A diversity-oriented approach to spirocyclic and fused hydantoins via olefin metathesis

Article abstract of DOI:10.1021/jo301234r

An efficient and general method is reported to prepare a diverse series of 5,5-spirocyclic and 1,5-, 4,5-, and 3,4-fused bicyclic imidazolidinone derivatives based on selective alkylation and ring closing metathesis (RCM) by exploiting the four possible p

Full text of DOI:10.1021/jo301234r

Article
pubs.acs.org/joc
A Diversity-Oriented Approach to Spirocyclic and Fused Hydantoins
via Olefin Metathesis
Kalyan Dhara,† Ganesh Chandra Midya,†,‡ and Jyotirmayee Dash*,†,‡
†Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741252,
India
‡Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
S
* Supporting Information
ABSTRACT: An efficient and general method is reported to prepare a diverse
series of 5,5-spirocyclic and 1,5-, 4,5-, and 3,4-fused bicyclic imidazolidinone
derivatives based on selective alkylation and ring closing metathesis (RCM) by
exploiting the four possible points of diversity in the hydantoin ring. Hydantoins
containing trienes and tetraenes undergo selective RCM and cross metathesis to
afford functionalized spirohydantoins. A tandem metathesis sequence involving
ring closing−ring opening−ring closing and cross metathesis (RC−RO−RC−CM)
occurred with a hydantoin triene to give a bicyclic hydantoin dimer in high yield.
The fused bicylic dimer could participate in cross metathesis to produce a
functionalized fused hydantoin derivative. The methodology establishes novel
routes to unnatural amino acids, proline homologues, and cyclic vicinal diamines.
acids have been used as the starting materials to prepare the
hydantoin precursors.17 On our efforts aimed at diversity
oriented synthesis18 of functionalized thiazole derivatives,19 we
recently reported ring-closing and cross metathesis of
thiazolidinedione derivatives to generate a quick access to
spirocyclic thiazolidinediones.20 We describe here a ring-closing
metathesis approach by utilizing the four possible points of
diversity in hydantoin 1 to produce a diverse series of
spirocyclic and 1,5-, 4,5- and 3,4-fused bicyclic imidazolidinone
derivatives (Figure 2).
INTRODUCTION
■
Imidazolidine-2,4-dione derivatives, generally called hydantoins,
represent an important class of biologically active scaffolds that
have broad applications in medicinal chemistry.1,2 Several
derivatives exhibit antidiabetic, antitumor, antiviral, antiulcer,
antiarrythmic and antimuscarinic activities.2 In most cases, the
biological activities arise from the different substituents that
have been appended to the hydantoins.1−5 In particular,
spirohydantoins3−6 and fused7,8 bicyclic hydantoin derivatives
have recently attracted much attention because they exhibit
various biological activities. Some of these biologically active
compounds are shown in Figure 1, which include naturally
occurring spironucleoside5 hydantocidin (X = O) and its
carbocyclic analogue4 (X = CH2), spirocyclic core of bio-
logically active alkaloids palau’amine and axinellamines,9
tetrantoin,10 tetrahydroisoquinoline-hydantoins.8 Hydantoin
derivatives have also been used as synthons for supramolecular
chemistry10 and β-strand mimetics.11
The synthesis of spiro-cyclopentane and cyclohexane
hydantoin derivatives has been accomplished by cycloaddition
using hydantoin dienophiles.6 There exists very few meth-
ods1−12 for the synthesis of spirohydantoins and fused bicyclic
hydantoin derivatives. Therefore the development of efficient
and elegant synthetic strategies for the preparation of new
functionalized hydantoin derivatives would be highly desirable
due to their similarity with drug-like molecules. Although ring-
closing metathesis has emerged as one of the most powerful
methods in organic synthesis,13−16 there have been no reports
on synthesis of spirocyclic hydantoins by using ring closing
metathesis. Only few examples have dealt with the construction
of six membered fused hydantoins using RCM, where amino
RESULTS AND DISCUSSION
■
Synthesis of Metathesis Precursors. For this purpose, a
series of metathesis precursors were constructed from the
commercially available hydantoin 1 by using 2−3 step
procedures involving selective N and C(5) alkylation.21 The
results obtained with various combinations of alkyl and alkenyl
halides and the hydantoin derivatives are summarized in Tables
1−4 and Scheme 1.
Hydantoin 1 was reacted with three different alkyl halides
and allyl bromide in the presence of K2CO3 in DMF at 60 °C
for 12 h. As shown in Table 1, this reaction afforded the
corresponding 1,3-disubstituted hydantoin derivatives 2a−d in
good to high yields (54−75%). To prepare spirocyclic
imidazolidinone ring systems it was decided to introduce
diallyl groups at C(5) position. Diallylation was successfully
carried out at C(5) position by reacting compounds 2 with base
Received: June 26, 2012
Published: August 31, 2012
© 2012 American Chemical Society
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Figure 1. Bioactive molecules containing spiro and fused imidazalodinones.
Table 1. Preparation of 5,5-Diallyl-1,3-Disubstituted
Imidazolidine-2,4-dione 3
Figure 2. Hydantoin as a scaffold for diversity oriented synthesis of
bicyclic and spirocyclic ring systems by RCM and CM.
such as LiHMDS in THF. The reactions were stirred at −20 °C
to rt for 12 h to afford diallyl imidazolidinedione derivatives
3a−3d in 51−70% yields (Table 1, entries 1−4). The reaction
did not proceed using other bases such as K2CO3and KOtBu.
In order to increase structural variation in the starting
materials for our study, we have incorporated two different N-
substituents in the hydantoin unit. First a selective N-protection
of 1 was carried out at N (3) position using K2CO3 in DMF at
rt to prepare 4a and 4b. Reacting 4 with 1 equiv of allyl
bromide in the presence of K2CO3 at 50 °C afforded the
corresponding 1,3-disubstituted hydantoins 5a,b in 70−73%
yields (Scheme 1). Hydantoin derivatives 4 were treated with
excess allyl bromide in the presence of LiHMDS at −40 °C to
rt for 12 h to give selectively the diallyl derivatives 6a,b in 75−
81% yields.
a
Yields are of isolated products after chromatography. Bn = benzyl,
PMB = p-methoxy benzyl.
(Table 2). These alkylation reactions proceeded well to give the
corresponding 1,3,5-trisubstituted hydantoin derivatives 7a−e
in yields ranging from 46 to 78%. Thus, we have an easy access
to five different substrates with double bonds suitably
The disubstituted hydantoins 2d and 5 were then treated
with four different alkenyl bromides using LiHMDS as the base
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Scheme 1. Synthesis of N-Protected Imidazolidine-2,4-
diones
Table 3. Preparation of 5,5-Dialkenyl-1,3-Disubstituted
Imidazolidine-2,4-dione 8
Table 2. Preparation of Trisubstituted Imidazolidine-2,4-
dione 7
a
Yields are of isolated products after chromatography.
RCM reaction utilizing the standard metathesis condition. Thus
these compounds were treated with 2 mol % Grubbs’ second-
generation catalyst (G-II) in dichloromethane at rt for 8 h
(Table 4). The desired 1,3-diazaspiro[4.4]non-7-ene-2,4-dione
ring systems 9a−g were obtained in excellent yields (entries 1−
8, Table 4). Spirocyclic compounds are important synthetic
targets that exhibit significant pharmacological activities due to
their conformational rigidity. The diallyl hydantoin starting
material 6a containing a free NH group could be effectively
used in RCM to give the corresponding spirocyclic compounds
9e (entries 5, Table 4). The crystal structure22 analysis of 9e
shows a dimeric structure that is held together by H-bonding
between imide hydrogen donor and carbonyl oxygen acceptor
(see Figure S1a, Supporting Information (SI).
It is interesting to note that RCM of tetraene 3d afforded
exclusively the spirocyclic compounds 9d and none of the fused
six membered or bridged bicyclic alternatives (entry 4, Table
4). Similarly, the RCM of trienes 8a and 8b resulted in highly
selective generation of spirocyclic compounds 9f and 9g,
respectively, in excellent yields (Table 4, entries 6−7). In these
cases, spirocyclic compounds prevailed over the formation of
corresponding fused ring systems.
Preparation of Cyclic Amino Acid. Since substituted
hydantoins are important building blocks for the synthesis of
non-natural amino acids by alkaline degradation, several rare
cyclic quaternary amino acids can be easily available using our
protocol.23,24 Cyclic amino acids can control peptide
conformations24 and act as ligand for glutamate receptors.25
RCM has been used for the synthesis of several amino acid
derivatives.13,26 We have exemplified that cyclic amino acid 10
can be efficiently prepared in high overall yield from the
hydantoin 1 in four steps (Schemes and 2). The diallyl
hydantoin 6b was treated with 2 mol % Grubbs’ second-
generation catalyst (G-II) in dichloromethane at rt for 8 h to
give the corresponding N-Boc spiro hydantoin 9h in near
quantitative yield (Scheme 2). Treatment of the N-Boc
hydantoin derivative 9h with Ba(OH)2 in THF−H2O at 180
°C for 72 h afforded the cyclopentene amino acid 10 in 93%
yield (Scheme 2).27
a
Yields are of isolated products after chromatography.
positioned to carry out ring-closing metathesis. The hydantoin
derivative 7b was then alkylated with allyl bromides under
similar conditions using LiHMDS to give the corresponding
tetrasubstituted hydantoin derivatives 8a and 8b (Table 3). The
products were obtained in high yields (68−85%).
Spirocyclic Hydantoins Using RCM. With the imdazoli-
dinone derivatives 3, 6 and 8 in our hands, we examined the
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°C, self-metathesis dimer of fused bicyclic hydantoin 11 was
obtained together with the spirocyclic compound 9f (Table 5).
