1105
was isolated by extraction of the aqueous solution with diethyl
ether (3ꢂ20 mL). The combined organic layers were dried (Na2SO4)
and evaporated. A residue was distilled under reduced pressure.
Compounds 2a,22f 2b,22g 2c,22h 2d,22d and 2e22e were known.
(s, 3H), 1.67e2.30 (m, 4H), 4.95e5.11 (m, 2H), 5.67e5.88 (m, 1H),
6.43 (br s, 1H), 8.96 (br s, 1H); 13C NMR (50 MHz, CDCl3)
23.9, 28.0,
36.8, 63.5, 115.9, 136.7, 155.8, 176.9. Anal. Calcd for C8H12N2O2: C:
57.13, H: 7.19, N: 16.66%. Found: C: 57.14, H: 7.22, N: 16.71%.
d
4.3.1. Hex-5-en-2-one (2a). Yield 1.57 g, 80%, liquid; IR (ATR) nmax
3080, 2979, 2921, 1718, 1642, 1431, 970 cmꢁ1 1H NMR (200 MHz,
CDCl3) 2.16 (s, 3H), 2.26e2.40 (m, 2H), 2.48e2.59 (m, 2H),
4.94e5.10 (m, 2H), 5.70e5.92 (m, 1H); 13C NMR (50 MHz, CDCl3)
27.8, 29.9, 42.7, 115.2, 137.0, 208.1. Anal. Calcd for C6H10O: C: 73.43,
:
4.4.2. 5-But-3-enyl-5-ethyl-imidazolidine-2,4-dione
solid (711 mg, 78%); mp 104 ꢀC; IR (KBr) nmax: 3170, 3068, 2975,
1753, 1716, 1642, 1406, 805, 765 cmꢁ1 1H NMR (200 MHz, CDCl3)
0.93 (t, J¼7.6 Hz, 3H), 1.59e2.29 (m, 6H), 4.94e5.10 (m, 2H),
5.66e5.88 (m, 1H), 6.42 (br s, 1H), 9.02 (br s, 1H); 13C NMR (50 MHz,
CDCl3) 7.6, 27.8, 30.0, 35.6, 67.5, 115.7, 136.8, 157.4, 177.0. Anal.
(3b). White
;
d
;
d
d
H: 10.27%. Found: C: 73.45, H: 10.21%.
d
Calcd for C9H14N2O2: C: 59.32, H: 7.74, N: 15.37%. Found: C: 59.38,
H: 7.72, N: 15.41%.
4.3.2. Hept-6-en-3-one (2b). Yield 2.89 g, 86%, liquid; IR (ATR) nmax
:
3081, 2987, 2931, 1715, 1643, 1444, 968 cmꢁ1 1H NMR (200 MHz,
;
CDCl3)
2H), 2.49 (t, J¼7.4 Hz, 2H), 4.94e5.03 (m, 2H), 5.69e5.91 (m, 1H);
13C NMR (50 MHz, CDCl3)
14.1, 27.4, 35.9, 40.1, 115.9, 143.8, 209.2.
d
1.04 (t, J¼7.3 Hz, 3H), 2.25e2.36 (m, 2H), 2.38e2.44 (m,
4.4.3. 5-But-3-enyl-5-propyl-imidazolidine-2,4-dione (3c). White
crystals (598 mg, 61%); mp 180 ꢀC; IR (KBr) nmax: 3216, 3052, 2961,
d
1764, 1712, 1644, 1435, 799, 778 cmꢁ1 1H NMR (200 MHz, CDCl3)
;
Anal. Calcd for C7H12O: C: 74.95, H: 10.78%. Found: C: 74.92, H:
10.83%.
d
0.92 (t, J¼7.2 Hz, 3H), 1.10e2.51 (m, 8H), 4.92e5.10 (m, 2H),
5.64e5.88 (m, 1H), 6.88 (br s, 1H), 9.47 (br s, 1H); 13C NMR (50 MHz,
CDCl3) 13.9, 16.6, 27.7, 35.9, 39.1, 67.1, 115.6, 136.8, 157.8, 177.3.
d
4.3.3. Oct-7-en-4-one (2c). Yield 2.80 g, 74%, liquid; IR (ATR) nmax
3081, 2984, 2937, 1716, 1651, 1459, 894 cmꢁ1 1H NMR (200 MHz,
CDCl3)
0.84 (t, J¼8.0 Hz, 3H), 1.48e1.61 (m, 2H), 2.25 (q, J¼8.0 Hz,
2H), 2.32 (t, J¼8.0 Hz, 2H), 2.44 (t, J¼8.0 Hz, 2H), 4.87e5.02 (m, 2H),
5.66e5.79 (m, 1H); 13C NMR (50 MHz, CDCl3)
13.6, 17.1, 27.6, 41.6,
:
Anal. Calcd for C10H16N2O2: C: 61.20, H: 8.22, N: 14.27%. Found: C:
61.21, H: 8.28, N: 14.24%.
;
d
4.4.4. 5-Methyl-5-(3-methyl-but-3-enyl)-imidazolidine-2,4-dione
d
(3d). White tiny crystals (774 mg, 85%); mp 159 ꢀC; IR (KBr) nmax
:
;
44.6, 114.9, 137.0, 210.1. Anal. Calcd for C8H14O: C: 76.14, H: 11.18%.
Found: C: 76.18, H: 11.15%.
