The preparation and characterization of nineteen new phthalidyl spirohydantoins

Article abstract of DOI:10.3987/COM-07-S(U)9

Abstract - Nineteen new N,N-disubstituted phthalidyl spirohydantoins (6a-s) were prepared for the purpose of pharmacological testing. Their structure was deduced from the IR, ¹H-NMR, ¹³C-NMR, mass spectra and elemental analysis. The two possible structural isomers - only one of which is formed - can be distinguished unequivocally on the basis of selective diastereotopicity of the α-methylene hydrogens adjacent to N-3′ of the hydantoin ring.

Full text of DOI:10.3987/COM-07-S(U)9

HETEROCYCLES, Vol. 73, 2007
349
HETEROCYCLES, Vol. 73, 2007, pp. 349 - 375. © The Japan Institute of Heterocyclic Chemistry
Received, 12th May, 2007, Accepted, 25th June, 2007, Published online, 29th June, 2007. COM-07-S(U)9
THE PREPARATION AND CHARACTERIZATION OF NINETEEN NEW
PHTHALIDYL SPIROHYDANTOINS
István Lengyel,*,a Hardik J. Patel,b and Ralph A. Stephani a,b
aDepartment of Chemistry and bDepartment of Pharmaceutical Sciences, St.
John’s University, 8000 Utopia Parkway, Jamaica, New York 11439, USA.
*Corresponding author: Tel: +1-718-990-6291; fax: +1-718-990-1876; e-mail
address: hardik.patel01@stjohns.edu
This paper is dedicated to the memory of Professor Ivar Ugi, a great chemist, a
noble man and a good friend.
Abstract - Nineteen new N,N’-disubstituted phthalidyl spirohydantoins (6a-s)
were prepared for the purpose of pharmacological testing. Their structure was
1
13
deduced from the IR, H-NMR, C-NMR, mass spectra and elemental analysis.
The two possible structural isomers – only one of which is formed – can be
distinguished unequivocally on the basis of selective diastereotopicity of the α-
methylene hydrogens adjacent to N-3’ of the hydantoin ring.
1. INTRODUCTION
In a short communication some of us recently reported1 the synthesis and pharmacological activity of
thirteen phthalidyl spirohydantoins, albeit without experimental details and without physical and spectral
properties of the products. Herein we give full characterization of nineteen new spirohydantoins (6,
Scheme 1) and detailed experimental procedure of their synthesis.
2. RESULTS AND DISCUSSION
A. Synthesis
These compounds were synthesized in three previously reported steps, outlined in Scheme 1: the ureas
not commercially available were prepared by the addition of a primary amine (2) to the appropriately
substituted isocyanate (1)2. The disubstituted ureas (3) were then reacted with ninhydrin (4) to give
4
indeno[1,2-d]imidazolidine-2,8-diones (5)3, the oxidation of which with NaIO4 yielding exclusively one
regioisomer of the N,N’-disubstituted phthalidyl spirohydantoins (6).

350
HETEROCYCLES, Vol. 73, 2007
Scheme 1. The synthesis of N,N’-disubstituted phthalidyl spirohydantoins, 6.
O
dry THF
0-5 0C
R1 N C O
1
H2N R2
R1 N
H
N R2
H
2
3
primary amine
isocyanate
N,N'-disubstituted urea
O
OH
OH
C6H6
reflux, 45 min.
4
O
ninhydrin
O
O
OH
R1
O
O
NaIO4
N
C
4'
aqueous
alcohol
5'
O
N
3'
N
1'
HO
N
2'
R2
R1
R2
O
5
6
indeno[1,2-d]-
imidazolidine-2,8-dione
N,N'-disubstituted
phthalidyl spirohydantoin
If unsymmetrically substituted ureas (R1 ≠R2) are used in the synthesis, two structural isomers are possible,
6 and 7 (Scheme 2), which differ from one another only in the site of attachment of the nitrogen
substituents. Selective diastereotopicity of the α-methylene hydrogens adjacent to N-3’ revealed that the
actual structure of the product is 6 (vide infra).
Scheme 2. The two possible structures of N,N’-disubstituted phthalidyl spirohydantoins, 6 and 7.
O
O
O
O
O
O
C
4'
C
4'
5'
5'
1'
3'
N
3'
1'
N
N
N
2'
2'
R1
R2
R2
R1
O
O
7
6

HETEROCYCLES, Vol. 73, 2007
351
The apparent reason why only one of the two possible structural isomers is formed in the condensation
reactions of the ureas with ninhydrin is that, as a rule, the more basic nitrogen of the unsymmetrically
disubstituted ureas (3) attacks the less electrophilic carbon of ninhydrin (4), and the less basic nitrogen
attacks the more electrophilic carbon. This principle can be illustrated by the reaction of N-ethyl-N’-
phenylurea (3e) with ninhydrin, which gave only adduct 5e, Scheme 3. No trace of the isomer 5e’ has
been detected.
Scheme 3. In the urea-ninhydrin condensation reactions the more basic nitrogen of the urea attacks the
less electrophilic carbon of the ninhydrin, giving a single product, eg. 5e.
O
OH
N
O
N
HO
less basic
nitrogen
more electrophilic
carbon
H2C
CH3
5e
(sole product)
C18H16N2O4
-H2O
O
H
H
N
N
OH
O
OH
O
CH3
O
X
OH
CH2
CH2
H3C
N
more basic
nitrogen
less electrophilic
carbon
O
N
HO
4
3e
5e'
(absent)
C18H16N2O4
ninhydrin
C9H6O4
N-ethyl,N'-phenylurea
C9H12N2O4
We prepared seventeen N,N’-disubstituted phthalidyl spirohydantoins by the synthesis outlined in Scheme
1, and recorded their 1H-NMR spectra. All show diastereotopicity in the α-methylene protons attached to
N-3’, while none show diastereotopicity in the α-methylene group attached to N-1’. The chemical shift
values, signal multiplicities, integration and coupling constants of the α-methylene protons in the 400
MHz 1H-NMR spectra of the seventeen phthalidyl spirohydantoins prepared are listed in Table 1.

352
HETEROCYCLES, Vol. 73, 2007
Table 1. The chemical shift values , δ (ppm), signal multiplicities, integration and coupling constants, J
(Hz), of the α-methylene protons in the 400 MHz 1H-NMR spectra of seventeen N,N’-disubstituted
phthalidyl spirohydantoins 6.
N-1'-α-Methylene (R1)
N-3'-α-Methylene (R2)
Compound
No.
multiplicity &
integration
multiplicity &
integration
δ ppm
δ ppm
R1
R2
J (Hz)
J (Hz)
7.3
6a
6b
6c
6d
6e
6f
C2H5
C2H5
3.65
3.52
4.77
quartet 2H
triplet 2H
singlet 2H
7.2
3.06
3.34
2.89
3.29
sextet 1H
sextet 1H
quintet 1H
quinlet 1H
doublet 1H
doublet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
sextet 1H
septet 1H
septet 1H
quintet 1H
quintet 1H
doublet 1H
doublet 1H
doublet 1H
doublet 1H
doublet 1H
doublet 1H
septet 1H
7.3
n-C3H7
n-C3H7
CH2C6H5
C2H5
7.0
7.2
7.4
CH2C6H5
CH3
N.A.* 4.28
4.49
3.00
3.28
3.14
3.39
3.15
3.42
3.13
3.38
3.14
3.37
3.16
3.40
3.11
3.37
3.00
3.36
2.88
3.26
4.34
4.57
4.24
4.46
16.0
16.0
7.3
7.4
C6H5
C2H5
7.1
7.1
o-F-C6H4
m-F-C6H4
p-F-C6H4
p-O2N-C6H4
C2H5
7.2
7.3
6g
6h
6i
C2H5
7.2
7.2
C2H5
7.3
7.3
C2H5
7.2
7.3
6j
p-CH3O-C6H4 C2H5
7.1
7.3
6k
6l
CH3
C6H5
CH3
C6H5
n-C3H7
6.8
8.0
n-C3H7
7.3
8.0
6m
6n
6o
6p
6q
CH2C6H5
CH2C6H5
15.8
15.8
16.0
16.0
15.9
15.9
6.8
CH2CH2C6H5 CH2C6H5
3.86
3.56
3.22
triplet 2H
quartet 2H
singlet 2H
6.9
4.22
4.36
3.38
C2H5
CH(CH3)2
CH(CH3)2
7.2
CH2C(CH3)3
N.A.* 3.37
septet 1H
6.8
N.A.* = Not applicable
It should be noted that in our spectra none of the spin-spin multiplets of the diastereotopic hydrogens are
sufficiently resolved to exhibit the theoretically calculated number of lines. However, this partial