The formation of dimer could occur by a simultaneous ab-
mode RCM followed by a self-metathesis of the intermediate
monomeric fused hydantoin. However, the highly selective
formation of the spiro compound 9f (entry 6, Table 4) suggests
that the aa-mode RCM reaction is much faster than the ab-
mode. To investigate the possibility of conversion of the spiro
product 9f to 11, the progress of the reaction was monitored
with time (entries 1−4, Table 5). Treatment of 8a in the
presence of 5 mol % with HG-II for 7 h at 45 °C for 12 h
afforded the corresponding products with a ratio of spiro
compound 9f and fused bicyclic dimer 11 as a ratio of 69:31 in
a combined yield of 93% (entry 1, Table 5). Under prolonged
reaction (ca. 6 days), the reaction afforded a mixture of spiro
compound 9f and the dimer 11 in a ratio of 20:80 in 85%
combined yields (entry 4, Table 5). However, the compound
8a was treated with the Grubbs’ second-generation catalyst (G-
II) in refluxing CH2Cl2 at 45 °C for 36 h to give exclusively the
spirocyclic compound 9f, with no trace of the dimer 11 in the
reaction (entries 5−6, Table 5).
Table 4. Synthesis of Spirocylic Hydantoin Derivatives by
RCM
a
These results indicate that the spiro compound 9f underwent
ring rearrangement metathesis13 in the presence of HG-II to
produce the thermodynamically preferred dimer 11. To
confirm these results, the spiro compound 9f was treated
with 5 mol % HG-II for 72 h in refluxing CH2Cl2 to provide the
dimer 11 in 73% isolated yield following a sequence of tandem
ROM−RCM−CM (Scheme 3). The structure of the bicyclic
hydantoin dimer 11 was unambiguously confirmed by single
crystal X-ray analysis22 (Figure S1b, SI).
The spirocyclic compound 9f was functionalized by a
selective cross-metathesis (CM)16 with methyl acrylate to
give exclusively the E-olefin 12 in 62% yield (Scheme 3). The
reaction was carried out using 5 mol % of HG-II in CH2Cl2 at
45 °C. The crude NMR analysis of the reaction shows the
formation of a trace amount (<10%) of dimer 11. We could
establish a highly selective “one-pot” sequential RCM and CM
to yield the spirohydantoin derivative 12 in 53% yields from the
triene 8a (Scheme 3). It is intriguing to note that the dimer 11
could be efficiently used as cross metathesis partner with
methyl acrylate to give the corresponding E-olefin 13 in 79%
yields (Scheme 3). This method would allow synthesis of
several fused hydantoin derivatives, which are otherwise
difficult to prepare by standard protocols. To our knowledge,
the aforementioned transformations are the first examples of
the ring-closing and cross metathesis to prepare spirocyclic
hydantoin derivatives and the functionalized spiro and fused
compounds.
a
All reactions were carried out using (0.2 mmol, 1.0 equiv) of 3, 6, or
8 and in CH2Cl2 (4 mL) with 2 mol % of G-II catalyst at rt for 8 h.
b
Yields are of isolated products after chromatography.
Scheme 2. Preparation of Cyclopentene Amino Acid 10
Synthesis of Fused Hydantoin Derivarives. In the next
step of this work, we have examined the feasibility of RCM
precursors 7 to prepare the bicyclic imidazolidinediones 14, n =
1−3. The 1,5-dialkenyl substituted hydantoin precursors 7 were
treated using Grubbs catalyst (G-II) in toluene at 80 °C (Table
6). Precursors 7a,b with allyl substituents at 1 and 3 positions
afforded dihydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione
14a,b in high yield (entries 1−2, Table 6). Similarly the
dimethyl analogue of diazabicyclic compound 14c was
synthesized in 51% yield from the precursor 7c (entry 3,
Table 6). Thus, we have an easy access to azabicyclic
compounds bearing nitrogen at the fusion of six-membered
rings, which are key building blocks in many multistep alkaloids
and drug syntheses.
Tandem Metathesis. Unlike RCM, the synthetic applica-
tions of ring-opening metathesis (ROM)15 and cross metathesis
(CM)16 have been relatively less explored. We envisioned that
the hydantoin containing triene derivative such as 8a could
serve as precursors for skeletal diversity using a domino/
tandem28 metathesis sequence. Tandem processes involving a
series of organic transformations are of high importance for the
rapid access of structural complexity.28 It is interesting to note
that refluxing the triene 8a with 5 mol % Hoveyda−Grubbs’
second-generation catalyst (HG-II) in dichloromethane at 45
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Table 5. One-Pot RCM−ROM−CM
a
a
b
entry
time
conv
ratio (9f/11)
yield (%)
1
2
3
4
12 h
29 h
66 h
6 d
>99
>99
>99
>99
>99
>99
69:31
33:67
23:77
20:80
93
91
87
85
98
98
c
c
5
c
12 h
36 h
100:0
c
6
100:0
a
b
1
The conv and ratios were determined by H NMR analysis of the crude mixture. Combined yields of isolated products after chromatography.
c
Using 5 mol % G-II.
a
Scheme 3. One-Pot RCM−CM
Table 6. Synthesis of Bicyclohydantoin Derivatives by RCM
This methodology was extended to access seven and eight
membered ring systems. (Z)-2-benzyl-5,6,9,9a-tetrahydro-1H-
imidazo[1,5-a]azepine-1,3(2H)-dione 14d and (Z)-2-benzyl-
5,6,10,10a-tetrahydroimidazo[1,5-a]azocine-1,3(2H,9H)-dione
14e were obtained in moderate yields under similar conditions
(entries 4−5, Table 6). Since hydantoins can give the
corresponding amino acids, these medium ring systems 14a−
e can serve as precursors for proline homologues and can be
used as the replacement for proline in polypeptides and
antibiotics.29
Synthesis of Fused Imidazolone Derivatives. Finally,
we have incorporated alkene substituents at C(4)−C(5) and
N(3)−C(4) positions of imidazolidinone (Scheme 4). The
dibenzyl hydantoin 2b was monoallylated at C(5) position to
give compound 15 in 70% yield. The C(4) lactam carbonyl
groups of 15 were then reduced with DIBAL-H, followed by
reaction of the crude resulting mixture with allyltrimethylsilane
in the presence of BF3·OEt2, furnishing the 4,5-diallylimidazo-
lidinone 16 in 78% yield (Scheme 4).30 Ring-closing metathesis
of the diene 16 with the catalyst G-II afforded diazabicyclic
compound 17 in near quantitative yield. The relative
configuration of the bicyclic urea 17 was confirmed to be
trans from single crystal X-ray analysis (Figure S2, SI).22 The
a
All reactions were carried out using (0.2 mmol, 1.0 equiv) of 8 and in
b
toluene (3 mL) with 2 mol % of G-II catalyst at rt for 8 h. Yields are
of isolated products after chromatography. Yields based on starting
material recovery.
c
compound 17 can serve as the immediate precursor for
stereoselective synthesis of cyclic vicinal diamines,31 ligand for
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and then the mixture was extracted with EtOAc (3 × 20 mL). The
combined organic phases were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The crude residue was
then purified by column chromatography on silica gel with EtOAc−
hexane (20/80 to 35/65) to give compound 2.
Scheme 4. Synthesis of Tetrahydrobenzoimidazolone 17 and
Tetrahydroimidazopyridinone 19 Derivatives
1,3-Dimethylimidazolidine-2,4-dione (2a).21b Using the general
procedure, methyl iodide (1.8 mL, 30 mmol, 3 equiv) provided
1
compound 2a (2.1 g, 54%) as a colorless oil: H NMR (500 MHz)
3.76 (2H, s), 2.87 (3H, s), 2.87 (3H, s); 13C NMR (125 MHz) 170.0,
157.0, 51.6, 29.5, 24.7; IR 3444, 2949, 2358, 1760, 1699, 1493, 1419,
1388, 1272, 1248, 1110, 1077, 10005, 756, 599; HRMS (ESI) calcd for
C5H9N2O2 [M + H]+ 129.0664, found 129.0689.
1,3-Dibenzylimidazolidine-2,4-dione (2b).21g Using the general
procedure, benzyl bromide (3.6 mL, 30 mmol, 3.0 equiv) provided
1
compound 2b (6.3 g, 75%) as a colorless solid: mp 66−67 °C; H
NMR (500 MHz) 7.45 (2H, d, J = 6.9 Hz), 7.35−7.34 (6H, m), 7.25
(2H, d, J = 6.9), 4.69 (2H, s), 4.54 (2H, s), 3.70 (2H, s); 13C NMR
(125 MHz) 169.5, 156.4, 136.0, 135.2, 129.0, 128.5, 128.5, 127.9,
127.7, 49.0, 47.0, 42.4; IR (KBr) 3465, 3063, 3032, 2926, 2363, 1769,
1710, 1496, 1453, 1383, 1358, 1237, 1204; HRMS (ESI) calcd for
C17H17N2O2 [M + H]+ 281.1290, found 281.1294.
metal complexes32 and chiral auxiliaries.33 Similarly the diallyl
hydantoin 2d was then treated under similar two step
conditions with DIBAL-H and allyl trimethylsilane in the
presence of BF3·OEt2 to give triallyl hydantoin 18 in 60% yield
(Scheme 4). A selective ring-closing metathesis of the triene 18
afforded the tetrahydroimidazo[1,5-a]pyridin-3(5H)-one ring
system 19.
1,3-Bis(4-methoxybenzyl)imidazolidine-2,4-dione (2c). Using the
general procedure, p-methoxybenzyl chloride (4.0 mL, 30 mmol, 3.0
equiv) provided compound 2c (7.7 g, 75%) as a colorless solid: mp
1
125−126 °C; H NMR (500 MHz) 7.37 (2H, d, J = 8.5 Hz), 7.15
(2H, d, J = 8.5 Hz), 6.87−6.82 (4H, m), 4.59 (2H, s), 4.45 (2H, s),
3.77 (3H, s), 3.76 (3H, s), 3.66 (2H, s); 13C NMR (125 MHz) 169.4,
159.3, 159.2, 156.4, 130.1, 129.4, 128.3, 127.3, 114.2, 113.8, 55.1, 55.0,
48.8, 45.9, 41.9; IR (KBr) 2929, 2837, 2362, 1767, 1710, 1612, 1514,
1462, 1354, 1295, 1247, 1177, 1140, 1109, 1033; HRMS (ESI) calcd
for C19H21N2O4 [M + H]+ 241.1501, found 241.1529.