3349, 3221, 3075, 2982, 1767, 1731, 1713, 1648, 1402, 791, 778 cmꢁ1
1H NMR (200 MHz, CDCl3)
d
1.47 (s, 3H), 1.72 (s, 3H), 1.76e2.18
(m, 4H), 4.66e4.76 (m, 2H), 6.65 (br s, 1H), 9.21 (br s, 1H); 13C NMR
(50 MHz, CDCl3) 22.3, 23.7, 31.6, 35.6, 63.5, 110.9, 144.0, 157.2,
4.3.4. 5-Methyl-hex-5-en-2-one (2d). Yield 3.00 g, 89%, liquid; IR
d
(ATR) nmax: 3089, 2945, 1708, 1647, 1363, 1208 cmꢁ1
;
1H NMR
177.7. Anal. Calcd for C9H14N2O2: C: 59.32, H: 7.74, N: 15.37%. Found:
C: 59.35, H: 7.77, N: 15.32%.
(200 MHz, CDCl3)
d
1.73 (s, 3H), 2.16 (s, 3H), 2.28 (t, J¼7.6 Hz, 2H),
2.58 (t, J¼7.6 Hz, 2H), 4.63e4.68 (m, 1H), 4.70e4.76 (m, 1H); 13C
NMR (50 MHz, CDCl3)
d
22.6, 29.9, 31.5, 41.9, 110.2, 144.5, 208.5.
4.4.5. 5-Ethyl-5-(3-methyl-but-3-enyl)-imidazolidine-2,4-dione
Anal. Calcd for C7H12O: C: 74.95, H: 10.78%. Found: C: 74.98, H:
10.70%.
(3e). White tiny crystals (805 mg, 82%); mp 143 ꢀC; IR (KBr) nmax
:
3361, 3216, 3076, 2971, 1725, 1709, 1401, 783, 758 cmꢁ1
(200 MHz, CDCl3)
0.94 (t, J¼7.4 Hz, 3H), 1.72 (s, 3H), 1.61e2.21
(m, 6H), 4.67e4.76 (m, 2H), 6.29 (br s, 1H), 8.81 (br s, 1H); 13C NMR
(50 MHz, CDCl3) 7.6, 22.3, 30.0, 31.5, 34.6, 67.5, 110.9, 144.1, 157.4,
;
1H NMR
d
4.3.5. 6-Methyl-hept-6-en-3-one (2e). Yield 3.18 g, 84%, liquid; IR
(ATR) nmax: 3086, 2971, 1714, 1651, 1115, 889 cmꢁ1
;
1H NMR
d
(200 MHz, CDCl3)
d
1.06 (t, J¼7.2 Hz, 3H), 1.73 (s, 3H), 2.05
176.9. Anal. Calcd for C10H16N2O2: C: 61.20, H: 8.22, N: 14.27%.
Found: C: 61.24, H: 8.21, N: 14.27%.
(t, J¼7.2 Hz, 2H), 2.45 (q, J¼7.2 Hz, 2H), 2.56 (t, J¼7.2 Hz, 2H),
4.64e4.69 (m, 1H), 4.70e4.76 (m, 1H); 13C NMR (50 MHz, CDCl3)
d
13.9, 21.3, 33.3, 35.9, 41.1, 112.1, 147.0, 210.0. Anal. Calcd for
4.4.6. 5-(3-Methyl-but-3-enyl)-5-propyl-imidazolidine-2,4-dione
C8H14O: C: 76.14, H: 11.18%. Found: C: 76.10, H: 11.23%.
(3f). White tiny crystals (746 mg, 71%); mp 127 ꢀC; IR (KBr) nmax
:
3246, 2964, 1773, 1711, 1651, 1402, 796, 776 cmꢁ1
(200 MHz, CDCl3)
0.93 (t, J¼7.2 Hz, 3H), 1.11e2.20 (m, 8H), 1.71
(s, 3H), 4.66e4.75 (m, 2H), 6.49 (br s, 1H), 9.11 (br s, 1H); 13C NMR
(50 MHz, CDCl3) 13.9, 16.7, 22.3, 31.4, 34.9, 39.1, 67.1, 110.8, 144.1,
;
1H NMR
4.3.6. 7-Methyl-oct-7-en-4-one (2f). Yield 3.02 g, 72%, liquid; IR
d
(ATR) nmax: 3079, 2971, 2944, 1715, 1652, 1115, 890 cmꢁ1 1H NMR
;
(200 MHz, CDCl3)
1.73 (s, 3H), 2.22e2.33 (m, 2H), 2.41 (t, J¼7.4 Hz, 2H), 4.63e4.67
(m, 1H), 4.70e4.75 (m, 1H); 13C NMR (50 MHz, CDCl3)
13.6, 17.2,
d
0.92 (t, J¼7.4 Hz, 3H), 1.61 (sex, J¼7.4 Hz, 4H),
d
157.3, 177.0. Anal. Calcd for C11H18N2O2: C: 62.83, H: 8.63, N: 13.32%.
Found: C: 62.85, H: 8.67, N: 13.34%.
d
22.5, 31.4, 40.8, 44.6, 110.0, 144.5, 210.4. Anal. Calcd for C9H16O: C:
77.09, H: 11.50%. Found: C: 77.01, H: 11.54%.