HETEROCYCLES, Vol. 73, 2007
353
degeneracy of the multiplets of the diastereotopic protons does not hamper interpretation. The
phenomenon can perhaps be best illustrated with the dibenzyl derivative 6c, which does not contain
hydrogen-substituted β-alkyl carbons either on R1 or R2, its spectrum (Figure 1) therefore is not
complicated by additional signal multiplicity.
Figure 1. The 400 MHz 1H-NMR spectrum of N-1’,N-3’-dibenzyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-
imidazolidine]-2’,3,5’-trione 6c.
* chiral center
O
O
O
*
4'
5'
Hb
3'
N
c
b
a
1'
N
2'
CH
2
c
Ha
O
6c
4.5
8.2
8.0
7.8
7.6
7.4
7.2
ppm
ppm
DMSO-d6
c
b a
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
ppm
The indeno[1,2-d]imidazolidine-2,8-dione intermediates (5), all of which contain two chiral centers, also
exhibit diastereotopicity. Indeed, both the α- and β-methylene protons, where present, are diastereotopic,
1
in both the R1 and R2 substituents (compare the H-NMR spectra in the Experimental). For this reason,
1
their diastereotopicity cannot be used for structure assignment. The H-NMR spectra of those
spirohydantoins which contain at least two adjacent methylene groups in R2 (6b, 6k, 6l, 6r and 6s), also
show diastereotopicity of the β-methylene protons e.g., 6r, Scheme 4.

354
HETEROCYCLES, Vol. 73, 2007
Scheme 4. Both the α- and β-methylene protons in N-1’-phenyl-N-3’-(2-phenylethyl)-2’H,3H,5’H-spiro-
[benzofuran-1,4’-imidazolidine]-2’,3,5’-trione, 6r, are diastereotopic.
* chiral center
O
R2 α-CH2:
a: 3.28 δ, septet, 1H
b: 3.60 δ, septet, 1H
R2 β-CH2:
c: 2.74 δ, sextet, 1H
d: 2.83 δ, sextet, 1H
O
O
4'
3'
5'
Ha
Hc
N
1'N
2'
Hb
O
Hd
6r
At this point, the following question arose: would replacement of the two α-hydrogens in 6r with
deuterium affect the diastereotopicity of the β-methylene protons? To address this question, we
synthesized
N-1’-phenyl-N-3’-(α,α-dideuterio-2-phenylethyl)-2’H,3H,5’H-spiro[benzofuran-1,4’-
imidazolidine]-2’,3,5’-trione, 6s. The required precursor for the synthesis of 6s was α,α-dideuterio-2-
phenylethylamine (2s) which was prepared from phenylacetonitrile with LiAlD4 in ether, followed by
1
hydrolysis of the resulting N,N-α,α-tetradeuterio-2-phenylethylamine (2s’) (Scheme 5)5. The H-NMR
spectrum of this compound, 6s, (Figure 2) shows two symmetrical doublets, centered at 2.71 and 2.80
ppm, respectively, each for one hydrogen, with a coupling constant of 13.5-13.6 Hz, demonstrating that
the β-methylene protons retained their diastereotopicity even in the absence of an α-CH2 group.
Simultaneously, the spectrum also proves that the α,α-dideuterio-2-phenylethyl substituent is attached to
N-3’ of the ring and that the structure of 6s is the one depicted in Figure 2.
Scheme 5. The synthesis of α,α-dideuterio-2-phenylethylamine (2s) from phenylacetonitrile.
LiAlD4
CH2 C N
CH2 CD2 ND2
dry ether
2s'
phenylacetonitrile
H2O
CH2 CD2 NH2
2s

HETEROCYCLES, Vol. 73, 2007
355
1
Figure 2. The 400 MHz H-NMR spectrum of N-1’-phenyl-N-3’-(α,α-dideuterio-2 phenylethyl)-
2’H,3H,5’H-spiro [benzofuran-1,4’-imidazolidine]-2’,3,5’-trione, 6s.
• chiral center
d
c
2.8
8.4
8.2
8.0
7.8
7.6
7.4
7.2
ppm
ppm
O
O
O
*
3'
4'
5'
1'
N
Hc
N
2'
CD2
DMSO-d6
O
Hd
4.5
6s
4.0
8.0
7.5
7.0
6.5
6.0
5.5
5.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
ppm
The chemical shift values, signal multiplicities, integration and coupling constants of the five
spirohydantoins which contain a β-methylene group in R2 are listed in Table 2.
Table 2. The chemical shift values , δ (ppm), signal multiplicities, integration and coupling constants, J
(Hz), of the β-methylene protons of R2 in five spirohydantoins, (6b, 6k, 6l, 6r, 6s).
β-Methylene (R2)
Compound
No.
multiplicity &
integration
R1
R2
δ (ppm)
J (Hz)
6b
CH2CH2CH3
CH2CH2CH3
1.32
dodecet, 2H
7.2
6k
6l
CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2C6H5
1.31
1.45
dodecet, 2H
nonet, 2H
6.9
7.1
C6H5
C6H5
6r
2.74
2.83
sextet, 1H
sextet, 1H
6.9
7.0
6s
C6H5
CD2CH2C6H5
2.71
2.80
doublet, 1H
doublet, 1H
13.6
13.5

356
HETEROCYCLES, Vol. 73, 2007
B. Structure Determination
The structure of the spirohydantoins was derived from infrared, NMR, mass spectra and elemental
analysis data. All compounds gave satisfactory elemental analysis values, within ± 0.25% of the
calculated ones.
A) Infrared Spectra
Scheme 6. The infrared absorption bands of the three carbonyl bonds in spirohydantoins 6.
spirolactone
O
1792-1803 cm-1
O
O
spirolactam
1780-1792 cm-1
N
N
R2
R1
O
urea
1720-1745 cm-1
As listed in the Experimental section, the three carbonyl groups in the spirohydantoins show absorption
bands in the following infrared ranges:
1. α, β-unsaturated γ-spirolactone: 1792-1803 cm-1
2. spirolactam carbonyl: 1780-1792 cm-1
3. urea: 1720-1745 cm-1
These values are well compatible with the proposed structure.
B) NMR Spectra
Diastereotopicity is well known and has been studied extensively; there are many examples reported in
the literature.6-11 The decisive criterion is the absence of symmetry elements. Diastereotopicity occurs
when geminal protons have neither a rotation axis, nor a plane of symmetry, nor a center of symmetry, nor
a rotation-reflection axis.11
Inspection of large molecular models of several spirohydantoins reveals the dissymmetric environment of
the α-methylene protons adjacent to N-3’. The CACHE® molecular model confirms this (Figure 3). It is
harder however, to discern the symmetry element causing the magnetic and stereochemical equivalence of
the other α-methylene hydrogens, adjacent to N-1’.

HETEROCYCLES, Vol. 73, 2007
357
Figure 3. The CACHE® molecular model of N-1’,N-3’-diethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-
imidazolidine]-2’,3,5’-trione, 6a.
C) Mass Spectra
The major primary fragmentation pathways of the molecular ions of the spirohydantoins prepared support
and corroborate the proposed structure. Loss of carbon monoxide, carbon dioxide and an alkyl or aryl
isocyanate constitute the predominant primary fragmentation paths, followed by ejection of a second
molecule of CO2 and RNCO (Scheme 7).
Scheme 7. Characteristic mass spectrometric fragmentation of phthalidyl spirohydantoins of type 6.
-CO2
(M-44)
M
-CO
(M-28)
-R2NCO
R1NCO
(M-CO-R2NCO)
-CO2
(M-CO-R2NCO-CO2)
O
-C2H2
-CH2NCO
(56)
-CO
C O
C4H2
C6H4
O
(26)
(28)
m/z 50
m/z 76
m/z 104
N
H2C
m/z 160
(C9H6NO2)