CONCLUSION
■
In conclusion, we have demonstrated that selective N and C(5)
alkylation of hydantoin followed by the RCM reaction provides
an easy access to a variety of spiro and fused bicyclic hydantoin
derivatives, a group of structures that represent alkaloid-like
scaffolds for lead generation. The methodology establishes that
the hydantoin containing triene can undergo tandem meta-
thesis sequences to prepare either the functionalized spiro
compound or bicyclic hydantoin dimer. Since hydantoin
derivatives are the immediate precursors for racemic and chiral
amino acid derivatives, the method establishes a RCM based
approach to prepare unsaturated cyclic amino acids from
commercially available hydantoin. Spirocyclic hydantoins can
produce cyclic α-amino acids as exemplified in a four-step
synthesis of cyclopentene amino acid. The fused hydantoins
can serve as the precursors for proline homologues. The
synthesis of tetrahydrobenzoimidazolone route can be used for
the stereoselective synthesis of cyclic vicinal diamines.
1,3-Diallylimidazolidine-2,4-dione (2d). Using the general proce-
dure, allyl bromide (2.5 mL, 30 mmol, 3.0 equiv) provided compound
1
2d (3.8 g, 70%) as a colorless oil: H NMR (400 MHz) 5.79−5.75
(2H, m), 5.25−5.20 (4H, m), 4.10 (2H, d, J = 7.32 Hz), 3.99 (2H, d, J
= 6.1 Hz), 3.82 (2H, s); 13C NMR (100 MHz) 169.6, 156.1, 131.5,
131.1, 119.2, 118.1, 49.1, 45.2, 41.0; IR 3430, 3085, 2968, 2925, 2352,
1769, 1463, 1883,1325, 1237, 1182, 1155; HRMS (ESI) calcd for
C9H13N2O2 [M + H]+ 181.0977, found 181.09559.
General Procedure for Preparation of Compounds 3. The
imidazolidinediones 2 (1 equiv) were dissolved in anhydrous THF (10
mL/1 mmol), and the solution was cooled to −20 °C under N2. Then
LiHMDS (3.0 equiv, solution in THF) was added at this temperature,
and the mixture was stirred for 30 min followed by addition of the allyl
bromide (3.0 equiv). The mixture was warmed up to room
temperature and stirred for 12 h. The reaction was subsequently
quenched by addition of saturated aqueous NH4Cl. The mixture was
extracted with EtOAc. The combined organic phases were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated.
The crude residue was then purified by column chromatography on
silica gel with EtOAc−hexane (5/95 to 20/80) to give compound 3.
5,5-Diallyl-1,3-dimethylimidazolidine-2,4-dione (3a). Using the
general procedure, 1,3-dimethylimidazolidine-2,4-dione 2a (500 mg,
3.9 mmol, 1.0 equiv) and allyl bromide (1.0 mL, 11.7 mmol, 3.0 equiv)
and LiHMDS (11.7 mL, 11.7 mmol, 3.0 equiv) provided compound
EXPERIMENTAL SECTION
■
General Information. All experiments were carried out under an
inert atomosphere of argon in flame-dried flasks. The solvents were
used as technical grade and freshly distilled prior use. All starting
materials were obtained from commercial suppliers and used as
received. Products were purified by flash chromatography on silica gel
(100−200 mesh). Unless otherwise stated, yields refer to analytical
1
3a (527 mg, 2.5 mmol, 65%) as a colorless oil: H NMR (400 MHz)
5.48−5.39 (2H, m), 5.12−5.05 (4H, m), 2.93 (3H, s), 2.84 (3H, s),
2.55 (2H, dd, J = 17.9, 8.8 Hz), 2.38 (2H, dd, J = 18.1, 9.3 Hz); 13C
NMR (100 MHz) 174.4, 156.2, 129.9, 120.3, 67.9, 38.4, 24.6, 24.4; IR
(KBr) 3424, 2939, 2348, 1750, 1679, 1483, 1429, 1288, 1272, 1248,
1110, 1067; HRMS (ESI) calcd for C11H17N2O2 [M + H]+ 209.1290,
found 209.12765.
pure samples. All melting points are uncorrected. H and 13C NMR
1
NMR spectra were recorded in CDCl3 at 278 K unless otherwise
stated and are reported in ppm relative to tetramethylsilane (TMS).
Infrared (FTIR) spectra were recorded with the KBr disk and KBr
plate techniques for solid and liquid samples, νmax cm−1. HRMS
analyses were performed with Q-TOF YA263 high resolution
instruments by positive mode electrospray ionization.
General Procedure for Preparation of Compounds 2. To a
suspension of hydantoin (1.0 g, 10 mmol, 1.0 equiv) and K2CO3 (4.1
g, 30 mmol, 3.0 equiv) in dry DMF (5 mL/1 mmol) was added MeI or
BnBr or allyl bromide or PMBCl (3 equiv). The resulting mixture was
stirred at 60 °C for 12 h. The reaction was stopped by adding water,
5,5-Diallyl-1,3-dibenzylimidazolidine-2,4-dione (3b). Using the
general procedure, 1,3-dibenzylimidazolidine-2,4-dione 2b (500 mg,
1.8 mmol, 1.0 equiv) and allyl bromide (0.5 mL, 5.4 mmol, 3.0 equiv)
and LiHMDS (5.4 mL, 5.4 mmol, 3.0 equiv) provided compound 3b
1
(402 mg, 1.1 mmol, 62%) as a colorless oil: H NMR (500 MHz)
7.44−7.42 (2H, m), 7.41−7.39 (2H, m), 7.35−7.26 (6H, m), 5.22−
5.14 (2H, m), 4.89−4.85 (4H, m), 4.67 (2H, s), 4.51 (2H, s), 2.49
(2H, dd, J = 14.3, 7.5 Hz), 2.38 (2H, dd, J = 14.3, 7.0 Hz); 13C NMR
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(125 MHz) 173.8, 156.6, 137.1, 135.9, 129.5, 128.7, 128.4, 128.3,
128.2, 127.7, 127.5, 120.3, 68.9, 43.6, 42.2, 38.9; IR (KBr) 3467, 3065,
3033, 2926, 1769, 1708, 1496, 1446, 1392, 1359, 1242, 1200, 1142,
1077, 995; HRMS (ESI) calcd for C23H25N2O2 [M + H]+ 361.1916,
found 361.19270.
mL). The combined organic phases were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated. The crude residue
was then purified by column chromatography on silica gel with
EtOAc−hexane (10/90 to 30/70) to give compound 5.
1-Allyl-3-benzylimidazolidine-2,4-dione (5a). Using the general
procedure, allyl bromide (0.3 mL, 3.7 mmol, 0.7 equiv) provided
compound 5a (889 mg, 73%) as a colorless oil: 1H NMR (400 MHz)
7.39−7.37 (2H, m), 7.28−7.25 (3H, m), 5.76−5.67 (1H, m), 5.21−
5.20 (2H, m), 4.62 (2H, s), 3.95−3.94 (2H, m), 3.76 (2H, s); 13C
NMR (100 MHz) 169.4, 156.1, 135.9, 131.5, 128.5, 128.4, 127.7,
118.9, 49.0, 45.1, 42.3; IR 3459, 2922, 2354, 1769, 1710, 1462, 1235,
1141, 996, 935, 755, 700; HRMS (ESI) calcd for C13H15N2O2 [M +
H]+ 231.1134, found 231.1157.
5,5-Diallyl-1,3-bis(4-methoxybenzyl)imidazolidine-2,4-dione (3c).
1,3-Bis(4-methoxybenzyl)imidazolidine-2,4-dione 2c (500 mg, 1.5
mmol, 1 equiv) and allyl bromide (0.4 mL, 4.5 mmol, 3.0 equiv)
and LiHMDS (4.5 mL, 4.5 mmol, 3 equiv) provided compound 3c
(441 mg, 0.95 mmol, 70%) as a white crystal (EtOAc/hexane): mp
1
101−103 °C; H NMR (400 MHz) 7.33−7.29 (4H, m), 6.85−6.80
(4H, m), 5.18−5.08 (2H, m), 4.89−4.83 (4H, m), 4.57 (2H, s), 4.42
(2H, s), 3.78 (3H, s), 3.77 (3H, s), 2.46 (2H, dd, J = 17.9, 9.4 Hz),
2.35 (2H, dd, J = 17.9, 9.4 Hz); 13C NMR (100 MHz) 173.9, 159.2,
159.0, 156.7, 130.2, 130.0, 129.7, 129.3, 128.4, 120.5, 113.8, 113.6,
69.0, 55.2 (2C), 43.2, 41.8, 39.1; IR (KBr) 3446, 2933, 2836, 2543,
2052, 1872, 1612, 1512, 1445, 1246, 1176, 1033, 930, 847; HRMS
(ESI) calcd for C25H29N2O4 [M + H]+ 421.2127, found 421.2141.
1,3,5,5-Tetraallylimidazolidine-2,4-dione (3d). 1,3-Diallylimidazo-
lidine-2,4-dione 2d (1.0 g, 5.6 mmol, 1.0 equiv) and allyl bromide (1.4
mL, 16.8 mmol, 3.0 equiv) and 16.8 mL of LiHMDS provided
compound 3d (742 mg, 51%) as a colorless oil: 1H NMR (400 MHz)
5.96−5.86 (1H, m), 5.78−5.68 (1H, m), 5.55−5.44 (2H, m), 5.31−
5.27 (1H, m), 5.23−5.18 (2H, m), 5.15−5.07 (5H, m), 4.05−4.03
(2H, m), 3.93 (2H, d, J = 7.83 Hz), 2.56 (2H, dd, J = 18.0, 8.8 Hz),
2.46 (2H, dd, J = 18.0, 8.8 Hz); 13C NMR (125 MHz) 173.7, 155.8,
133.5, 131.1, 129.9, 120.6, 118.1, 117.7, 68.7, 42.9, 40.6, 38.9; IR
(KBr) 3468, 3082, 2983, 2925, 1771, 1710, 1644, 1452, 1414, 1157,
993, 928, 760, 682, 547; HRMS (ESI) calcd for C15H21N2O2 [M +
H]+ 261.1603, found 261.1619.