4.4.7. 2-(4-Methyl-2,5-dioxo-imidazolidin-4-yl)-pent-4-enoic acid
ethyl ester (3g). White needle crystals (997 mg, 83%); mp 106 ꢀC; IR
4.4. General procedure for preparation of 5-alkenyl hydan-
toins (3aei)
(KBr) nmax
: 3270, 3051, 2982, 1772, 1721, 1645, 1423, 1377,
1184 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
1.28 (t, J¼7.2 Hz, 3H), 1.46
(s, 3H), 2.13e2.29 (m, 1H), 2.31e2.52 (m, 1H), 2.94 (dd, J¼10.4,
4.8 Hz, 1H), 4.20 (q, J¼7.2 Hz, 2H), 4.97e5.14 (m, 2H), 5.56e5.80
(m, 1H), 6.77 (br s, 1H), 9.49 (br s, 1H); 13C NMR (50 MHz, CDCl3)
A mixture of ketones 2aeg or 2-alkenyl
b-ketoesters 1aef
(5 mmol), NaCN (0.49 g,10 mmol), and (NH4)2CO3 (1.92 g, 20 mmol)
in 50% aqueous EtOH (30 mL) was stirred and heated to reflux for
24 h. The reaction mixture was cooled to ambient temperature and
filtered off. The filtrate was acidified to pH w2 by dropwise addition
of concd HCl. After cooling overnight, the product was separated by
filtration and dried.
d
14.2, 23.1, 32.3, 50.5, 61.2, 63.7, 117.9, 133.3, 156.7, 172.6, 176.0.
Anal. Calcd for C11H16N2O4: C: 54.99, H: 6.71, N: 11.66%. Found: C:
54.93, H: 6.73, N: 11.59%.
4.4.8. 4-Methyl-2-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-pent-4-
enoic acid ethyl ester (3h). White needle crystals (1.03 g, 83%); mp
105 ꢀC; IR (KBr) nmax: 3330, 3181, 3075, 2987, 1783, 1717, 1651, 1408,
4.4.1. 5-But-3-enyl-5-methyl-imidazolidine-2,4-dione (3a). White
crystals (697 mg, 83%); mp 118 ꢀC; IR (KBr) nmax: 3231, 3051, 1766,
1208 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
1.27 (t, J¼7.2 Hz, 3H), 1.46
1710, 1643, 1431, 795, 775 cmꢁ1 1H NMR (200 MHz, CDCl3)
; d 1.46
(s, 3H), 1.73 (s, 3H), 2.06 (dd, J¼13.4, 4.4 Hz, 1H), 2.41 (dd, J¼13.4,

ꢀ
ꢁ
B.M. Smit, R.Z. Pavlovic / Tetrahedron 71 (2015) 1101e1108
1106
11.2 Hz, 1H), 3.07 (dd, J¼11.2, 4.4 Hz, 1H), 4.06e4.29 (m, 2H),
4.69e4.82 (m, 2H), 6.29 (br s, 1H), 8.50 (br s, 1H); 13C NMR (50 MHz,
(5 mL) was stirred at room temperature for 24 h. After dilution with
dichloromethane (20 mL), the mixture was filtered off, washed
with saturated NaHCO3 aqueous solution and brine, dried (Na2SO4),
and concentrated under reduced pressure. The products were
isolated by column chromatography on silica gel (hexane/EtOAc).
Diastereoisomeric ratio (cis/trans) was determined from 1H NMR
spectrum of crude reaction mixture.
CDCl3)
d 13.8, 21.4, 22.6, 36.0, 49.2, 60.9, 63.6, 113.3, 140.8, 157.3,
172.3, 176.1. Anal. Calcd for C12H18N2O4: C: 56.68, H: 7.13, N: 11.02%.
Found: C: 56.61, H: 7.18, N: 11.09%.
4.4.9. 5-Methyl-5-(4-methyl-pent-3-enyl)-imidazolidine-2,4-dione
(3i). White amorphous solid (1.59 g, 81%); mp 144 ꢀC; IR (KBr) nmax
:
3336, 3214, 3071, 2977, 1768, 1726, 1709, 1402, 768, 757 cmꢁ1
NMR (200 MHz, CDCl3)
1.45 (s, 3H), 1.58 (d, J¼1.4 Hz, 3H), 1.66 (d,
J¼1.4 Hz, 3H), 1.73e2.24 (m, 4H), 5.04 (tsep, J¼7.0, 1.4 Hz, 1H), 6.50
(br s,1H), 9.00 (br s,1H); 13C NMR (50 MHz, CDCl3)
17.6, 22.5, 23.9,
;
1H
4.7.1. cis- and trans-7a-Methyl-5-phenylselanylmethyl-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione (4a). White amorphous solid
(155 mg, 96%, cis/trans¼86:14). cis-4a: mp 145 ꢀC; Rf (hexane/
EtOAc¼1:1) 0.76; IR (KBr) nmax: 3204, 3058, 2976, 1768, 1710,
d
d
25.6, 37.4, 63.6, 122.3, 133.1, 157.0, 177.7. Anal. Calcd for C10H16N2O2:
C: 61.20, H: 8.22, N: 14.27%. Found: C: 61.25, H: 8.20, N: 14.23%.