358
HETEROCYCLES, Vol. 73, 2007
Fragment ion m/z 160 (C9H6NO2) is present in the mass spectra of all spirohydantoins prepared, and is the
base peak in the spectra of eight of them. In the spectrum of the dideuterated derivative 6s it is shifted to
m/z 162, which confirms the structure and composition of this important ion (Scheme 7).
All new ureas (3), indeno[1,2-d]imidazolones (5), and phthalidyl spirohydantoins (6) synthesized during
1
13
this study were characterized by a detailed and complete interpretation of the IR, H-NMR, C-NMR,
APT (Attached Proton Test), and mass spectra. To illustrate how the structures of the spirohydantoins
were determined, we provide a summary of the spectra interpretation for compound 6d below:
Scheme 8. IR and NMR Spectra of 6d.
1794 cm-1
1785 cm-1
IR (KBr): 1794, 1785, 1732 cm-1
Hh
O
1H-NMR (DMSO-d6):
a: 0.93, t, 3H
b: 3.00, sextet, 1H
c: 3.28, sextet, 1H
d: 3.36, s, 3H
e: 7.79, d, 1H
f: 7.84, t, 1H
g: 7.94, t, 1H
h: 8.05, d, 1H
Hf
O
O
Hg
He
Hc
N
N
CH3 d
1732 cm-1
aH3C H
b O
6d
13C-NMR (DMSO-d6) of 6d:
APT: CH3, CH ↑
O
i
j
k
CH2, C, C=O ↓
e
_________________________________
O
O
d
f
δ
APT
δ
APT
g
m
a:
b:
c:
15.20
26.13
35.65
↑
↑
↓
↓
h: 133.22 ↑
h
N
i:
j:
136.61 ↑
141.61 ↓
N
H2C
CH3
b
c
l
H3C
a
d: 93.53
e:
f:
k: 155.85 ↓
l: 167.51 ↓
m: 167.87 ↓
O
125.10 ↑
126.56 ↑
127.67 ↓
g:

HETEROCYCLES, Vol. 73, 2007
359
Scheme 9. The main mass spectrometric fragmentation pathways of spirohydantoin 6d.
O
O
O
C13H12N2O4
m.w. 260
N
N
6d
H3C H2C
CH3
O
.
C2H5
CO2
(44)
m/z 216
m/z 260 M
m/z 231
(44)
(29)
.
.
(15) CH3
(15)
CO2
CH3
CO2
(44)
m/z 201
m/z 245
C O
m/z 187
O
C
(85)
N
CH3
O
.
CO
CH2NCO
(56)
C6H4
C O
O
(28)
C
N
m/z 76
m/z 104
CH2
m/z 160
(base peak)
3. CONCLUSION
Nineteen new N-1’-N-3’-disubsituted phthalidyl spirohydantoins (6a-s) have been synthesized in three
steps. Their structure was determined from the infrared, 1H-NMR, 13C-NMR, mass spectra and elemental
analysis. An unequivocal distinction between two possible structural isomers - only one of which is
formed - could be made on the basis of selective diastereotopicity of the α-methylene hydrogens adjacent
to N-3’ of the hydantoin ring.
The same method is applicable to β-methylene groups too, if the α-carbon in the R2 substituent is
dideuterated.

360
HETEROCYCLES, Vol. 73, 2007
4. EXPERIMENTAL
Melting points were determined on a Thomas-Hoover Capillary Melting Point Apparatus and are
1
13
uncorrected. H and C NMR spectra were recorded on a Bruker 400 UltrashieldTM spectrophotometer
with tetramethylsilane as internal standard. Chemical shifts are reported in ppm (δ). IR spectra were
recorded on Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer. Mass spectra were recorded on a
Hewlett-Packard GC-MS GCD system. For column chromatography, JT Baker silica gel (40 microns)
was used. Thin layer chromatography (TLC) was performed with Analtech silica gel glass backed plates
(250 micron). Elemental analyses were performed by Atlantic Microlab Inc., Norcross, Georgia.
I. α,α-Dideuterio-2-phenylethylamine 2s
To a cooled solution of lithium aluminium deuteride 2.5 g (0.06 moles) in anhydrous Et2O(140 mL) was
slowly added phenylacetonitrile 7.03 g (0.06 moles) in Et2O(14 mL). After all of nitrile has been added,
ice-bath was removed and the mixture was stirred at rt for another hour. With continued cooling and
vigorous stirring, water(2.4 mL), 20% aqueous NaOH(1.8 mL) and water(8.4 mL) were slowly added in
succession. The ether solution was decanted from the white, granular inorganic residue. This residue was
washed twice with Et2O and the combined ether fractions were washed thoroughly with water in a
separatory funnel and dried. Pure product was obtained by distillation at 35 mm Hg with bp 112-113 ºC.
1
Yield: 21.35%. H-NMR (THF-d8): δ = 2.65 (s, 3H), 7.16 (d, 2H), 7.22 (t, 2H), 7.32 (t, 1H). 13C-NMR
(THF-d8): δ = 23.43, 41.26, 126.73, 129.13, 128.92, 129.83, 141.59.
II. General procedure for the preparation of N-1,N-3-disubstituted ureas
The appropriately substituted phenylisocyanate in THF(20 mL) was added dropwise to the appropriate
alkylamine at 0ºC with stirring. The ice-bath was removed after the completion of addition of the
isocyanate and the mixture was stirred at rt for 30 min then filtered with suction and the precipitate
washed with water. The products were allowed to air-dry.
1-Ethyl-3-methylurea 3d (R1 = C2H5, R2 = CH3)
Yield: 96.5%, mp 52-55 ºC (lit.,12 54-55 ºC). IR (KBr) ν: 3359, 1641 cm-1. MS: m/z 102 (M+), 87, 74, 58,
44, 30 (base peak).
1-Ethyl-3-phenylurea 3e (R1 = C2H5, R2 = C6H5)
Yield: 77.3%, mp 92-95 ºC (lit.,13 94-95 ºC). IR (KBr) ν: 3323, 1649 cm-1. MS: m/z 164 (M+), 135, 106,
93 (base peak), 77, 66, 44.

HETEROCYCLES, Vol. 73, 2007
361
1-Ethyl-3-(2’-fluorophenyl)urea 3f (R1 = C2H5, R2 = o-F-C6H4)
Yield: 91.4%, mp 112-116 ºC (lit.,14, 15 115-116 ºC). IR (KBr) ν: 3337, 1638 cm-1. MS: m/z 182 (M+),
153, 137, 111 (base peak), 95, 91, 83, 75, 64, 44.
1-Ethyl-3-(3’-fluorophenyl)urea 3g (R1 = C2H5, R2 = m-F-C6H4)
1
Yield: 91.8%, mp 111-113 ºC. IR (KBr) ν: 3327, 1650 cm-1. H-NMR (DMSO-d6): δ = 1.06 (t, 3H), 3.12
(quintet, 2H), 6.58 (s, 1H), 6.91 (d, 1H), 7.07 (t, 1H), 7.16 (t, 1H), 8.14 (t, 1H), 8.23 (s, 1H). 13C-NMR
(DMSO-d6): δ = 15.30, 33.92, 114.61, 120.15, 121.39, 124.32, 128.36, 150.39, 154.77. MS: m/z 182
(M+), 153, 137, 111 (base peak), 95, 83, 75, 63, 44. Anal. Calcd for C9H11FN2O4: C, 59.33; H, 6.09; N,
15.38. Found C, 59.38; H, 6.04; N, 15.19
1-Ethyl-3-(4’-fluorophenyl)urea 3h (R1 = C2H5, R2 = p-F-C6H4)
Yield: 75.3%, mp 173-175 ºC. IR (KBr) ν: 3326, 1632cm-1. MS: m/z 182 (M+), 153, 137, 111 (base
peak), 95, 83, 75, 44. Anal. Calcd for C9H11FN2O4: C, 59.33; H, 6.09; N, 15.38. Found C, 59.38; H,
6.04; N, 15.19.
1-Ethyl-3-(4’-nitrophenyl)urea 3i (R1 = C2H5, R2 = p-NO2-C6H4)
Yield: 94.6%, mp 157-160 ºC. IR (KBr) υ: 3326, 1632, 1559, 1339 cm-1. MS: m/z 209 (M+), 180, 165,
164, 138 (base peak), 122, 108, 90, 75, 65.
1-Ethyl-3-(4’-methoxyphenyl)urea 3j (R1 = C2H5, R2 = p-OCH3-C6H4)
Yield: 93.6%, mp 132-135 ºC. IR (KBr) υ: 3326, 1632, 1244, 1031 cm-1. MS: m/z 194 (M+), 149, 134,
123, 108 (base peak), 80, 65, 52.
1-Methyl-3-n-propylurea 3k (R1 = CH3, R2 = n-C3H7)
Yield: 98.0%, mp 59-61 ºC, (lit.,16 61-62 ºC). IR (KBr) υ: 3347, 2961, 1631 cm-1. MS: m/z 116 (M+),
101, 87, 74, 58 (base peak), 56, 44, 43, 40.
1-Phenyl-3-n-propylurea 3l (R1 = C6H5, R2 = n-C3H7)
Yield: 55.6%, mp 114-116 ºC (lit.,13, 15 113-114 ºC). IR (KBr) υ: 3325, 2961, 1644 cm-1. MS: m/z 178
(M+), 149, 135, 119, 93 (base peak), 77, 66, 65, 51, 43.
1-Benzyl-3-methylurea 3m (R1 = CH2C6H5, R2 = CH3):
Yield: 71.8%, mp 94-96 ºC (lit.,17 97-98 ºC). IR (KBr) υ: 3331, 1628 cm-1. MS: m/z 164 (M+), 134, 133,