3-Benzyl-1-(2-methylallyl)imidazolidine-2,4-dione (5b). Using the
general procedure, 3-bromo-2-methylprop-1-ene (0.4 mL, 3.7 mmol,
0.7 equiv) provided compound 5b (905 mg, 70%) as a colorless oil:
1H NMR (500 MHz) 7.38−7.37 (2H, m), 7.28−7.23 (3H, m), 4.92
(1H, s), 4.81 (1H, s), 4.64−4.62 (2H, m), 3.88−3.86 (2H, m), 3.73−
3.71 (2H, m), 1.67 (3H, s); 13C NMR (125 MHz) 169.3, 156.2, 139.2,
135.8, 128.3, 128.2, 127.5, 113.6, 48.9, 48.5, 42.2, 19.5; IR 3469, 2912,
2344, 1759, 1700, 1262, 1235, 1041, 996, 925, 705, 603; HRMS (ESI)
calcd for C14H17N2O2 [M + H]+ 245.1290, found 245.1279.
General Procedure for the Preparation of 5,5-Diallyl-3-
substitutedimidazolidine-2,4-dione 6. The compounds 4 (1.0
equiv) were dissolved in anhydrous THF (10 mL/1 mmol), and the
solution was cooled to −40 °C under N2. LiHMDS (3.0 equiv,
solution in THF) was added at this temperature, and the mixture was
stirred for 30 min followed by addition of the allyl bromide (3 equiv).
The mixture was stirred at room temperature for 12 h, and the
reaction was then quenched by addition of saturated aqueous NH4Cl.
The mixture was extracted with EtOAc. The combined organic phases
were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated. The crude residue was then purified by column
chromatography on silica gel with EtOAc−hexane (5/95 to 20/80)
to give compound 6.
5,5-Diallyl-3-benzylimidazolidine-2,4-dione (6a). Using the gen-
eral procedure, compound 4a (1.0 g, 5.3 mmol, 1 equiv) and allyl
bromide (1.4 mL, 15.9 mmol, 3.0 equiv) and 15.9 mL of LiHMDS
provided compound 6a (1.1 g, 75%) as a colorless oil: 1H NMR (400
MHz) 7.34−7.31 (2H, m), 7.30−7.24 (3H, m), 6.74 (1H, brs, NH),
5.59−5.49 (2H, m), 5.10−5.01 (4H, m), 4.60 (2H, s), 2.48 (2H, dd, J
= 17.3, 9.4 Hz), 2.39 (2H, dd, J = 17.5, 9.1 Hz); 13C NMR (100 MHz)
175.1, 157.2, 135.9, 130.1, 128.4, 128.3, 126.7, 120.7, 64.8, 42.0, 40.6;
IR (KBr) 3323, 2076, 1771, 1642, 1444, 1349, 1122, 1074, 995, 924,
756, 698; HRMS (ESI) calcd for C16H19N2O2 [M + H]+ 271.1447,
found 271.1450.
Preparation of 3-Benzylimidazolidine-2,4-dione (4a).21g To a
suspension of hydantoin (1.0 g, 10 mmol, 1.0 equiv) and K2CO3 (4.0
g, 30 mmol, 3.0 equiv) in dry DMF (25 mL) was added BnBr (1.4 mL,
36 mmol, 1.2 equiv). The resulting mixture was stirred at rt for 12 h.
The reaction was stopped by adding water, and then the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic phases
were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated. The crude residue was then purified by column
chromatography on silica gel with EtOAc−hexane (20/80 to 35/65)
to give compound 4a (1.24 g, 65%) as a colorless solid: mp 132−133
1
°C; H NMR (500 MHz) 7.37−7.36 (2H, m), 7.32−7.26 (3H, m),
6.84 (1H, sbr, NH), 4.64 (2H, s), 3.91 (2H, s); 13C NMR (125 MHz)
171.3, 158.6, 136.0, 128.7, 128.5, 128.0, 46.6, 42.2; IR (KBr) 3460,
3025, 2948, 2915, 2352, 1759, 1463, 1883, 1325, 1237, 1182, 1155,
1118, 994, 934, 757, 700, 582, 550; HRMS (ESI) calcd for
C10H11N2O2 [M + H]+ 191.0821, found 191.0824.
tert-Butyl 4,4-diallyl-2,5-dioxoimidazolidine-1-carboxylate (6b).
Using the general procedure, compound 4b (1.0 g, 5.0 mmol, 1 equiv)
and allyl bromide (1.3 mL, 15.0 mmol, 3.0 equiv) and 15.0 mL of
LiHMDS provided compound 6a (1.13 g, 81%) as a white crystal
Preparation of tert-Butyl 2,5-dioxoimidazolidine-1-carbox-
ylate (4b). To a suspension of hydantoin 1 (1.0 g, 10 mmol, 1.0
equiv) in CH3CN (50 mL), Boc2O (4.8 g, 22 mmol, 2.2 equiv) and
DMAP (122 mg, 1 mmol, 0.1 equiv) were added at room temperature.
The resulting solution was stirred for 12 h at room temperature, and
then the solvent was evaporated under reduced pressure. The reaction
was stopped by adding water, and then the mixture was extracted with
EtOAc (3 × 20 mL). The combined organic phases were washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated. The
crude residue was then purified by column chromatography on silica
gel with EtOAc−hexane (20/80 to 35/65) to give compound 4b (1.7
1
(EtOAc/hexane): mp 103−105 °C; H NMR (400 MHz) 8.72 (1H,
sbr), 5.62−5.52 (2H, m), 5.17 (2H, sbr), 5.14 (2H, d, J = 2.7 Hz), 2.92
(2H, dd, J = 17.3, 10.2 Hz), 2.61(2H, dd, J = 17.3, 8.5 Hz), 1.56 (9H,
s); 13C NMR (125 MHz) 173.1, 152.1, 148.3, 129.4, 121.2, 84.3, 71.0,
39.0, 28.0; IR (KBr) 3424, 3228, 3152, 2929, 2726, 2358, 1650, 1629,
1413, 1422, 1218, 1200, 1148, 1110, 1047; HRMS (ESI) calcd for
C14H20N2O4Na [M + Na]+ 303.1321, found 303.1326.
1
g, 89%) as a colorless solid: mp 141−143 °C; H NMR (500 MHz)
General Procedure for the Preparation of Trisubstituted
Imidazolidine-2,4-dione 7b−e. Alkenyl bromide (0.7 equiv) was
added to a solution of 1-allyl-3-benzylimidazolidine-2,4-dione 5 (1
equiv) and LiHMDS (1.2 equiv) in anhydrous THF (10 mL/1 mmol)
at −20 °C. The mixture was stirred at room temperature for 12 h, and
the reaction was then quenched by addition of saturated aqueous
NH4Cl. The mixture was extracted with EtOAc. The combined
organic phases were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated. The crude residue was then purified by
column chromatography on silica gel with EtOAc−hexane (5/95 to
20/80) to give compound 7.
8.93 (1H, br, s), 4.24 (2H, s), 1.52 (9H, s); 13C NMR (125 MHz)
168.2, 152.3, 148.3, 84.7, 50.1, 28.0; IR (KBr) 3460, 3225, 3048, 2915,
2752, 1719, 1563, 1783, 1425, 1237, 1172, 1145, 1018, 994, 834, 787,
720, 522, 500; HRMS (ESI) calcd for C8H13N2O4 [M + H]+ 201.0875,
found 201.0881.
General Procedure for the Preparation of N(1)-Substituted
Hydantoin 5. To a suspension of 3-benzylimidazolidine-2,4-dione
(1.0 g, 5.3 mmol, 1.0 equiv) and K2CO3 (726 mg, 5.3 mmol, 1.0
equiv) in dry DMF (5 mL/1 mmol) was added allyl bromide or 3-
bromo-2-methylprop-1-ene (3.7 mmol, 0.7 equiv). The resulting
mixture was stirred at 50 °C for 8 h. The reaction was stopped by
adding water, and then the mixture was extracted with EtOAc (3 × 20
1,5-Diallyl-3-benzylimidazolidine-2,4-dione (7b). Using the gen-
eral procedure, compound 5a (500 mg, 2.2 mmol, 1.0 equiv) and allyl
8077
dx.doi.org/10.1021/jo301234r | J. Org. Chem. 2012, 77, 8071−8082

The Journal of Organic Chemistry
Article
bromide (0.1 mL, 1.5 mmol, 0.7 equiv) and LiHMDS (2.64 mL, 2.64
2904, 2223, 1742, 1620, 1425, 1318, 1226, 1104, 1025; HRMS (ESI)
calcd for C12H17N2O2 [M + H]+ 221.1290, found 221.1268.
mmol, 1.2 equiv) provided compound 7b (463 mg, 78%) as a colorless
1
oil: H NMR (400 MHz) 7.38−7.36 (2H, m), 7.30−7.26 (3H, m),
5-Allyl-1,3-dibenzylimidazolidine-2,4-dione (15). 1,3-Dibenzylimi-
dazolidine-2,4-dione 2b (1.0 g, 3.6 mmol, 1.0 equiv) and allyl bromide
(0.2 mL, 2.5 mmol, 0.7 equiv) and LiHMDS (4.32 mL, 4.32 mmol, 1.2
5.76−5.71 (1H, m), 5.52−5.44 (1H, m), 5.26−5.22 (2H, m), 5.09
(2H, dd, J = 17.1, 9.8 Hz), 4.69−4.59 (2H, m), 4.43−4.38 (1H, m),
4.01 (1H, t, J = 5.5 Hz), 3.64−3.59 (1H, m), 2.62−2.57 (2H, m); 13C
NMR (100 MHz) 172.0, 159.9, 135.9, 131.8, 130.0, 128.4, 127.7,
120.3, 119.0, 58.4, 43.4, 42.4, 32.8; IR (KBr) 3452, 3070, 3023, 2921,
2353, 1757, 1720, 1435, 1328, 1254, 1123, 1075; HRMS (ESI) calcd
for C16H19N2O2 [M + H]+ 271.1447, found 271.1462.