1578, 1398, 738, 692 cmꢁ1 1H NMR (200 MHz, CDCl3)
; d 1.42
(s, 3H), 1.67e1.82 (m, 1H), 1.83e2.19 (m, 2H), 2.24e2.49 (m, 1H),
3.22 (dd, A of ABX, JAB¼12.8 Hz, JAX¼8.4 Hz, 1H), 3.80 (dd, B of
ABX, JBA¼12.8 Hz, JBX¼3.8 Hz, 1H), 3.85e4.00 (m, X of ABX, 1H),
7.21e7.33 (m, 3H), 7.47e7.59 (m, 2H), 9.11 (br s, 1H); 13C NMR
4.5. General procedure for N(3)-alkylation of hydantoin 3i
A mixture of methanolic solution of KOH (57.2 mg, 1.02 mmol, in
15 mL MeOH) and hydantoin 3i (200 mg, 1.02 mmol) was heated to
reflux. After 30 min, alkyl halide (1.12 mmol) was added dropwise
and stirring under reflux was continued for 3 h. Reaction mixture
was cooled and filtered off. The solvent was evaporated and crude
product was purified by recrystallization from toluene.
(50 MHz, CDCl3) d 23.1, 28.6, 31.1, 33.0, 58.0, 71.3, 127.1, 129.1,
129.8, 132.6, 156.4, 177.1. Anal. Calcd for C14H16N2O2Se: C: 52.02,
H: 4.99, N: 8.67%. Found: C: 52.04, H: 4.95, N: 8.71%. 1H NMR
spectral data for trans-4a were obtained from the 1H NMR
spectrum of the diastereoisomeric mixture: 1.47 (s, 3H),
1.69e1.82 (m, 1H), 1.81e2.11 (m, 2H), 2.20e2.44 (m, 1H), 3.02
(dd, A of ABX, JAB¼12.4 Hz, JAX¼8.4 Hz, 1H), 3.33 (dd, B of ABX,
JBA¼12.4 Hz, JBX¼5.8 Hz, 1H), 7.21e7.33 (m, 3H), 7.47e7.59
(m, 2H), 9.38 (br s, 1H).
4.5.1. 3,5-Dimethyl-5-(4-methyl-pent-3-enyl)-imidazolidine-2,4-
dione (3j). White amorphous solid (207 mg, 82%); mp 83 ꢀC; IR (KBr)
nmax: 3296, 2926, 1783, 1715, 1468, 1400, 722 cmꢁ1 1H NMR
;
(200 MHz, CDCl3)
J¼1.4 Hz, 3H),1.69e2.04 (m, 4H), 3.00 (s, 3H), 4.96 (tsep, J¼7.0, 1.4 Hz,
1H), 6.86 (br s, 1H); 13C NMR (50 MHz, CDCl3)
17.5, 22.4, 23.9, 24.3,
25.5, 37.3, 61.9, 122.4, 132.8, 157.4, 177.1. Anal. Calcd for C11H18N2O2:
C: 62.83, H: 8.63, N: 13.32%. Found: C: 62.87, H: 8.62, N: 13.35%.
d
1.42 (s, 3H), 1.57 (d, J¼1.4 Hz, 3H), 1.66 (d,
4.7.2. cis- and trans-7a-Ethyl-5-phenylselanylmethyl-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione (4b). White tiny crystals (153 mg,
92%, cis/trans¼84:16). cis-4b: mp 121 ꢀC; Rf (hexane/EtOAc¼1:1)
0.80; IR (KBr) nmax: 3205, 3057, 2969, 1766, 1703, 1578, 1394, 738,
d
691 cmꢁ1
;
1H NMR (200 MHz, CDCl3)
d
0.90 (t, J¼7.4 Hz, 3H),
1.55e2.00 (m, 4H), 2.04e2.41 (m, 2H), 3.28 (dd, A of ABX,
JAB¼12.4 Hz, JAX¼7.8 Hz, 1H), 3.80 (dd, B of ABX, JBA¼12.4 Hz,
JBX¼4.0 Hz, 1H), 3.79e3.94 (m, X of ABX, 1H), 7.22e7.31 (m, 3H),
4.5.2. 3-Benzyl-5-methyl-5-(4-methyl-pent-3-enyl)-imidazolidine-
2,4-dione (3k). White tiny crystals (216 mg, 74%); mp 84 ꢀC; IR
(KBr) nmax: 3285, 3082, 3060, 3026, 2924, 2850, 1772, 1702, 1601,
7.49e7.60 (m, 2H), 8.67 (br s, 1H); 13C NMR (50 MHz, CDCl3)
d 7.9,
1583, 1493, 1452, 757, 699 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
1.40
28.9, 29.2, 30.8, 33.1, 58.5, 75.3, 127.2, 129.2, 130.0, 132.8, 156.9,
176.4. Anal. Calcd for C15H18N2O2Se: C: 53.42, H: 5.38, N: 8.31%.
Found: C: 53.48, H: 5.31, N: 8.34%. 1H NMR spectral data for trans-
4b were obtained from the 1H NMR spectrum of the di-
astereoisomeric mixture: 0.92 (t, J¼7.4 Hz, 3H), 1.56e2.23 (m, 6H),
3.11 (dd, A of ABX, JAB¼13.0 Hz, JAX¼9.0 Hz, 1H), 3.80 (dd, B of ABX,
JBA¼13.0 Hz, JBX¼5.2 Hz,1H), 3.91e4.06 (m, X of ABX,1H), 7.23e7.34
(m, 3H), 7.47e7.57 (m, 2H), 8.41 (br s, 1H).
(s, 3H), 1.49 (d, J¼1.4 Hz, 3H), 1.64 (d, J¼1.4 Hz, 3H), 1.56e2.02
(m, 4H), 4.64 (s, 2H), 4.98 (tsep, J¼7.0, 1.4, 1H), 5.54 (br s, 1H),
7.24e7.41 (m, 5H); 13C NMR (50 MHz, CDCl3)
d 17.5, 22.3, 23.9, 25.5,
37.6, 42.0, 61.9, 122.4, 127.7, 128.2, 128.6, 132.9, 136.2, 156.9, 176.6.