362
HETEROCYCLES, Vol. 73, 2007
132, 106 (base peak), 91, 79, 77, 65, 58, 51, 39.
1-Benzyl-3-phenylurea 3n (R1 = CH2C6H5, R2 = C6H5):
Yield: 84.2%, mp 169-170 ºC (lit.,18 169-171 ºC). IR (KBr) υ: 3330, 1635 cm-1. MS: m/z 226 (M+), 133,
119, 106, 104, 93 (base peak), 91, 77, 66, 65, 51.
1-Benzyl-3-(2’-phenylethyl)urea 3o (R1 = CH2C6H5, R2 = CH2CH2C6H5)
Yield: 94.3%, mp 93-96 ºC (lit.,19, 20 95-96 ºC). IR (KBr) υ: 3345, 3030, 1626 cm-1. MS: m/z 254 (M+),
177, 163, 147, 133, 106, 104, 91 (base peak), 77, 65, 51.
1-Ethyl-3-i-propylurea 3p (R1 = C2H5, R2 = i-C3H7)
Yield: 60.2%, mp 153-155 ºC (lit.,13 155-157 ºC). IR (KBr) υ: 3341, 2970, 1625 cm-1. MS: m/z 130 (M+),
115, 73, 72, 58, 44 (base peak).
1-Neopentyl-3-i-propylurea 3q (R1 = CH2(CH3)3, R2 = i-C3H7)
1
Yield: 98.0%, mp 153-155 ºC. IR (KBr) υ: 3348, 2965, 1630 cm-1. H-NMR (DMSO-d6): δ = 0.81 (s,
9H), 1.01 (d, 6H), 2.75 (d, 2H), 3.66 (septet, 1H), 5.63 (d, 1H), 5.72 (t, 1H). 13C-NMR (DMSO-d6): δ =
22.96, 23.60, 23.98, 26.83, 27.31, 31.81, 41.35, 50.44, 157.71. MS: m/z 172 (M+), 157, 117, 116, 115,
101 (base peak), 86, 72, 58, 57, 44. Anal. Calcd for C9H20N2O: C, 62.75; H, 11.70; N, 16.26. Found C,
62.82; H, 11.71; N, 16.26.
1-(2’-Phenylethyl)-3-phenylurea 3r (R1 = CH2CH2 C6H5, R2 = C6H5)
Yield: 97.7%, mp 152-154 ºC (lit.,21, 22 153.5-154.5 ºC). IR (KBr) ν: 3346.53, 1647 cm-1. MS: m/z 240
(M+), 149, 147, 136, 119, 105, 93 (base peak), 91, 77, 65, 51.
1-(α,α-Dideuterio-2-phenylethyl)-3-phenylurea 3s (R1 = CH2CD2C6H5, R2 = C6H5)
1
Yield: 93.5%, mp 152-153 ºC. IR (KBr) ν: 3304, 1645, 1595, 1564 cm-1. H-NMR δ = 2.73 (s, 2H), 6.09
(s, 1H), 6.88 (t, 1H), 7.19-7.25 (multiplet, 5H), 7.31 (t, 2H), 7.38 (d, 2H), 8.47 (s, 1H). 13C-NMR
(DMSO-d6): δ = 36.06, 41.32, 120.38, 121.49, 123.30, 124.26, 126.63, 127.68, 137.81, 138.81, 157.52.
MS: m/z 242 (M+), 151, 149, 136, 135, 119, 107, 93 (base peak), 91, 77, 65, 51. Anal. Calcd for
C15H14D2N2O4: C, 74.35; H, 6.71; N, 11.65. Found C, 73.97; H, 6.51; N, 11.77.
ІІI. General procedure for the synthesis of indeno[1,2-d]imidazolones, 5, (ninhydrin-1,3-disubstituted
urea adducts)

HETEROCYCLES, Vol. 73, 2007
363
Ninhydrin (20-35 mmol) was added to benzene(100 mL) containing an equivalent amount of the
appropriately substituted urea in a 500 mL round-bottom flask and refluxed for 45 min with stirring. The
mixture was cooled, filtered with suction, and the precipitate washed with water. The crude product was
allowed to air-dry overnight and recrystallized from aqueous MeOH (~ 90%) to a constant melting point.
1,3,3a,8a-Tetrahydro-3a,8a-dihydroxy-1,3-diethylindeno[1,2-d]imidazole-2,8-dione (5a)
Diethylurea,(7.9 g ,50.0 mmol) was reacted with ninhydrin ( 8.9 g , 50.0 mmol). The product was
recrystallized two times from aqueous MeOH and resulted in 5a as white crystals. Yield: 74.8 %, mp
235-237 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.36. IR (KBr) ν: 3420, 3310, 2974, 2935, 1721, 1683
1
cm-1. H-NMR (DMSO-d6): δ = 1.09 (t,3H), 1.12 (t, 3H), 3.36 (q, 2H), 3.44 (q, 2H), 6.82 (s,1H), 6.96
(s,1H), 7.68 (t, 1H), 7.84 (d, 1H), 7.92 (t, 1H), 7.95 (d, 1H). 13C-NMR (DMSO-d6): δ = 15.59, 15.89,
87.68, 88.71, 124.84, 125.99, 131.32, 133.11, 137.62, 151.07, 155.56, 197.78. Anal. Calcd for
C14H16N2O4: C, 60.86; H, 5.79; N, 10.14. Found C, 60.78; H, 5.83; N, 10.25.
1,3,3a,8a-Tetrahydro-3a,8a-dihydroxy-1,3-di-n-propylindeno[1,2-d]imidazole-2,8-dione (5b)
Di-n-propylurea,(7.9 g ,50.0 mmol) was reacted with ninhydrin,(8.9 g , 50.0 mmol). The product was
recrystallized two times from aqueous MeOH and resulted in 5b as white crystals. Yield: 72.0 %, mp
139-141 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.53. IR (KBr) ν: 3435, 2973, 2931, 1720, 1685 cm-1.
1H-NMR (DMSO-d6): δ = 0.821 (dt, 6H), 1.46-1.65 (m, 4H), 3.21-3.32 (m, 4H), 6.77 (s, 1H), 6.92 (s, 1H),
7.64 (t, 1H), 7.81 (d, 1H), 7.88 (t, 1H), 7.93 (d, 1H). 13C-NMR (DMSO-d6) δ = 11.35, 11.40, 22.17, 22.53,
41.03, 41.11, 86.90, 87.91, 123.96, 125.25, 130.42, 132.41, 136.63, 150.24, 155.12, 196.95. Anal. Calcd
for C16H20N2O4: C, 63.17; H, 6.58; N, 9.21. Found C, 63.29; H, 6.65; N, 9.35.
1,3,3a,8a-Tetrahydro-3a,8a-dihydroxy-1,3-dibenzylindeno[1,2-d]imidazole-2,8-dione (5c):
N,N’-Dibenzylurea, (3.67 g ,20.64 mmol) was reacted with ninhydrin, (4.96 g , 20.64 mmol). The product
was recrystallized two times from aqueous MeOH yielding 5c as white crystals. Yield: 41.5 %, mp 180-
182 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.57. IR (KBr) ν: 3340, 1730, 1665 cm-1. 1H-NMR
(DMSO-d6): δ = 4.50 (s, 1H), 4.58 (s, 1H), 4.60 (s, 1H), 4.71 (s, 1H), 7.07 (s, 1H), 7.16 (d, 7H), 7.24 (d,
4H), 7.51-7.63 (multiplet, J = 8.0, 3H), 7.72 (d, 1H). 13C-NMR (DMSO-d6): δ = 36.12, 42.46, 87.11,
88.29, 123.84, 125.61, 126.42, 126.61, 127.02, 127.26, 127.37, 128.00, 130.46, 132.26, 136.30, 138.89,
139.07, 150.03, 155.72, 196.67. Anal. Calcd for C24H20N2O4: C, 71.98; H, 5.03; N, 6.99. Found C,
71.94; H, 5.08; N, 6.96.
3-Ethyl-3a,8a-dihydroxy-1-methyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5d):