1
equiv) provided compound 15 (806 mg, 70%) as a colorless oil: H
NMR (500 MHz) 7.38−7.36 (2H, m), 7.34−7.26 (6H, m), 7.24−7.22
(2H, m), 5.46−5.39 (1H, m), 5.09−5.00 (3H, m), 4.71−4.62 (2H, m),
4.06 (1H, d, J = 15.1 Hz), 3.82−3.81(1H, m), 2.57−2.52 (2H, m); 13C
NMR (125 MHz) 171.9, 156.4, 135.9, 135.4, 129.9, 128.8, 128.4,
128.0, 127.7, 127.4, 126.8, 120.3, 58.1, 44.6, 42.5, 32.7; IR 3455, 3043,
3012, 2976, 2343, 1883,1315, 1237, 1182, 1145; HRMS (ESI) calcd
for C20H21N2O2 [M + H]+ 321.1603, found 321.1631.
General Procedure for the Preparation of 5,5-Dialkenyl-1,3-
disubstituted imidazolidine-2,4-dione 8. Allyl bromide or 3-
bromo-2-methylprop-1-ene or bromobutene (1.5 equiv) was added to
a solution of 7a (1.0 equiv) and LHMDS (1.5 equiv) in dry THF at
−20 °C. The mixture was stirred at room temperature for 12 h, and
the reaction was then quenched by addition of saturated aqueous
NH4Cl. The mixture was extracted with EtOAc. The combined
organic phases were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated. The crude residue was then purified by
column chromatography on silica gel with EtOAc−hexane (5/95 to
20/80) to give compounds 8.
3-Benzyl-1,5-bis(2-methylallyl)imidazolidine-2,4-dione (7c).
Using the general procedure, compound 5b (500 mg, 2.0 mmol, 1.0
equiv) and 3-bromo-2-methylprop-1-ene (0.2 mL, 1.4 mmol, 0.7
equiv) and LiHMDS (2.4 mL, 2.4 mmol, 1.2 equiv) provided
1
compound 7c (327.8 mg, 55%) as a colorless oil: H NMR (500
MHz) 7.32−7.30 (2H, m), 7.25−7.19 (3H, m), 4.86 (1H, d, J = 1.3
Hz), 4.73−4.71 (2H, m), 4.69 (1H, sbr), 4.64−4.54 (2H, m), 4.33 (1H,
d, J = 15.8 Hz), 3.94 (1H, t, J = 5.3 Hz), 3.49 (1H, d, J = 15.5 Hz),
2.47 (2H, dd, J = 9.5, 5.3 Hz), 1.58 (3H, s), 1.53 (3H, s); 13C NMR
(125 MHz) 172.4, 156.4, 139.7, 139.6, 136.0, 128.5, 127.8, 115.2,
113.8, 57.2, 46.8, 42.6, 37.5, 22.5, 19.9; IR (KBr) 3437, 2926, 1710,
1448, 1417, 1390, 1353,1142, 753, 700, 627; HRMS (ESI) calcd for
C18H23N2O2 [M + H]+ 299.1760, found 299.1748.
1-Allyl-3-benzyl-5-(but-3-enyl)imidazolidine-2,4-dione (7d).
Using the general procedure, compound 5a (500 mg, 2.2 mmol, 1.0
equiv) and 4-bromobut-1-ene (0.2 mL, 1.5 mmol, 0.7 equiv) and
LiHMDS (2.64 mL, 2.64 mmol, 1.2 equiv) provided compound 7d
1,5,5-Triallyl-3-benzylimidazolidine-2,4-dione (8a). Using the
general procedure, 1,5-diallyl-3-benzylimidazolidine-2,4-dione 7b
(500 mg, 1.9 mmol, 1.0 equiv) and allyl bromide (0.25 mL, 2.9
mmol, 1.5 equiv) and LiHMDS (2.85 mL, 2.85 mmol, 1.5 equiv)
1
(300 mg, 48%) as a colorless oil: H NMR (400 MHz) 7.40−7.38
1
provided compound 8a (401 mg, 68%) as a colorless oil: H NMR
(2H, m), 7.32−7.24 (3H, m), 5.79−5.63 (2H, m), 5.24−5.20 (2H, m),
4.92 (2H, t, J = 15.5 Hz), 4.68−4.59 (2H, q, J = 18.1 Hz), 4.39−4.33
(1H, m), 3.99−3.97 (1H, m), 3.62−3.56 (1H, m), 2.85−1.97 (2H, m),
1.93−1.76 (2H, m); 13C NMR (100 MHz) 172.5, 156.0, 136.3, 136.0,
131.8, 128.5, 127.8, 119.0, 115.8, 58.2, 43.4, 42.4, 27.4, 27.3; IR (KBr)
3458, 3072, 2973, 2915, 1761, 1720, 1634, 1442, 1424, 1147, 993, 928,
760; HRMS (ESI) calcd for C17H21N2O2 [M + H]+ 285.1603, found
285.1610.
(400 MHz) 7.29−7.26 (2H, m), 7.22−7.13 (3H, m), 5.89−5.79 (1H,
m), 5.38−5.26 (2H, m), 5.23−5.18 (1H, m), 5.14−5.09 (1H, m),
4.97−4.90 (2H, m), 4.89 (2H, d, J = 12.7 Hz), 4.53 (2H, s), 3.85 (2H,
d, J = 8.1 Hz), 2.46 (2H, dd, J = 17.7, 9.2 Hz), 2.37 (2H, dd, J = 18.0,
8.9 Hz); 13C NMR (100 MHz) 173.8, 156.0, 135.9, 133.6, 129.8,
128.5, 128.2, 127.6, 120.5, 118.1, 68.7, 42.9, 42.2, 39.0; IR 3462, 3080,
3033, 2921, 2353, 1767, 1710, 1445, 1338, 1254, 1133, 1075, 994, 926,
755, 700; HRMS (ESI) calcd for C19H23N2O2 [M + H]+ 311.1760,
found 311.1776.
1-Allyl-3-benzyl-5-(pent-4-enyl)imidazolidine-2,4-dione (7e).
Using the general procedure, compound 5a (700 mg, 3.0 mmol, 1.0
equiv) and 5-bromopent-1-ene (0.24 mL, 2.1 mmol, 0.7 equiv) and
LiHMDS (3.6 mL, 3.6 mmol, 1.2 equiv) provided compound 7e (411
mg, 46%) as a colorless oil: 1H NMR (400 MHz) 7.38−7.32 (2H, m),
7.31−7.22 (3H, m), 5.76−5.61 (2H, m), 5.22−5.18 (2H, m), 4.94−
4.90 (2H, m), 4.63 (2H, q, J = 17.9 Hz), 4.37−4.31 (1H, m), 3.96−
3.94 (1H, dd, J = 7.0, 4.3 Hz), 3.58−3.52 (1H, m), 2.01−1.94 (2H,
m), 1.90−1.83 (1H, m), 1.76−1.68 (1H, m), 1.32−1.23 (1H, m),
1.20−1.12 (1H, m); 13C NMR (100 MHz) 172.6, 156.1, 137.4, 137.0,
131.8, 128.5, 128.4, 127.7, 119.0, 115.2, 58.6, 43.4, 42.4, 33.0, 27.6,
21.9; IR (KBr) 3464, 3067, 3033, 2928, 2862, 1769, 1710, 1641, 1496,
1448, 1417, 1390, 1353, 1235, 1144, 1073; HRMS (ESI) calcd for
C18H23N2O2 [M + H]+ 299.1760, found 299.1757.
General Procedure for the Preparation of 5-Allyl-1,3-
disubstitutedimidazolidine-2,4-dione 7a, 15. Allyl bromide (0.7
equiv) was added to a solution of 1,3-dibenzylimidazolidine-2,4-dione
2 (1.0 g, 1.0 equiv) and LHMDS (1.2 equiv) in anhydrous THF (10
mL/1 mmol) at −20 °C. The mixture was stirred at room temperature
for 12 h, and the reaction was then quenched by addition of saturated
aqueous NH4Cl. The mixture was extracted with EtOAc. The
combined organic phases were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The crude residue was
then purified by column chromatography on silica gel with EtOAc−
hexane (5/95 to 20/80) to give compound 7a, 15.
1,5-Diallyl-3-benzyl-5-(2-methylallyl)imidazolidine-2,4-dione
(8b). Using the general procedure, 1,5-diallyl-3-benzylimidazolidine-
2,4-dione 7b (500 mg, 1.9 mmol, 1.0 equiv) and 3-bromo-2-
methylprop-1-ene (0.29 mL, 2.9 mmol, 1.5 equiv) and LiHMDS
(2.85 mL, 2.85 mmol, 1.5 equiv) provided compound 8b (523 mg,
1
85%) as a colorless oil: H NMR (400 MHz) 7.35−7.33 (2H, m),
7.25−7.18 (3H, m), 5.95−5.85 (1H, m), 5.44−5.34 (1H, m), 5.25
(1H, d, J = 21.4 Hz), 5.15 (1H, d, J = 12.2 Hz), 5.01−4.95 (1H, m),
4.49 (1H, d, J = 12.9 Hz), 4.66 (1H, s), 4.58 (3H, d, J = 11.05), 4.12−
4.04 (1H, m), 3.73−3.66 (1H, m), 2.53−2.38 (4H, m), 1.39 (3H, s);
13C NMR (100 MHz) 173.9, 155.9, 138.7, 135.7, 133.6, 129.7, 128.7,
128.2, 127.6, 120.7, 118.1, 116.1, 68.5, 43.3, 42.3, 41.8, 40.4, 23.2; IR
(KBr) 3437, 2926, 1710, 1645, 1453, 1359, 1441, 1242, 1132, 1018,
746, 699; HRMS (ESI) calcd for C20H25N2O2 [M + H]+ 325.1916,
found 325.1921.