Anal. Calcd for C17H24N2O2: C: 70.83, H: 8.33, N: 9.72%. Found: C:
70.89, H: 8.31, N: 9.76%.
4.6. Procedure for N(1)-alkylation of hydantoin 3i
4.7.3. cis- and trans-5-Phenylselanylmethyl-7a-propyl-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione (4c). White tiny crystals (126 mg,
72%, cis/trans¼62:37). cis-4c: mp 106 ꢀC; Rf (hexane/EtOAc¼3:1)
0.78; IR (KBr) nmax: 3058, 2960, 2930, 2873, 1725, 1579, 1477, 1274,
Hydantoin 3i (333 mg,1.7 mmol) in acetanhydride (5 mL, freshly
distilled) was heated to reflux. After 3 h, the reaction mixture was
poured into water and cooled. The white crystalline product was
filtered off, washed with distilled water, and dried in a desiccator
over anhydrous CaCl2.
737, 690 cmꢁ1
;
1H NMR (200 MHz, CDCl3)
d
0.90 (t, J¼7.2 Hz, 3H),
1.09e1.67 (m, 3H), 1.69e1.99 (m, 3H), 2.02e2.41 (m, 2H), 3.28 (dd,
A of ABX, JAB¼12.5 Hz, JAX¼8.0 Hz, 1H), 3.80 (dd, B of ABX,
JBA¼12.5 Hz, JBX¼4.0 Hz, 1H), 3.81e3.95 (m, X of ABX, 1H),
7.23e7.32 (m, 3H), 7.48e7.58 (m, 2H), 8.66 (br s, 1H); 13C NMR
4.6.1. 1-Acetyl-5-methyl-5-(4-methyl-pent-3-enyl)-imidazolidine-
2,4-dione (3l). White solid (327 mg, 81%); mp 81 ꢀC; IR (KBr) nmax
:
3205, 3042, 2924, 1798, 1746, 1678 cmꢁ1; 1H NMR (200 MHz, CDCl3)
1.54 (d, J¼1.4 Hz, 3H), 1.65 (d, J¼1.4 Hz, 3H), 1.66 (s, 3H), 1.80e2.04
(m, 4H), 2.36e2.58 (m, 1H), 2.55 (s, 3H), 4.98 (tsep, J¼7.3 Hz, 1.4 Hz,
1H); 13C NMR (50 MHz, CDCl3)
17.5, 22.7, 23.1, 25.6, 26.1, 34.2, 68.7,
(50 MHz, CDCl3) d 13.8, 16.9, 28.9, 31.1, 33.1, 38.4, 58.7, 74.9, 127.2,
d
129.2, 130.0, 132.8, 156.8, 176.5. Anal. Calcd for C16H20N2O2Se: C:
54.70, H: 5.74, N: 7.97%. Found: C: 54.71, H: 5.74, N: 7.93%. 1H NMR
spectral data for trans-4c were obtained from the 1H NMR spec-
trum of the diastereoisomeric mixture: 0.97 (t, J¼7.4 Hz, 3H),
1.22e2.07 (m, 6H), 2.19e2.46 (m, 2H), 3.04 (dd, A of ABX,
JAB¼12.4 Hz, JAX¼5.6 Hz, 1H), 3.29 (dd, B of ABX, JBA¼12.4 Hz,
JBX¼5.2 Hz, 1H), 4.06e4.35 (m, X of ABX, 1H), 7.21e7.30 (m, 3H),
7.57e7.64 (m, 2H), 8.10 (br s, 1H).
d
122.1, 133.3, 153.1, 169.7. Anal. Calcd for C12H18N2O3: C: 60.49, H:
7.61, N: 11.76%. Found: C: 60.47, H: 7.67, N: 11.72%.
4.7. General procedure for synthesis of bicyclic hydantoins
(4aek)
A mixture of SiO2 (150 mg, 2.5 mmol), PhSeCl (105 mg,
4.7.4. cis- and trans-5,7a-Dimethyl-5-phenylselanylmethyl-tetrahy-
0.55 mmol), and alkenyl hydantoin 3aek (0.5 mmol) in acetonitrile
dro-pyrrolo[1,2-c]imidazole-1,3-dione (4d). White crystals (150 mg,

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B.M. Smit, R.Z. Pavlovic / Tetrahedron 71 (2015) 1101e1108
1107
89%, cis/trans¼64:36). cis-4d: mp 137 ꢀC; Rf (hexane/EtOAc¼1:1)
0.69; IR (KBr) nmax: 3204, 3070, 2973, 1770, 1717, 1579, 1385, 738,
174.5. Anal. Calcd for C17H20N2O4Se: C: 51.65, H: 5.10, N: 7.09%.
Found: C: 51.61, H: 5.12, N: 7.03%.