364
HETEROCYCLES, Vol. 73, 2007
N-1-Ethyl-N-3-methylurea, (5.1 g ,50.0 mmol) was reacted with ninhydrin, (8.9 g ,50.0 mmol). The
product was recrystallized two times from aqueous MeOH to give 5d as white crystals. Yield: 76.3 %,
1
mp 258-262 ºC. TLC (95% EtOAc: 5% MeOH) Rf = 0.41. IR (KBr) ν: 3436, 1727, 1678 cm-1. H-NMR
(DMSO-d6): δ = 1.08 (t, 3H), 3.37-3.44 (multiplet, J = 7.0 Hz, 2H), 6.81 (s, 1H), 6.98 (s, 1H), 7.63 (t, 1H),
7.80 (d, 1H), 7.87 (t, 1H), 7.94 (t, 1H). 13C-NMR (DMSO-d6): δ = 15.91, 25.56, 34.86, 87.50, 88.69,
124.83, 126.00, 131.29, 133.18, 137.56, 151.22, 156.52, 197.03. Anal. Calcd for C13H14N2O4: C, 59.54;
H, 5.38; N, 10.68. Found C, 59.47; H, 5.41; N, 10.84.
3-Ethyl-3a,8a-dihydroxy-1-phenyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5e):
N-1-Ethyl-N-3-phenylurea, (6.0 g ,36.0 mmol) was reacted with ninhydrin, (6.51 g ,36.0 mmol). The
product was recrystallized two times from aqueous MeOH, resulting in 5e as white crystals. Yield:
52.7 %, mp 159-162 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.41. IR (KBr) ν: 3385, 2936, 1735, 1679
1
cm-1. H-NMR (DMSO-d6): δ = 1.17 (t, 3H), 3.16 (sextet, 1H), 3.39 (sextet, 1H), 7.13 (s, 1H), 7.22 (t,
1H), 7.35 (t, 2H), 7.42 (s, 1H), 7.49 (d, 2H), 7.65 (t, 1H), 7.78 (d, 1H), 7.91 (t, 1H), 8.00 (t, 1H). 13C-
NMR (DMSO-d6): δ = 14.96, 34.40, 87.94, 88.67, 124.14, 125.27, 125.73, 126.85, 128.14, 130.65, 132.45,
136.42, 150.00, 153.69, 195.31. Anal. Calcd for C18H16N2O4: C, 66.65; H, 4.97; N, 8.63. Found C,
66.85; H, 4.94; N, 8.65.
3-Ethyl-3a,8a-dihydroxy-1-(o-fluorophenyl)-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione
(5f):
N-1-Ethyl-N-3-(2-fluorophenyl)urea, (5.0 g ,27.47 mmol) was reacted with ninhydrin, (4.89 g ,27.47
mmol). The product was recrystallized from aqueous MeOH to give 5f as white crystals. Yield: 74.8 %,
mp 104-106 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.36. IR (KBr) ν: 3328, 3238, 1734, 1697 cm-1.
1H-NMR (DMSO-d6): δ = 1.17 (t, 3H), 3.47-3.55 (multiplet, J = 7.2 Hz, 2H), 7.18 (s, 1H), 7.23 (d, 1H),
7.26 (d, 1H), 7.38 (s, 1H), 7.41 (t, 1H), 7.51 (t, 1H), 7.66 (t, 1H), 7.80 (d, 1H), 7.91 (t, 1H), 8.02 (d, 1H).
13C-NMR (DMSO-d6): δ = 15.00, 34.41, 87.79, 88.54, 115.69, 115.89, 123.26, 124.22, 125.28, 129.81,
130.72, 132.40, 136.88, 150.29, 153.31, 157.91, 160.38, 195.13. Anal. Calcd for C18H15N2O4F: C, 63.15;
H, 4.41; N, 8.18. Found C, 63.25; H, 4.17; N, 8.03.
3-Ethyl-3a,8a-dihydroxy-1-(m-fluorophenyl)-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione
(5g):
N-1-Ethyl-N-3-(3-fluorophenyl)urea, (5.0 g ,27.47 mmol) was reacted with ninhydrin, (4.89 g ,27.47
mmol). The product was recrystallized from aqueous MeOH yielding 5g as white crystals. Yield: 69.5 %,
mp 169-172 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.49. IR (KBr) ν: 3355, 3241, 1734, 1694 cm-1.

HETEROCYCLES, Vol. 73, 2007
365
1H-NMR (DMSO-d6): δ = 1.15 (t, 3H), 3.47-3.58 (multiplet, J = 7.25 Hz, 2H), 7.03 (t, 1H), 7.23 (s, 1H),
7.37 (d, 1H), 7.50 (d, 1H), 7.54 (s, 1H), 7.60 (s, 1H), 7.67 (t, 1H), 7.79 (d, 1H), 7.92 (t, 1H), 8.02 (d, 1H).
13C-NMR (DMSO-d6): δ = 14.80, 34.43, , 87.79, 88.78, 111.89, 121.27, 124.28, 125.34, 129.44, 130.78,
132.41, 136.95, 138.43, 149.92, 153.20, 157.91, 160.43, 195.24. Anal. Calcd for C18H15N2O4F: C, 63.15;
H, 4.41; N, 8.18. Found C, 63.32; H, 4.31; N, 8.24.
3-Ethyl-3a,8a-dihydroxy-1-(p-fluorophenyl)-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione
(5h):
N-1-Ethyl-N-3-(4-fluorophenyl)urea, (4.0 g ,22.0 mmol) was reacted with ninhydrin, (3.91 g ,22.0 mmol).
The product was recrystallized from aqueous MeOH yielding 5h as white crystals. Yield: 64.5 %, mp
1
173-175 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.40. IR (KBr) ν: 3385, 2936, 1735, 1679 cm-1. H-
NMR (DMSO-d6): δ = 1.16 (t, 3H), 3.13 (sextet, 1H), 3.37 (sextet, 1H), 7.16 (s, 1H), 7.19 (t, 2H), 7.45 (s,
1H), 7.47 (d, 2H), 7.66 (t, 1H), 7.81 (d, 1H), 7.91 (t, 1H), 8.01 (d, 1H). 13C-NMR (DMSO-d6): δ = 14.94,
34.40, 87.97, 88.47, 124.14, 125.73, 126.85, 128.14, 130.65, 132.45, 136.85, 150.08, 153.68, 159.01,
161.42, 195.36. Anal. Calcd for C18H15N2O4F: C, 63.15; H, 4.41; N, 8.18. Found C, 63.25; H, 4.17; N,
8.03.
3-Ethyl-3a,8a-dihydroxy-1-(p-nitrophenyl)-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione
(5i):
N-1-Ethyl-N-3-(4-nitrophenyl)urea, (5.0 g ,23.92 mmol) was reacted with ninhydrin, (4.16 g ,23.92 mmol).
The product was recrystallized from aqueous MeOH to give 5i as white crystals. Yield: 76.6 %, mp 217-
219 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.53. IR (KBr) ν: 3352, 3180, 1731, 1680, 1595, 1338 cm-1.
1H-NMR (DMSO-d6): δ = 1.14 (t, 3H), 3.39-3.63 (multiplet, J = 7.0, 2H), 7.36 (s, 1H), 7.69 (t, 1H), 7.81
(d, 1H), 7.85 (s, 2H), 7.95 (t, 1H), 8.04 (d, 1H), 8.15 (d, 2H), 8.25 (d, 2H). 13C-NMR (DMSO-d6): δ =
14.56, 34.59, 87.70, 89.21, 123.21, 123.65, 124.41, 125.39, 130.95, 132.27, 137.13, 143.07, 143.56,
149.60, 152.70, 195.13. Anal. Calcd for C18H15N3O6: C, 58.53; H, 4.09; N, 11.37. Found C, 58.50; H,
4.03; N, 11.26.
3-Ethyl-3a,8a-dihydroxy-1-(p-methoxyphenyl)-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-
dione (5j):
N-1-Ethyl-N-3-(4-methoxyphenyl)urea, (4.0 g ,20.60 mmol) was reacted with ninhydrin, (3.66 g ,20.60
mmol). The product was recrystallized from aqueous MeOH yielding 5j as white crystals. Yield: 74.3 %,
mp 170-172 ºC. TLC (70% toluene: 30% MeCN), Rf = 0.52. IR (KBr) ν: 3298, 1729, 1604, 1447cm-1.
1H-NMR (DMSO-d6): δ = 1.16 (t, 3H), 3.41-3.51 (multiplet, J = 7.7, 2H), 6.90 (d, 2H), 6.97 (s, 1H), 7.18