General Procedure for the Preparation of Spirocylic
Hydantoin Derivatives 9 by RCM. To a stirring solution of 3, 6,
8 (0.2 mmol, 1 equiv) in CH2Cl2 (4 mL) was added G-II (2 mol %),
and the mixture was stirred for 8 h at room temperature. The reaction
mixture was then concentrated and purified on silica gel (EtOAc−
hexane, 10/90 to 20/80) to give compound 9.
1,3-Dimethyl-1,3-diazaspiro[4.4]non-7-ene-2,4-dione (9a). Using
the general procedure, compound 3a (50 mg, 0.24 mmol, 1.0 equiv)
provided compound 9a (41 mg, 95%) as a colorless oil: 1H NMR (400
MHz) 5.73(2H, s), 3.02(3H, s), 2.95 (2H, d, J = 16.5 Hz), 2.80 (3H,
s), 2.49 (2H, d, J = 16.5 Hz); 13C NMR (125 MHz) 176.8, 155.3,
127.8, 68.8, 41.7, 29.7, 24.9; IR (KBr) 3424, 2929, 2348, 1660, 1599,
1433, 1429, 1318, 1262, 1238, 1210, 1047; HRMS (ESI) calcd for
C9H13N2O2 [M + H]+ 181.0977, found 181.0980.
1,3,5-Triallylimidazolidine-2,4-dione (7a). Using the general
procedure, 1,3-diallylimidazolidine-2,4-dione 2d (1.0 g, 5.6 mmol,
1.0 equiv) and allyl bromide (0.33 mL, 3.9 mmol, 0.7 equiv) and
LiHMDS (6.72 mL, 6.72 mmol, 1.2 equiv) provided compound 7a
1
(801 mg, 65%) as a colorless oil: H NMR (400 MHz) 5.77−5.66
(2H, m), 5.59−5.49 (1H, m), 5.22−5.08 (6H, m), 4.38−4.33(1H, m),
4.09−3.97 (3H, dt, J = 11.3, 6.9 Hz), 3.61−3.55 (1H, m), 2.63−2.51
(2H, m); 13C NMR (100 MHz) 171.8, 155.7, 131.7, 131.0, 130.1,
120.3, 118.9, 117.6, 58.3, 43.3, 40.7, 32.7; IR (KBr) 3252, 3060, 3010,
1,3-Dibenzyl-1,3-diazaspiro[4.4]non-7-ene-2,4-dione (9b). Using
the general procedure, compound 3b (50 mg, 0.14 mmol, 1.0 equiv)
provided compound 9b (45 mg, 97%) as a white crystal (EtOAc/
8078
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1
hexane): mp 78−80 °C; H NMR (500 MHz) 7.41−7.39 (2H, m),
carboxylate 9h (100 mg, 0.39 mmol) in THF (5 mL), an aqueous
solution of 4% Ba(OH)2 (5 mL) was added. The reaction mixture was
stirred at 180 °C for 72 h. After cooling, the mixture was evaporated to
dryness, and the residue was washed with Et2O (50 mL) and H2O (50
mL). The organic layer was discarded, and the aqueous phase was
washed with an additional portion of Et2O (20 mL). The aqueous
phase was then concentrated to dryness to give the compound 10 (46
mg, 93%) as a colorless solid: mp 219−220 °C; 1H NMR (500 MHz)
5.78 (2H, s), 3.17 (2H, dbr, J = 17.0 Hz), 2.75 (2H, dbr, J = 16.4 Hz);
13C NMR (125 MHz) 174.7, 127.3, 63.5, 43.3; IR (KBr) 3214, 3012,
2713, 2605, 1721, 1640, 1564, 1245; HRMS (ESI) calcd for
C6H9NO2Na[M + Na]+ 150.0531, found 150.0535.
Preparation of Dimer 11. (a). From the Triene 8a. To a solution
of 8a (50 mg, 0.16 mmol, 1.0 equiv) in CH2Cl2 (4 mL) was added
HG-II (5 mg, 0.008 mmol, 5 mol %), and the mixture was refluxed for
6 d at 45 °C. The reaction mixture was then concentrated and purified
on silica gel (EtOAc−hexane, 20/80 to 40/60) to give compound 9f
(7 mg, 16%) and compound 11 (30 mg, 70%). Compound 11 was
obtained as a colorless crystal (EtOAc−hexane): mp 187−188 °C; 1H
NMR (500 MHz) 7.28−7.19 (10H, m), 5.69−5.60 (4H, m), 4.97−
4.92 (2H, m), 4.58−4.52 (4H, m), 4.28−4.23 (2H, m), 3.38−3.35
(1H, dt, J = 7.3, 4.5 Hz), 3.26−3.20 (1H, m), 2.20−2.08 (8H, m); 13C
NMR (125 MHz) 175.2, 175.2, 154.3, 154.2, 136.4, 136.4, 128.6,
128.6, 128.5, 128.4, 128.0, 127.8, 127.8, 127.7, 123.2, 123.1, 121.8,
121.6, 60.5, 60.4, 42.1, 42.1, 37.6, 37.5, 36.6, 36.4, 30.8, 30.7; IR (KBr)
3448, 3082, 2953, 2935, 1771, 1720, 1664, 1422, 1409, 1147, 973, 908;
HRMS (ESI) calcd for C32H33N4O4 [M + H]+ 537.2502, found
537.2528.
7.33−7.30 (2H, m), 7.28−7.23 (6H, m), 5.62 (2H, s), 4.71 (2H, s),
4.39 (2H, s), 2.85 (2H, d, J = 16.4 Hz), 2.31 (2H, d, J = 16.4 Hz) ; 13C
NMR (125 MHz) 176.4, 155.5, 137.7, 136.2, 128.6, 128.4, 128.4,
128.1, 127.9, 127.8, 127.6, 69.5, 43.6, 42.6, 42.4; IR (KBr) 3425, 3043,
3022, 2916, 2333, 1709, 1700, 1466, 1423, 1363, 1358, 1277, 1204,
1139, 1021, 1019; HRMS (ESI) calcd for C21H21N2O2 [M + H]+
333.1603, found 333.1627.
1,3-Bis(4-methoxybenzyl)-1,3-diazaspiro[4.4]non-7-ene-2,4-
dione (9c). Using the general procedure, compound 3c (60 mg, 0.14
mmol, 1.0 equiv) provided compound 9c (49 mg, 89%) as a colorless
solid: mp 86−87 °C; 1H NMR (400 MHz) 7.41 (2H, d, J = 10.7 Hz),
7.25 (2H, d, J = 10.7 Hz), 6.90 (2H, d, J = 10.8 Hz), 6.84 (2H, d, J =
10.7 Hz), 5.69 (2H, s), 4.69 (2H, s), 4.38 (2H, s), 3.82 (3H, s), 3.81
(3H, s), 2.91−2.86 (2H, m), 2.38−2.34 (2H, m) ; 13C NMR (100
MHz) 176.4, 159.0, 158.9, 155.3, 129.9, 129.8, 129.3, 128.4, 127.9,
113.8, 113.6, 69.2, 55.1, 42.9, 42.3, 42.0; IR (KBr) 3078, 2934, 2837,
1765, 1710, 1613, 1513, 1343, 1294, 1247, 1177, 1033, 996; HRMS
(ESI) calcd for C23H25N2O4 [M + H]+ 393.1814, found 393.1819.
1,3-Diallyl-1,3-diazaspiro[4.4]non-7-ene-2,4-dione (9d). Using
the general procedure, compound 3d (50 mg, 0.28 mmol, 1.0 equiv)
provided compound 9d (62 mg, 95%) as a colorless oil: 1H NMR (400
MHz) 5.84−5.73 (3H, m), 5.61−6.50 (1H, m), 5.23−5.08 (4H, m),
4.45−4.39 (1H, m), 4.15−4.05 (2H, m), 3.62−3.56 (1H, m), 2.55
(2H, d, J = 9.4 Hz), 2.32 (2H, d, J = 3.8 Hz); 13C NMR (125 MHz)
175.3, 154.3, 131.2, 130.4, 123.1, 121.9, 120.5, 117.7, 60.7, 40.5, 37.6,
31.0; IR (KBr) 3430, 3085, 2968, 2925, 2352, 1769, 1710, 1365, 1246,
1136; HRMS (ESI) calcd for C13H17N2O2 [M + H]+ 233.1290, found
233.1285.
3-Benzyl-1,3-diazaspiro[4.4]non-7-ene-2,4-dione (9e). Using the
general procedure, compound 6a (50 mg, 0.19 mmol, 1.0 equiv)
provided compound 9e (45.5 mg, 99%) as a white crystal (EtOAc/
hexane): mp 146−148 °C; 1H NMR (400 MHz) 7.36−7.33 (2H, m),
7.32−7.24 (3H, m), 6.52 (1H, sbr), 5.68 (2H, s), 4.64 (2H, s), 2.98
(2H, d, J = 15.9 Hz), 2.51 (2H, d, J = 15.9 Hz); 13C NMR (100 MHz)
176.8, 156.4, 136.0, 128.6, 128.2, 127.7, 127.6, 66.6, 42.5, 42.1; IR
(KBr) 3225, 3103, 2945, 2843, 1777, 1710, 1495, 1451, 1411, 1345,
1291, 1219, 1155, 1119, 1027, 964; HRMS (ESI) calcd for
C14H15N2O2 [M + H]+ 243.1134, found 243.1130.
(b). From the Spiro Compound 9f. To a stirring solution of 9f (50
mg, 0.18 mmol, 1 equiv) in CH2Cl2 (4 mL) was added HG-II (6 mg,
0.009 mmol, 5 mol %) and the mixture was refluxed for 6 d at 45 °C.
The reaction mixture was then concentrated and purified on silica gel
(EtOAc−hexane, 20/80 to 40/60) to give compound 11 (35 mg,
73%).