692 cmꢁ1 1H NMR (200 MHz, CDCl3)
; d 1.50 (s, 3H), 1.56 (s, 3H),
1.76e2.09 (m, 3H), 2.34e2.55 (m, 1H), 3.25 (d, J¼12.6 Hz, 2H), 3.41
4 . 7 . 8 . c i s - a n d t r a n s - 5 , 7 a - D i m e t h y l - 1, 3 - d i o x o - 5 -
phenylselanylmethyl-hexahydro-pyrrolo[1,2-c]imidazole-7-
carboxylic acid ethyl ester (4h). Light yellow powder (51.2 mg, 25%,
cis/trans¼56:44). cis-4h: mp 186 ꢀC; Rf (hexane/EtOAc¼2:1) 0.76;
IR (ATR) nmax: 3227, 3059, 2978, 1771, 1705, 1578, 1379, 1295, 1139,
(d, J¼12.6 Hz, 2H), 7.20e7.30 (m, 3H), 7.48e7.56 (m, 2H), 8.68 (br s,
1H); 13C NMR (50 MHz, CDCl3)
d 22.7, 24.4, 30.7, 39.9, 40.5, 65.4,
71.8, 126.9, 129.1, 130.7, 132.2, 156.6, 177.3. Anal. Calcd for
C
15H18N2O2Se: C: 53.42, H: 5.38, N: 8.31%; Found: C: 53.45, H: 5.36,
N: 8.38%. 1H NMR spectral data for trans-4d were obtained from the
1H NMR spectrum of the diastereoisomeric mixture: 1.48 (s, 3H),
1.52 (s, 3H), 1.66e1.77 (m, 1H), 2.08e2.29 (m, 3H), 3.43 (d,
J¼12.8 Hz, 2H), 3.73 (d, J¼12.8 Hz, 2H), 7.21e7.33 (m, 3H), 7.51e7.66
(m, 2H), 9.19 (br s, 1H).
735, 692; 1H NMR (200 MHz, CDCl3)
d
1.30 (t, J¼7.0 Hz, 3H), 1.48
(s, 3H), 1.56 (s, 3H), 2.29 (dd, J¼13.6, 7.8 Hz, 1H), 2.45 (dd, J¼14.0,
12.4 Hz, 1H), 3.50 (dd, J¼12.4, 7.8 Hz, 1H), 3.34 (d, J¼13.0 Hz, 2H),
3.90 (d, J¼13.0 Hz, 2H), 4.06e4.33 (m, 2H), 7.20e7.32 (m, 3H),
7.48e7.59 (m, 2H), 9.02 (br s, 1H); 13C NMR (50 MHz, CDCl3)
d 14.0,
20.8, 30.6, 36.8, 42.8, 46.2, 61.2, 63.4, 71.2, 127.4, 129.2, 130.2, 132.9,
155.3, 169.2, 174.5. Anal. Calcd for C18H22N2O4Se: C: 52.82, H: 5.42,
N: 6.84%. Found: C: 52.76, H: 5.49 N: 6.87%. trans-4h: mp 191 ꢀC; Rf
(hexane/EtOAc¼2:1) 0.58; IR (ATR) nmax: 3224, 3071, 2978, 1773,
1713, 1578, 1438, 1379, 1289, 1197, 735, 691; 1H NMR (200 MHz,
4.7.5. cis- and trans-7a-Ethyl-5-methyl-5-phenylselanylmethyl-tet-
rahydro-pyrrolo[1,2-c]imidazole-1,3-dione
(4e). White crystals
(172 mg, 98%, cis/trans¼54:46). cis-4e: mp 116 ꢀC; Rf (hexane/
EtOAc¼1:1) 0.79; IR (KBr) nmax: 3194, 3057, 2969, 1766, 1705, 1578,
1384, 738, 692 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
0.93 (t, J¼7.4 Hz,
CDCl3)
d
1.30 (t, J¼7.0 Hz, 3H), 1.46 (s, 3H), 1.59 (s, 3H), 2.21
3H), 1.52 (s, 3H), 1.65e2.35 (m, 6H), 3.44 (d, J¼12.6 Hz, 2H), 3.82
(dd, J¼13.2, 6.4 Hz, 1H), 2.79 (t, J¼13.0 Hz, 1H), 3.12 (dd, J¼13.0,
6.4 Hz, 1H), 3.26 (d, J¼12.6 Hz, 2H), 3.38 (d, J¼12.6 Hz, 2H),
4.12e4.30 (m, 2H), 7.20e7.32 (m, 3H), 7.47e7.59 (m, 2H), 8.65 (br s,
(d, J¼12.6 Hz, 2H), 7.19e7.31 (m, 3H), 7.47e7.59 (m, 2H), 9.08 (br s,
1H); 13C NMR (50 MHz, CDCl3)
d 7.4, 29.8, 30.3, 31.3, 36.6, 40.0, 64.9,
75.6, 127.2, 129.1, 130.5, 132.7, 156.6, 176.3. Anal. Calcd for
1H); 13C NMR (50 MHz, CDCl3)
d 14.0, 21.0, 23.3, 40.4, 43.1, 45.6,
C
16H20N2O2Se: C: 54.70, H: 5.74, N: 7.97%. Found: C: 54.73, H: 5.69,
61.4, 63.6, 71.3, 127.0, 129.1, 130.4, 132.4, 155.8, 168.9, 174.8. Anal.
Calcd for C18H22N2O4Se: C: 52.82, H: 5.42, N: 6.84%. Found: C: 52.87,
H: 5.34, N: 6.81%.