366
HETEROCYCLES, Vol. 73, 2007
(s, 1H), 7.26 (d, 2H), 7.64 (t, 1H), 7.77 (d, 1H), 7.89 (t, 1H), 7.98 (d, 1H). 13C-NMR (DMSO-d6): δ =
14.84, 34.22, 55.15, 87.85, 88.27, 113.39, 123.95, 125.12, 128.67, 129.11, 130.44, 132.46, 136.54, 149.96,
153.90, 157.58, 195.22. Anal. Calcd for C19H18N2O5: C, 64.40; H, 5.11; N, 7.90. Found C, 64.29; H,
5.08; N, 7.84.
1-Methyl -3a,8a-dihydroxy-3-propyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5k):
N-1-Methyl-N-3-propylurea, (2.5 g ,21.55 mmol) was reacted with ninhydrin, (3.83 g ,21.55 mmol). The
product was recrystallized two times from aqueous MeOH and resulted in 5k as white crystals. Yield:
71.0 %, mp 205-207 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.34. IR (KBr) ν: 3301, 2967, 1713, 1686
1
cm-1. H-NMR (DMSO-d6): δ = 0.83 (t, 3H), 1.46 (octet, 1H), 1.61 (octet, 1H), 2.79 (s, 3H), 3.21-3.46
(multiplet, J=5.32, 2H), 6.80 (s, 1H), 6.98 (s, 1H), 7.65 (t, 1H), 7.81 (d, 1H), 7.88 (t, 1H), 7.93 (d, 1H).
13C-NMR (DMSO-d6): δ = 11.39, 22.52, 24.80, 41.14, 86.66, 87.92, 123.99, 125.27, 130.45, 132.42,
136.66, 150.37, 154.93, 196.27. Anal. Calcd for C14H16N2O4: C, 60.71; H, 5.84; N, 10.14. Found C,
60.37; H, 6.03; N, 10.11.
1-Phenyl-3a,8a-dihydroxy-3-propyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5l):
N-1-Phenyl-N-3-propylurea, (4.0 g ,22.30 mmol) was reacted with ninhydrin, (4.0 g ,22.30 mmol). The
product was recrystallized two times from aqueous MeOH, resulting in 5l as white crystals. Yield: 82.4 %,
mp 184-186 ºC. TLC (60% n-hexane: 40% EtOAc) Rf = 0.30. IR (KBr) ν: 3384, 3338, 2978, 1735, 1692
1
cm-1. H-NMR (DMSO-d6): δ = 0.926 (t, 3H), 1.62 (octet, 1H), 1.77 (octet, 1H), 3.47 (sextet,1H), 3.52
(sextet, 1H), 7.12 (s, 1H), 7.28 (t, 1H), 7.36 (t, 2H), 7.40 (s, 1H), 7.42 (d, 2H), 7.64 (t, 1H), 7.83 (d, 1H),
7.88 (t, 1H), 7.96 (d, 1H). 13C-NMR (DMSO-d6): δ = 11.42, 22.43, 41.40, 88.00, 88.72, 124.16, 125.39,
125.73, 126.83, 128.15, 130.66, 132.56, 136.47, 136.74, 149.99, 153.96, 195.41. Anal. Calcd for
C19H18N2O4: C, 67.44; H, 5.36; N, 8.27. Found C, 67.50; H, 5.28; N, 8.22.
3-Benzyl-3a,8a-dihydroxy-1-methyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5m):
N-1-Benzyl-N-3-methylurea, (2.7 g ,16.4 mmol) was reacted with ninhydrin, (2.93 g ,16.4 mmol). The
product was recrystallized two times from aqueous MeOH, resulting in 5m as white crystals. Yield:
61.2 %, mp 166-167 ºC. (70% toluene: 30% MeCN) Rf = 0.31. IR (KBr) ν: 3350, 3057, 1735, 1668 cm-1.
1H-NMR (DMSO-d6): δ = 2.85 (s, 3H), 4.55 (d, 1H), 4.67 (d, 1H), 7.01 (s, 1H), 7.08 (s, 1H), 7.10 (d, 2H),
7.15 (t, 1H), 7.18 (t, 2H), 7.52-7.63 (multiplet, J= 7.63, 3H), 7.78 (d, 1H). 13C-NMR (DMSO-d6): δ =
24.99, 42.40, 87.03, 88.01, 123.85, 125.58, 126.47, 127.12, 127.93, 130.38, 132.32, 136.26, 139.13,
150.21, 155.35, 196.27. Anal. Calcd for C18H16N2O4: C, 66.65; H, 4.97; N, 8.63. Found C, 66.60; H,
4.98; N, 8.60.

HETEROCYCLES, Vol. 73, 2007
367
3-Benzyl-3a,8a-dihydroxy-1-phenyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5n):
N-1-Benzyl-N-3-phenylurea, (1.0 g ,4.58 mmol) was reacted with ninhydrin, (0.78 g ,4.58 mmol). The
product was recrystallized two times from aqueous MeOH to give 5n as white crystals. Yield: 73.8 %,
1
m.p. 222-223 ºC. (70% toluene: 30% MeCN) Rf = 0.47. IR (KBr) ν: 3343, 1736, 1665, 1644 cm-1. H-
NMR (DMSO-d6): δ = 4.65 (d, 1H), 4.78 (d, J = 16.35 Hz, 1H), 7.15-7.27 (multiplet, 6H), 7.31 (s, 1H),
7.35 (t, 2H), 7.51 (s, 1H), 7.52-7.57 (multiplet, J = 7.07, 3H), 7.62-7.66 (multiplet, 2H), 7.75 (d, 1H). 13C-
NMR (DMSO-d6): δ = 42.70, 88.07, 89.07, 124.01, 125.69, 125.90, 126.58, 126.91, 127.18, 128.02,
128.22, 130.58, 132.45, 136.34, 136.38, 138.81, 149.77, 154.39, 195.31. Anal. Calcd for C23H18N2O4: C,
71.50; H, 4.69; N, 7.25. Found C, 71.72; H, 4.60; N, 7.27.
3-Benzyl-3a,8a-dihydroxy-1-(2’-phenylethyl)-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione
(5o):
N-1-Benzyl-N-3-(2’-phenylethyl)urea,(2.54 g ,10.0 mmol) was reacted with ninhydrin, (1.78 g ,10.0
mmol). The product was recrystallized two times from aqueous MeOH yielding 5o as white crystals.
Yield: 59.0 %, mp 182-184 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.51. IR (KBr) ν: 3384, 3130, 2945,
1
1725, 1682 cm-1. H-NMR (DMSO-d6): δ = 2.90 (dt, 2H), 3.54 (t, 2H), 4.58 (d, 1H), 4.70 (d, 1H), 7.04 (s,
1H), 7.13-7.23 (multiplet, 9H), 7.28 (d, 2H), 7.55 (d, 2H), 7.60 (d, 1H), 7.77 (d, 1H). 13C-NMR (DMSO-
d6): δ = 35.15, 41.14, 42.35, 87.20, 88.09, 123.90, 125.56, 126.17, 126.46, 127.14, 127.93, 128.43,
128.60,130.33, 132.25, 136.24, 139.09, 139.22, 150.07, 155.36, 196.88. Anal. Calcd for C25H22N2O4: C,
72.44; H, 5.35; N, 6.76. Found C, 72.41; H, 5.35; N, 6.73.
1-Ethyl-3a,8a-dihydroxy-3-isopropyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5p):
N-1-Ethyl-N-3-isopropylurea, (2.0 g ,15.38 mmol) was reacted with ninhydrin, (2.73 g ,15.38 mmol). The
product was recrystallized two times from aqueous MeOH to give 5p as white crystals. Yield: 79.1 %,
mp 221-222 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.45. IR (KBr) ν: 3420, 3279, 2998, 2973, 1719,
1
1684 cm-1. H-NMR (DMSO-d6): δ = 1.07 (t, 3H), 1.44 (d, 6H), 3.30 (q, 2H), 4.08 (septet, 1H), 6.72 (s,
1H), 6.89 (s, 1H), 7.64 (t, 1H), 7.81 (d, 1H), 7.87 (t, 1H), 7.95 (d, 1H). 13C-NMR (DMSO-d6): δ = 14.87,
20.36, 21.43, 33.63, 43.21, 86.56, 87.75, 123.97, 124.87, 130.38, 132.25, 136.76, 150.47, 153.81, 196.93.
Anal. Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found C, 61.96; H, 6.24; N, 9.56.
1-Ethyl-3a,8a-dihydroxy-3-neopentyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5q):
N-1-Ethyl-N-3-neopentylurea, (4.0 g ,23.25 mmol) was reacted with ninhydrin, (4.13 g ,23.25 mmol).
The product was recrystallized two times from aqueous MeOH yielding 5q as white crystals. Yield:
75.0 %, mp 201-204 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.59. IR (KBr) ν: 3437, 3248, 2973, 1723,