Preparation of Cross-Metathesis Product 12. To a solution of
1-allyl-3-benzyl-1,3-diazaspiro[4.4]non-7-ene-2,4-dione 9f (30 mg,
0.12 mmol, 1 equiv) and methyl acrylate (52 mg, 0.60 mmol, 5
equiv) in CH2Cl2 (0.05 M) was added HG-II (2.5 mg, 0.004 mmol, 3
mol %), and the mixture was stirred at 45 °C for 12 h. The reaction
mixture was concentrated and purified on silica gel (ethyl acetate−
hexane, 5/95 to 20/80) to yield 12 (25 mg, 62%) as a colorless oil: 1H
NMR (400 MHz) 7.33−7.24 (5H, m), 6.62−6.54 (1H, m), 5.86−5.82
(1H, m), 5.79 (2H, s), 4.66 (2H, d, J = 4.7 Hz), 4.49−4.44 (1H, m),
3.66 (3H, s), 3.62−3.56 (1H, m), 2.70 (2H, dd, J1 =9.8, 1.3 Hz), 2.33
(2H, dd, J = 6.1, 3.1 Hz); 13C NMR (125 MHz) 174.7, 165.6, 154.4,
140.0, 135.9, 128.6, 128.2, 127.7, 125.9, 123.3, 121.6, 60.4, 51.5, 42.3,
37.7, 35.9, 31.2; IR 3237, 2924, 2374, 1727, 1710, 1687, 1423, 1345,
1225, 1060; HRMS (ESI) calcd for C19H21N2O4 [M + H]+ 341.1501,
found 341.1505.
1-Allyl-3-benzyl-1,3-diazaspiro[4.4]non-7-ene-2,4-dione (9f).
Using the general procedure, compound 8a (50 mg, 0.16 mmol, 1.0
equiv) provided compound 9f (43.7 mg, 97%) as a colorless oil: H
1
NMR (400 MHz) 7.31−7.28 (2H, m), 7.25−7.16 (3H, m), 5.72−5.70
(2H, m), 5.42−5.31 (1H, m), 5.02−5.00 (1H, m), 4.92−4.89 (1H, m),
4.58 (2H, s), 4.37−4.32 (1H, m), 3.54−3.48 (1H, m), 2.47 (2H, d, J =
9.1 Hz), 2.23 (2H, d, J = 4.3 Hz); 13C NMR (125 MHz) 175.4, 154.4,
136.1, 130.3, 128.5, 128.4, 127.7, 123.1, 121.9, 120.4, 60.7, 42.1, 37.6,
37.6, 30.9; IR (KBr) 3437, 2925, 2364, 1767, 1710, 1587, 1443, 1355,
1125, 1070; HRMS (ESI) calcd for C17H19N2O2 [M + H]+ 283.1447,
found 283.1429.
Preparation of Olefin 13. To a solution of dimer 11 (20 mg,
0.037 mmol, 1.0 equiv) and methyl acrylate (32 mg, 0.370 mmol, 10.0
equiv) in CH2Cl2 (4 mL) was added HG-II (1.3 mg, 0.002 mmol, 5
mol %), and the mixture was stirred at 45 °C for 72 h. The reaction
mixture was concentrated and purified on silica gel (ethyl acetate−
hexane, 5/95 to 20/80) to yield 13 (10 mg, 79%) as a colorless oil: 1H
NMR (500 MHz) 7.34−7.27 (5H, m), 6.59 (1H, td, J = 7.7, 15.4 Hz),
5.84 (1H, td, J = 101, 15.5 Hz), 5.80−5.79 (2H, m), 4.66 (2H, d, J =
5.4 Hz), 4.47 (1H, dd, J = 1.7, 17.9 Hz), 3.67 (3H, s), 3.63−3.57 (1H,
m), 2.70 (2H, dd, J = 1.2, 7.7 Hz), 2.35−2.33 (2H, m); 13C NMR (125
MHz) 174.8, 165.7, 154.4, 140.1, 136.0, 128.7, 128.2, 127.7, 126.0,
123.4, 121.7, 60.4, 51.6, 42.3, 37.8, 36.0, 31.2; IR 3460, 3285, 3032,
2905, 2752, 2369, 1863, 1780, 1625, 1437, 1280, 1150, 1042; HRMS
(ESI) calcd for C19H21N2O4 [M + H]+ 341.1501, found 341.1505.
Preparation of Bicyclohydantoin Derivatives 14 by RCM. To
a stirring solution of 7 (0.2 mmol, 1 equiv) in toluene (3.0 mL) was
added G-II (3.4 mg, 0.004 mmol, 2 mol %), and the mixture was
stirred for 8 h at 80 °C. The reaction mixture was then concentrated
and purified on silica gel (EtOAc−hexane, 10/90 to 20/80) to give
compound 14.
1-Allyl-3-benzyl-7-methyl-1,3-diazaspiro[4.4]non-7-ene-2,4-
dione (9g). Using the general procedure, compound 8b (50 mg, 0.15
mmol, 1.0 equiv) provided compound 9g (42.6 mg, 96%) as a
colorless oil: H NMR (400 MHz) 7.38−7.34 (2H, m), 7.30−7.23
1
(3H, m), 5.76 (2H, s), 4.67−4.68 (1H, m), 4.64 (3H, s), 4.42−4.37
(1H, m), 3.65−3.59 (1H, m), 2.53 (2H, s), 2.28−2.26 (2H, m), 1.42
(3H, s); 13C NMR (100 MHz) 175.6, 154.7, 139.2, 135.9, 128.6, 128.4,
127.7, 123.1, 121.8, 116.1, 60.7, 42.2, 41.2, 37.9, 32.1, 23.0; IR (KBr)
3437, 2926, 1708, 1441, 1132, 1018, 746, 699; HRMS (ESI) calcd for
C18H21N2O2 [M + H]+ 297.1603, found 297.1609.
tert-Butyl 2,4-dioxo-1,3-diazaspiro[4.4]non-7-ene-3-carboxylate
(9h). Using the general procedure, compound 6b (50 mg, 0.18
mmol, 1.0 equiv) provided compound 9h (44.5 mg, 98%) as a
colorless solid: mp 178−179 °C; 1H NMR (400 MHz) 8.56 (1H, sbr),
5.71 (2H, s), 2.94 (4H, s), 1.50 (9H, s); 13C NMR (100 MHz) 175.9,
151.7, 147.9, 127.9, 84.6, 69.1, 43.5, 28.0; IR (KBr) 3237, 3026, 2922,
1708, 1622, 1441, 1232, 1132, 1018, 742, 629; HRMS (ESI) calcd for
C12H17N2O4 [M + H]+ 253.1188, found 253.1190.
Preparation of 1-Aminocyclopent-3-enecarboxylic acid (10).
To a solution of tert-butyl 2,4-dioxo-1,3-diazaspiro[4.4]non-7-ene-3-
8079
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2-Allyl-8,8a-dihydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione
(14a). Using the general procedure, compound 7a (40 mg, 0.18 mmol,
1.0 equiv) provided compound 14a (29.4 mg, 85%) as a colorless oil:
1H NMR (400 MHz) 5.86−5.76 (3H, m), 5.24−5.16 (2H, m), 4.37−
4.32 (1H, m), 4.12−4.09 (2H, dt, J = 2.8, 1.7 Hz), 3.94 (1H, dd, J =
13.5, 6.7 Hz), 3.74−3.67 (1H, m), 2.65−2.58 (1H, m), 2.22−2.14
(1H, m); 13C NMR (100 MHz) 172.9, 154.6, 131.2, 123.7, 122.5,
117.9, 53.3, 40.5, 39.1, 25.9; IR (KBr) 3428, 3064, 2923, 2905, 1721,
1710, 1624, 1432, 1224, 1047, 963, 928; HRMS (ESI) calcd for
C10H13N2O2 [M + H]+ 193.0977, found 193.0981.
removed, and the reaction was stirred for an additional 15 min. The
reaction was then quenched by addition of saturated aqueous
NaHCO3. The mixture was extracted with CH2Cl2. The combined
organic phases were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated. The crude residue was then purified by
column chromatography on silica gel with EtOAc−hexane (5/95 to
20/80) to give compounds 16 and 19, respectively.
4,5-Diallyl-1,3-dibenzylimidazolidin-2-one (16). Using the general
procedure, compound 15 (1.0 g, 3.1 mmol, 1.0 equiv) provided
1
compound 16 (837 mg, 78%) as colorless oil: H NMR (500 MHz)
7.38−7.33 (5H, m), 7.31−7.27 (5H, m), 5.53−5.45 (2H, m), 4.99
(2H, d, J = 10.2 Hz), 4.96 (1H, s), 4.94−4.90 (3H, m), 4.02 (2H, d, J
= 15.3 Hz), 3.20−3.18 (2H, m), 2.16 (4H, d, J = 6.0 Hz); 13C NMR
(125 MHz) 159.4, 137.0, 132.1, 128.3, 127.9, 127.1, 118.7, 55.1, 45.1,
35.9; IR (KBr) 3416, 3064, 3030, 2921, 2358, 1710, 1453, 1359, 1242,
1142, 1078, 1028, 996; HRMS (ESI) calcd for C23H27N2O [M + H]+
347.2123, found 347.2139.
1,3,4-Triallylimidazolidin-2-one (18). Using the general procedure,
compound 2d (1.0 g, 5.6 mmol, 1.0 equiv) provided compound 18
(692 mg, 60%) as colorless oil: 1H NMR (500 MHz) 5.77−5.64 (3H,
m), 5.21−5.09 (6H, m), 4.15−4.10 (1H, dt, J = 15.7, 4.9 Hz), 3.84−
3.79 (1H, dt, J = 15.4, 6.0 Hz), 3.76−3.74 (1H, dt, J = 15.4, 6.2 Hz),
3.62−3.55 (2H, m), 3.30 (1H, t, J = 8.8 Hz), 2.94 (1H,dd, J = 8.9, 7.1
Hz), 2.45−2.40 (1H, m), 2.21−2.15 (1H, m); 13C NMR (125 MHz)
160.2, 133.7, 133.5, 132.6, 118.5, 117.5, 117.4, 52.0, 47.4, 46.8, 44.5,
36.5; IR (KBr) 3443, 2922, 2351, 1647, 1539, 1270, 1116, 1053, 772,
665; HRMS (ESI) calcd for C12H19N2O [M + H]+ 207.1497, found
207.1493.