N: 7.99%. trans-4e: mp 122 ꢀC; Rf (hexane/EtOAc¼1:1) 0.58; IR (KBr)
nmax: 3199, 3058, 2969, 1767, 1704, 1579, 1375, 733, 691 cmꢁ1 1H
;
NMR (200 MHz, CDCl3)
d
0.88 (t, J¼7.4 Hz, 3H), 1.58 (s, 3H),
1.76e2.14 (m, 5H), 2.25e2.49 (m, 1H), 3.25 (d, J¼12.4 Hz, 2H), 3.40
(d, J¼12.4 Hz, 2H), 7.20e7.32 (m, 3H), 7.46e7.57 (m, 2H), 8.65 (br s,
4.7.9. cis- and trans-7a-Methyl-5-(1-methyl-1-phenylselanyl-ethyl)-
tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (4i). White tiny crys-
tals (98.3 mg, 56%, cis/trans¼81:19). cis-4i: mp 116 ꢀC; Rf (hexane/
EtOAc¼1:1) 0.64; IR (KBr) nmax: 3206, 2980, 1772, 1713, 1638, 1399,
1H); 13C NMR (50 MHz, CDCl3)
d 7.5, 22.8, 29.9, 30.5, 40.0, 40.7, 65.6,
75.7, 126.9, 129.2, 130.8, 132.2, 157.3, 176.6. Anal. Calcd for
16H20N2O2Se: C: 54.70, H: 5.74, N: 7.97%. Found: C: 54.77, H:
C
1385, 741, 695 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d 1.41 (s, 3H), 1.44
5.69 N: 7.94%.
(s, 3H), 1.52 (s, 3H), 1.68e2.00 (m, 2H), 2.20e2.55 (m, 2H), 3.91
(dd, J¼10.0, 8.0 Hz, 1H), 7.26e7.38 (m, 3H), 7.62e7.70 (m, 2H), 8.93
4.7.6. cis- and trans-5-Methyl-5-phenylselanylmethyl-7a-propyl-
tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (4f). White crystals
(133 mg, 73%, cis/trans¼72:28). cis-4f: mp 121 ꢀC; Rf (hexane/
EtOAc¼1:1) 0.81; IR (KBr) nmax: 3192, 3057, 2962, 1766, 1699, 1579,
(br s, 1H); 13C NMR (50 MHz, CDCl3)
d 22.2, 25.7, 30.0, 30.3, 33.7,
49.1, 68.1, 71.7, 126.8, 128.8, 134.8, 138.2, 160.7, 177.1. Anal. Calcd for
C
16H20N2O2Se: C: 54.70, H: 5.74, N: 7.97%. Found: C: 54.72, H:
5.79 N: 7.90%. trans-4i: mp 122 ꢀC; Rf (hexane/EtOAc¼1:1) 0.40; IR
1376, 735, 691 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
0.93 (t, J¼7.2 Hz,
(KBr) nmax: 3179, 3055, 2993, 1767, 1698, 1578, 1396, 740, 693 cmꢁ1
;
3H), 1.20e1.47 (m, 2H), 1.51 (s, 3H), 1.59e1.96 (m, 4H), 2.08e2.29
(m, 2H), 3.43 (d, J¼12.6 Hz, 2H), 3.82 (d, J¼12.6 Hz, 2H), 7.19e7.29
(m, 3H), 7.48e7.70 (m, 2H), 8.52 (br s, 1H); 13C NMR (50 MHz,
1H NMR (200 MHz, CDCl3)
d 1.55 (s, 3H), 1.66 (s, 3H), 1.69 (s, 3H),
1.68e2.00 (m, 2H), 2.20e2.55 (m, 2H), 3.48 (dd, J¼9.0, 5.0 Hz, 1H),
7.26e7.38 (m, 3H), 7.62e7.70 (m, 2H), 9.07 (br s, 1H); 13C NMR
CDCl3)
d
13.9, 16.5, 30.4, 31.7, 36.7, 39.1, 40.1, 65.1, 75.3, 127.3, 129.2,
(50 MHz, CDCl3) d 24.2, 26.7, 27.9, 28.5, 35.9, 51.7, 59.2, 62.4, 128.0,
130.6, 132.8, 156.2, 176.3. Anal. Calcd for C17H22N2O2Se: C: 55.89, H:
6.07, N: 7.67%. Found: C: 55.83, H: 6.01 N: 7.68%. trans-4f: mp
128 ꢀC; Rf (hexane/EtOAc¼1:1) 0.52; IR (KBr) nmax: 3200, 3058,
128.8, 129.3, 138.3, 167.7, 176.3. Anal. Calcd for C16H20N2O2Se: C:
54.70, H: 5.74, N: 7.97%. Found: C: 54.65, H: 5.71, N: 7.92%.
2961, 1766, 1705, 1579, 1376, 734, 691 cmꢁ1
;
1H NMR (200 MHz,
4.7.10. cis- and trans-2,7a-Dimethyl-5-(1-methyl-1-phenylselanyl-
ethyl)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (4j). White tiny
crystals (120 mg, 66%, cis/trans¼83:17). cis-4j: mp 88 ꢀC; Rf (hex-
ane/EtOAc¼3:1) 0.79; IR (KBr) nmax: 3056, 2976, 1771, 1702, 1438,
CDCl3)
d
0.90 (t, J¼7.2 Hz, 3H), 1.04e1.50 (m, 2H), 1.57 (s, 3H),
1.70e2.12 (m, 5H), 2.25e2.52 (m, 1H), 3.22 (d, J¼12.6 Hz, 2H), 3.42
(d, J¼12.6 Hz, 2H), 7.20e7.32 (m, 3H), 7.46e7.58 (m, 2H), 8.89 (br s,
1H); 13C NMR (50 MHz, CDCl3)
d
13.8, 16.4, 23.0, 30.7, 39.0, 40.0,
736, 694 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d 1.43 (s, 3H), 1.47 (s, 3H),
40.5, 65.5, 75.2, 126.9, 129.2, 130.8, 132.1, 157.5, 177.0. Anal. Calcd for
17H22N2O2Se: C: 55.89, H: 6.07, N: 7.67%. Found: C: 55.93, H:
6.08 N: 7.64%.
1.52 (s, 3H), 1.62e1.77 (m, 1H), 1.95 (dd, J¼12.0, 7.0 Hz, 1H),
2.20e2.52 (m, 2H), 2.97 (s, 3H), 3.90 (dd, J¼10.0, 8.0 Hz, 1H),
7.21e7.40 (m, 3H), 7.57e7.68 (m, 2H); 13C NMR (50 MHz, CDCl3)
C
d
22.3, 25.1, 25.6, 29.9, 30.2, 33.8, 49.1, 68.8, 70.4, 126.8, 128.8, 132.6,
4.7.7. cis- and trans-7a-Methyl-1,3-dioxo-5-phenylselanylmethyl-
hexahydro-pyrrolo[1,2-c]imidazole-7-carboxylic acid ethyl ester
(4g). Light yellow powder (86.9 mg, 44%, cis/trans¼91:9). cis-4g:
mp 174 ꢀC; Rf (hexane/EtOAc¼1:1) 0.80; IR (KBr) nmax: 3233, 3070,
138.2, 161.1, 176.5. Anal. Calcd for C17H22N2O2Se: C: 55.89, H: 6.07,
N: 7.67%. Found: C: 55.91, H: 6.07, N: 7.68%.
4.7.11. cis- and trans-2-Benzyl-7a-methyl-5-(1-methyl-1-
phenylselanyl-ethyl)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione
(4k). Light yellow powder (92.7 mg, 42%, cis/trans¼85:15). cis-4k:
mp 94 ꢀC; Rf (hexane/EtOAc¼3:1) 0.81; IR (KBr) nmax: 3064, 3032,
2982, 2936, 1773, 1721, 1578, 1400, 1199, 1097, 739, 692 cmꢁ1 1H
;
NMR (200 MHz, CDCl3)
d
1.30 (t, J¼7.2 Hz, 3H), 1.40 (s, 3H), 2.18
(ddd, J¼11.8, 8.2, 3.6 Hz, 1H), 2.72 (ddd, J¼13.8, 10.6, 8.6 Hz, 1H),
3.26 (dd, J¼10.8, 8.2 Hz, 1H), 3.38 (dd, J¼13.0, 7.4 Hz, 1H), 3.70 (dd,
J¼13.0, 3.6 Hz, 1H), 4.01e4.34 (m, 3H), 7.21e7.31 (m, 3H), 7.49e7.59
2956, 1768, 1705, 1435, 1410, 735, 697 cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d 1.42 (s, 3H), 1.44 (s, 3H), 1.52 (s, 3H), 1.65e1.73 (m, 1H), 1.94
(m, 2H), 8.91 (br s, 1H); 13C NMR (50 MHz, CDCl3)
d
14.0, 19.3, 29.2,
(dd, J¼12.0, 6.0 Hz, 1H), 2.20e2.50 (m, 2H), 3.89 (dd, J¼10.0, 8.0 Hz,
36.1, 45.7, 56.1, 61.4, 71.4, 127.4, 129.3, 129.7, 132.8, 155.4, 169.5,
1H), 4.59 (s, 2H), 7.22e7.40 (m, 6H), 7.60e7.66 (m, 4H); 13C NMR

ꢀ
ꢁ
1108
B.M. Smit, R.Z. Pavlovic / Tetrahedron 71 (2015) 1101e1108
Stilz, H. U.; Jablonka, B.; Just, M.; Knolle, J.; Paulus, E. F.; Zoller, G. J. Med. Chem.
1996, 39, 2118e2122.
11. (a) Moloney, G. P.; Martin, G. R.; Mathews, N.; Milne, A.; Hobbs, H.; Dosworth,
(50 MHz, CDCl3)
d 22.3, 25.8, 29.9, 30.2, 33.9, 42.7, 49.3, 69.0, 70.3,
126.9, 127.8, 128.5, 128.6, 128.7, 128.8, 136.1, 138.3, 160.7, 176.1. Anal.
Calcd for C23H26N2O2Se: C: 62.58, H: 5.94, N: 6.35%. Found: C: 62.51,
H: 5.99, N: 6.29%.
S.; Sang, P. Y.; Knight, C.; Williams, M.; Maxwell, M.; Glen, R. C. J. Med. Chem.
}
ꢁ
ꢁ
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1999, 42, 2504e2526; (b) Somsak, L.; Kovacz, L.; Toth, M.; Osz, E.; Szilagyi, L.;
€
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Gyorgydeak, Z.; Dinya, Z.; Docsa, T.; Toth, B.; Gergely, P. J. Med. Chem. 2001, 44,
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Acknowledgements
This work was supported by the Ministry of Education, Science
and Technological Development of the Republic of Serbia (Pr. No.
172016).
12. (a) Fujiwara, Y.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 12293e12297; (b) Fraile, J.
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M.; Lafuente, G.; Mayoral, J. A.; Pallares, A. Tetrahedron 2011, 67, 8639e8647; (c)
Supplementary data
Wehner, V.; Blum, H.; Kurz, M.; Stilz, H. U. Synthesis 2002, 2023e2036; (d)
Pesquet, A.; Daïch, A.; Hijfte, L. V. J. Org. Chem. 2006, 71, 5303e5311.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.12.088.
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