368
HETEROCYCLES, Vol. 73, 2007
1
1682 cm-1. H-NMR (DMSO-d6): δ = 0.845 (s, 9H), 1.10 (d, 3H), 1.42 (d, 3H), 3.03 (d, 1H), 3.11 (d, 1H),
4.08 (septet, 1H), 6.71 (s, 1H), 6.87 (s, 1H), 7.63 (t, 1H), 7.78 (d, 1H), 7.87 (t, 1H), 7.953(d, 1H). 13C-
NMR (DMSO-d6): δ = 20.25, 21.27, 28.69, 32.39, 43.29, 50.63, 87.39, 87.81, 123.79, 124.84, 130.35,
132.66, 136.58, 150.15, 155.48, 197.18. Anal. Calcd for C18H24N2O4: C, 65.04; H, 7.27; N, 8.42; Found
C, 65.06; H, 7.31; N, 8.43.
3-Phenethyl-3a,8a-dihydroxy-1-phenyl-1,3,3a,8a-tetrahydroindeno[1,2-d]imidazole-2,8-dione (5r):
N-1-Phenethyl-N-3-phenylurea, (2.25 g ,12.5 mmol) was reacted with ninhydrin, (3.0 g ,12.5 mmol). The
product was recrystallized two times from aqueous MeOH to give 5r as white crystals. Yield: 82.5 %, mp
178-179 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.30. IR (KBr) ν: 3926, 3117, 1734, 1688, 1603 cm-1.
1H-NMR (DMSO-d6): δ = 2.80 (sextet, 1H), 2.99 (sextet, 1H), 3.64 (dodecet, 2H), 7.19-7.32 (multiplet,
7H), 7.36 (t, 2H), 7.47, (s, 1H), 7.51 (d, 2H), 7.66 (t, 1H), 7.78 (d, 1H), 7.90 (t, 1H), 8.03 (d, 1H). 13C-
NMR (DMSO-d6): δ = 35.34, 41.36, 87.99, 88.77, 124.16, 125.29, 125.79, 126.25, 126.85, 128.15, 128.47,
128.65, 130.67, 132.50, 136.34, 136.85, 139.12, 149.85, 153.82, 195.27. Anal. Calcd for C24H20N2O4: C,
71.98; H, 4.99; N, 6.99. Found C, 72.00; H, 4.97; N, 6.99.
3-(α,α-Dideutero-2-phenylethyl)-3a,8a-dihydroxy-1-phenyl-1,3,3a,8a-tetrahydroindeno[1,2-
d]imidazole-2,8-dione (5s):
N-1-(α,α-Dideutero-2-phenylethyl)-N-3-phenylurea, (1.5 g ,6.20 mmol) was reacted with ninhydrin, (1.10
g ,6.20 mmol). The product was recrystallized two times from aqueous MeOH yielding 5s as white
crystals. Yield: 78.3 %, mp 177-178 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.43. IR (KBr) ν: 3306,
1735, 1686, 1603 cm-1. 1H-NMR (CD3OD): δ = 2.86 (d, 1H), 3.02 (d, 1H), 4.88 (s, 2H), 7.14-7.19
(multiplet, 1H), 7.22-7.30 (multiplet, 5H), 7.37 (t, 2H), 7.45 (d, 2H), 7.61 (t, 1H), 7.80-7.85 (two doublets,
2H), 7.93 (d, 1H). 13C-NMR (CD3OD): δ = 36.55, 51.00, 89.86, 90.07, 125.60, 126.10, 127.41, 128.05,
129.28, 129.55, 129.56, 129.82, 131.92, 134.32, 136.81, 138.00, 140.35, 151.03, 156.84, 196.75. Anal.
Calcd for C24H18D2N2O4: C, 71.64; H, 4.97; N, 6.96. Found C, 71.48; H, 4.98; N, 6.93.
ІV. General procedure for the synthesis of N-1’,N-3’-disubstituted 2’H,3H,5’H-spiro[2-benzofuran-
1,4’-imidazolidine]-2’,3,5’-triones, 6.
Sodium periodate, (5-20 mmol) in 50 mL of water was added dropwise to 100 mL of ethanol containing
5-20 mmol of the appropriate adduct (5a-s) and the mixture was stirred at room temperature for suitable
amount of time (usually 12-24h) as determined by TLC monitoring. At the end of reaction inorganic
precipitate was filtered off. The filtrate was concentrated to one-half of its volume, and the resultant
precipitate filtered with suction and washed thoroughly with water. The crude product was allowed to air-

HETEROCYCLES, Vol. 73, 2007
369
dry overnight and recrystallized from aqueous methanol to a constant melting point, except for compound
6b which is an oil.
N-1’,N-3’-Diethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6a):
Product 5a, 3 g (10.0 mmol) was reacted with sodium periodate, 2.11 g (10.0 mmol) for 20 h. Two
recrystallizations from aqueous MeOH resulted in 6a as white crystals. Yield: 58.2 %, mp 96-98 ºC.
1
TLC (70% n-hexane: 30% EtOAc) Rf = 0.57. IR (KBr) ν: 1803 1792, 1736 cm-1. H-NMR (DMSO-d6):
δ = 1.02 (t,3H), 1.25 (t, 3H), 3.06 (quintet, 1H), 3.34 (quintet, 1H), 3.65 (q, 2H), 7.68 (d, 1H), 7.79 (t, 1H),
7.87 (t, 1H), 8.01 (d, 1H). 13C-NMR (DMSO-d6): δ = 13.672, 14.875, 35.132, 35.686, 93.315, 124.410,
126.608, 127.294, 133.345, 136.855, 141.302, 155.610, 166.893, 167.716, MS: m/z 274 (M+), 259, 230,
201, 175, 174, 160 (base peak), 104, 90, 76, 50. Anal. Calcd for C14H14N2O4: C, 61.31; H, 5.11; N, 10.22;
Found C, 61.39; H, 5.03; N, 10.25.
N-1’,N-3’-Di-n-propyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6b):
Product 5b, 3 g (10.0 mmol) was reacted with sodium periodate, 2.11 g (10.0 mmol) for 20 h.
Purification by flash chromatography (70% n-hexane/ 30% EtOAc) yielded pure 6b, as an oil. Yield:
82.0%. TLC (70% n-hexane: 30% EtOAc) single spot, Rf = 0.76. IR (KBr) ν: 2973, 2931, 1785, 1720
cm-1. 1H-NMR (DMSO-d6): δ = 0.756 (t,3H), 0.883 (t, 3H), 1.298 (doublet of sextet, 2H), 1.64 (sextet,
2H), 2.90 (quintet, 1H), 3.29 (quintet, 1H), 3.521 (t, 2H), 7.85 (t, 1H), 7.92 (t, 1H), 7.94 (d, 1H), 8.07 (d,
1H). 13C-NMR (DMSO-d6): δ = 10.85, 10.90, 20.74, 21.84, 40.73, 41.54, 92.51, 135.89, 123.90, 125.81,
126.77, 132.44, 140.72, 155.16, 166.59, 167.04. MS: m/z 302 (M+), 273, 258, 216, 188, 174, 160, 145,
130, 117, 104, 90, 76, 70, 56, 41 (base peak). Anal. Calcd for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27;
Found C, 63.86; H, 6.02; N, 9.14.
N-1’,N-3’-Dibenzyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6c):
Product 5c, 2 g (5.000 mmol) was reacted with sodium periodate, 1.321 g (5.000 mmol) for 24 h. Two
recrystallizations from aqueous MeOH resulted in 6c as white crystals. Yield: 71.0 %, mp 164-167 ºC.
1
TLC (70% toluene: 30% MeCN) Rf = 0.80. IR (KBr) ν: 1783, 1732, 1601 cm-1. H-NMR (DMSO-d6): δ
= 4.282 (d, 1H), 4.492 (d, 1H), 4.775 (s, 2H), 7.029 (s, 2H), 7.182 (s, 3H), 7.339 (d, 2H), 7.415(t, 3H),
7.711 (d, 3H), 7.975 (s, 1H). 13C-NMR (DMSO-d6): δ = 42.61, 43.32, 92.33, 124.14, 125.10, 125.61,
126.63, 127.34, 127.46, 127.84, 128.21, 128.81, 132.25, 135.47, 135, 64, 135.94, 140.19, 155.03, 166.31,
166.87. MS: m/z 398 (M·+), 355, 293, 265, 222, 193, 174, 160, 132, 104, 91 (base peak), 77, 65, 51. Anal.
Calcd for C24H18N2O4: C, 72.36; H, 4.52; N, 7.03; Found: C, 72.30; H, 4.59; N, 7.01.