2-Benzyl-8,8a-dihydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione
(14b). Using the general procedure, compound 7b (50 mg, 0.19 mmol,
1.0 equiv) provided compound 14b (38.6 mg, 84%) as a colorless oil:
1H NMR (400 MHz) 7.42−7.39 (2H, m), 7.34−7.26 (3H, m), 5.89−
5.83 (1H, m), 5.80−5.75 (1H, m), 4.67 (2H, s), 7.38−4.33 (1H, m),
3.94 (1H, dd, J = 13.5, 6.6 Hz), 3.74−3.67 (1H, m), 2.65−2.56 (1H,
m), 2.21−2.12 (1H, m); 13C NMR (100 MHz) 172.9, 154.7, 136.2,
128.6, 128.6, 127.8, 123.8, 122.5, 53.4, 42.2, 39.2, 26.0; IR (KBr) 3458,
3072, 2953, 2925, 1761, 1710, 1634, 1442, 1424, 1147, 983, 918;
HRMS (ESI) calcd for C14H15N2O2 [M + H]+ 243.1134, found
243.1138.
2-Benzyl-6,7-dimethyl-8,8a-dihydroimidazo[1,5-a]pyridine-1,3-
(2H,5H)-dione (14c). Using the general procedure, compound 7c (50
mg, 0.17 mmol, 1.0 equiv) provided compound 14c (23.4 mg, 51%) as
1
a colorless oil: H NMR (500 MHz) 77.41−7.39 (2H, m), 7.33−7.25
(3H, m), 4.66 (2H, d, J = 2.6 Hz), 4.17 (1H, d, J = 17.7 Hz), 3.93 (1H,
dd, J = 11.1, 5.5 Hz), 3.53 (1H, d, J = 16.7 Hz), 2.40 (1H, dd, J = 16.5,
5.3 Hz), 2.17−2.10 (1H, m), 1.70 (3H, s), 1.66 (3H, s); 13C NMR
(125 MHz) 173.2, 154.6, 136.3, 128.6, 128.5, 127.8, 122.7, 122.4, 54.2,
43.2, 42.2, 31.7, 18.9, 15.9; IR (KBr) 3448, 3062, 2943, 2915, 1751,
1730, 1534, 1432, 1414, 1147, 973, 928; HRMS (ESI) calcd for
C16H19N2O2 [M + H]+ 271.1447, found 271.1442.
Preparation of 1,3-Dibenzyl-3a,4,7,7a-tetrahydro-1H-benzo-
[d]imidazol-2(3H)-one (17). To a solution of 16 (0.14 mmol, 1.0
equiv) in CH2Cl2 (4 mL) was added G-II (2.5 mg, 0.003 mmol, 2 mol
%), and the mixture was stirred for 8 h at room temperature. The
reaction mixture was then concentrated and purified on silica gel
(EtOAc−hexane, 10/90 to 20/80) to give compound 17 (44 mg,
(Z)-2-Benzyl-5,6,9,9a-tetrahydro-1H-imidazo[1,5-a]azepine-
1,3(2H)-dione (14d). Using the general procedure, compound 7d (50
mg, 0.18 mmol, 1.0 equiv) provided compound 14d (20.7 mg, 45%) as
1
99%) as a colorless crystal (EtOAc/hexane): mp 137−139 °C; H
1
NMR (500 MHz) 7.36 (4H, d, J = 4.5 Hz), 7.32−7.30 (1H, m), 5.56
(1H, d, J = 3.3 Hz), 4.61 (1H, d, J = 15.0 Hz), 4.38 (1H, d, J = 15.0
Hz), 2.96−2.93 (1H, m), 2.25−2.20 (1H, m), 1.95−1.90 (1H, m) ;
13C NMR (125 MHz) 163.1, 137.3, 128.4, 128.3, 127.2, 125.0, 57.1,
colorless oil: H NMR (500 MHz) 7.34−7.32 (2H, m), 7.27−7.19
(3H, m), 5.91−5.87 (1H, m), 5.84−5.82 (1H m), 4.59 (2H, s), 4.02−
3.98 (1H, m), 3.80 (1H, dd, J = 11.4, 2.5 Hz), 2.98−2.93 (1H, m),
2.70−2.64 (1H, m), 2.29−2.17 (3H, m); 13C NMR (125 MHz) 172.0,
155.4, 136.2, 132.2, 128.6, 128.6, 127.9, 127.7, 59.4, 42.4, 41.0, 31.0,
27.8; IR (KBr) 3243, 2905, 2844, 2328, 1780, 1415, 1328, 1181, 1005,
928, 749, 701; HRMS (ESI) calcd for C15H17N2O2 [M + H]+
257.1290, found 257.1286.
47.1, 29.7; IR (KBr) 3422, 2911, 2334, 1720, 1355, 1236, 1126, 1116,
1053, 772, 665; HRMS (ESI) calcd for C21H23N2O [M + H]+
319.1810, found 319.1817.
Preparation of 2-Allyl-1,2,8,8a-tetrahydroimidazo[1,5-a]-
pyridin-3(5H)-one (19). To a solution of 18 (50 mg, 0.24 mmol,
1.0 equiv) in CH2Cl2 (4 mL) was added G-II (4 mg, 0.005 mmol, 2
mol %), and the mixture was stirred for 8 h at room temperature. The
reaction mixture was then concentrated and purified on silica gel
(EtOAc−hexane, 10/90 to 20/80) to give compound 19 (26 mg,
(Z)-2-Benzyl-5,6,10,10a-tetrahydroimidazo[1,5-a]azocine-1,3-
(2H,9H)-dione (14e). Using the general procedure, compound 7e (50
mg, 0.17 mmol, 1.0 equiv) provided compound 14e (21.6 mg, 47%) as
1
colorless oil: H NMR (400 MHz) 7.34−7.31 (2H, m), 7.26−7.16
(3H, m), 5.80−5.73 (1H, m), 5.60−5.52 (1H, m), 4.59 (2H, s), 4.20−
4.14 (1H, m), 3.90−3.85 (2H, m), 2.26−2.18 (1H, m), 2.13−2.06
(2H, m), 1.74−1.61 (2H, m), 1.45−1.35 (1H, m); 13C NMR (100
MHz) 173.0, 155.3, 136.2, 132.5, 128.6, 127.8, 124.8, 61.1, 42.6, 38.5,
28.5, 24.7, 24.6; IR (KBr) 3443, 2945, 2644, 2428, 1750, 1415, 1228,
1171, 1105, 958, 749, 701; HRMS (ESI) calcd for C16H19N2O2 [M +
H]+ 271.1447, found 271.1443.
1
60%) as a colorless oil: H NMR (400 MHz) 5.79−5.71 (3H, m),
5.22−5.15 (2H,m), 4.18−4.12 (1H, m), 3.82 (2H, d, J = 7.57 Hz),
3.60−3.54 (2H, m), 3.46 (1H, t, J = 10.3 Hz), 2.97 (1H, dd, J = 10.7,
6.7 Hz), 2.17−2.13 (2H, m) ; 13C NMR (125 MHz) 164.8, 133.6,
124.8, 123.5, 117.5, 49.5, 48.4, 46.8, 40.8, 29.7; IR 3433, 2912, 2341,
1657, 1549, 1260, 1126, 1043, 772, 665; HRMS (ESI) calcd for
C10H15N2O [M + H]+ 179.1184, found 179.1158.
General Procedure for the Preparation of 4,5-Diallyl-1,3-
dibenzylimidazolidin-2-one 16 and 1,3,4-triallylimidazolidin-
2-one 18. A 1 M solution of DIBAL-H in toluene (10.0 mL, 10.0
mmol) was added dropwise over 30 min to a stirred solution of 15 and
2d (1.0 g, 3.1 mmol) in THF (50 mL) at −78 °C. The reaction
mixture was stirred for 4 h, and MeOH (0.60 mL, 13 mmol) was
added dropwise over 15 min. The reaction was poured into saturated
NH4Cl (50 mL) with vigorous stirring for 1 h, and then the layers
were separated. The aqueous layer was extracted with EtOAc, and the
combined organic layers were washed with saturated NaCl, dried with
Na2SO4, and concentrated under reduced pressure. The residual
solvent was removed under high vacuum for 1 h. The crude mixture
was dissolved in CH2Cl2 (30 mL) under argon and cooled to −78 °C.
Allyltrimethylsilane (2.0 mL, 13 mmol) was added in one portion with
stirring, and then BF3−OEt2 (1.6 mL, 13 mmol) was added dropwise
over 10 min. Stirring was continued for 8 h, the ice bath was then
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data and NMR spectra of all synthetic
compounds, and X-ray crystallographic data (CIF) of 9e, 11,
and 17. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: +91-33-2587-3020. Tel: +91-33-2587-3119. E-mail:
jyotidash@iiserkol.ac.in.
8080
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The Journal of Organic Chemistry
Article
Mukherjee, M. Cryst. Growth Des. 2010, 10, 4476. (c) Park, Y. S.; Seo,
S.; Kim, E.-H.; Paek, K. Org. Lett. 2011, 13, 5904.
(11) Jamieson, A. G.; Russell, D.; Hamilton, A. D. Chem. Commun.
Notes
The authors declare no competing financial interest.
2012, 48, 3709.
ACKNOWLEDGMENTS
■
(12) For recent examples on synthesis of substituted hydantoins:
(a) Beller, M.; Eckert, M.; Moradi, W.; Neumann, H. Angew. Chem.,
Int. Ed. 1999, 38, 1454. (b) Chowdari, N. S.; Barbas, C. F., III Org.
Lett. 2005, 7, 867. (c) Gao, M.; Yang, Y.; Wu, Y.-D.; Deng, C.; Shu,
W.-M; Zhang, D.-X.; Cao, L.-P.; She, N.-F.; Wu, A.-X. Org. Lett. 2010,
12, 4026. (d) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Nicolini, S.;
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We thank DST India for funding. K.D. thanks UGC and
G.C.M. thanks CSIR for a research fellowship.
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