370
HETEROCYCLES, Vol. 73, 2007
N-1’-Methyl-N-3’-ethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6d):
Product 5d, 2.6 g (10.0 mmol) was reacted with sodium periodate, 2.14 g (10.0 mmol) at 50-60 ºC with
stirring for 10 h. Two recrystallizations from MeOH-water (9:1) resulted in 6d as white crystals. Yield:
1
77.4 %, mp 112-114 ºC. TLC (95% EtOAc: 5% MeOH) Rf = 0.54. IR (KBr) ν: 1785, 1732cm-1. H-
NMR (DMSO-d6): δ = 0.93 (t, 3H), 3.00 (sextet, 1H), 3.28 (sextet, 1H), 3.36 (s, 3H), 7.79 (d, 1H), 7.84 (t,
1H), 7.94 (t, 1H), 8.05 (d, 1H). 13C-NMR (DMSO-d6): δ = 15.20, 26.13, 35.65, 93.53, 125.10, 126.56,
127.67, 133.22, 136.61, 141.68, 155.85, 167.51, 167.87. MS: m/z 260 (M·+), 245, 231, 216, 201, 187, 160
(base peak), 104, 76. Anal. Calcd for C13H12N2O4: C, 60.00; H, 4.65; N, 10.76; Found C, 60.08, H, 4.59;
N, 10.73.
N-1’-Phenyl-N-3’-ethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione, (6e):
Product 5e, 3 g (10 mmol) was reacted with sodium periodate, 2.07 g (10 mmol) for 18 h. Two
recrystallizations from aqueous MeOH resulted in 6e as white crystals. Yield: 67.0 %, mp 169-171 ºC.
TLC (70% n-hexane: 30% EtOAc) Rf = 0.54. IR (KBr) ν: 1797, 1783, 1735, 1598 cm-1. 1H-NMR
(DMSO-d6): δ = 1.019 (t, 3H), 3.12 (sextet, 1H), 3.38 (sextet, 1H), 7.48 (d, 5H), 7.86 (t, 1H), 7.98 (t, 1H),
8.09 (d, 1H), 8.19 (d, 1H). 13C-NMR (DMSO-d6): δ = 14.35, 35.16, 92.44, 124.50, 125.78, 127.65,
132.51, 135.87, 140.76, 153.65, 166.04, 166.59. MS: m/z 322 (M·+), 278, 249, 223, 174, 160, 131, 119
(base peak), 104, 76. Anal. Calcd for C18H14N2O4: C, 67.10; H, 4.37; N, 8.69; Found: C, 67.10; H, 4.35;
N, 8.66.
N-1’-o-Fluorophenyl-N-3’-ethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione
(6f):
Product 5f, 4 g (12.0 mmol) was reacted with sodium periodate, 2.53 g (12.0 mmol) for 16 h. Two
recrystallizations from aqueous MeOH resulted in 6f as white crystals. Yield: 72.8 %, mp 138-140 ºC.
1
TLC (70% n-hexane: 30% EtOAc) Rf = 0.54. IR (KBr) ν: 1800, 1788, 1744 cm-1. H-NMR (DMSO-d6):
δ = 1.018 (t, 3H), 3.127 (sextet, 1H), 3.381 (sextet, 1H), 7.402 (t, 1H), 7.634 (dd, 2H), 7.869 (t, 1H), 7.990,
(t, 1H), 8.093 (d, 1H), 8.206 (d, 1H). 13C-NMR (DMSO-d6): δ = 14.23, 35.15, 92.40, 115.95, 124.54,
125.77, 127.21, 129.15, 132.51, 135.85, 140.75, 153.58, 160.38, 162.83, 166.02, 166.58. MS: m/z 340
(M·+), 241, 197, 174, 160, 137 (base peak), 131, 104, 76, 50. Anal. Calcd for C18H13N2O4F: C, 63.52; H,
3.85; N, 8.23; Found: C, 63.65; H, 3.84; N, 8.08.
N-1’-m-Fluorophenyl-N-3’-ethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione
(6g):
Product 5g, 4 g (12.0 mmol) was reacted with sodium periodate, 2.53 g (12.0 mmol) for 16 h. Two

HETEROCYCLES, Vol. 73, 2007
371
recrystallizations from aqueous MeOH resulted in 6g as white crystals. Yield: 66.0 %, mp 139-141 ºC.
1
TLC (70% toluene: 30% MeCN) Rf = 0.77. IR (KBr) ν: 1799, 1782, 1745, 1601 cm-1. H-NMR (DMSO-
d6): δ = 1.020 (t, 3H), 3.132 (sextet, 1H), 3.376 (sextet, 1H), 7.350 (t, 1H), 7.445 (d, 1H), 7.751 (dt, 1H),
7.760, (t, 1H), 8.098 (d, 1H), 8.204 (d, 1H). 13C-NMR (DMSO-d6): δ = 14.23, 35.20, 92.32, 114.25,
115.62, 122.94, 124.61, 125.81, 126.77, 130.68, 132.47, 135.89, 140.71, 153.26, 160.48, 162.91, 165.80,
166.59. MS: m/z 340 (M·+), 241, 197, 175, 160 (base peak), 137, 131, 104, 76, 50. Anal. Calcd for
C18H13N2O4F: C, 63.52; H, 3.85; N, 8.23; Found: C, 63.65; H, 3.84; N, 8.08.
N-1’-p-Fluorophenyl-N-3’-ethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione
(6h):
Product 5h, 4 g (12.0 mmol) was reacted with sodium periodate, 2.53 g (12.0 mmol) for 16 h. Two
recrystallizations from aqueous MeOH resulted in 6h as white crystals. Yield: 47.0 %, mp 131-133 ºC.
1
TLC (70% n-hexane: 30% EtOAc) Rf = 0.54. IR (KBr) ν: 1800, 1786, 1734 cm-1. H-NMR (DMSO-d6):
δ = 1.018 (t, 3H), 3.127 (sextet, 1H), 3.381 (sextet, 1H), 7.402 (t, 2H), 7.634 (dd, 2H), 7.869 (t, 1H), 7.990,
(t, 1H), 8.093 (d, 1H), 8.206 (d, 1H). 13C-NMR (DMSO-d6): δ = 14.23, 35.15, 92.40, 115.95, 124.54,
125.77, 127.21, 129.15, 132.51, 135.85, 140.75, 153.58, 160.38, 162.83, 166.02, 166.58. MS: m/z 340
(M·+), 241, 197, 174, 160, 137 (base peak), 131, 104, 76, 50. Anal. Calcd for C18H13N2O4F: C, 63.52; H,
3.85; N, 8.23; Found: C, 63.41; H, 3.70; N, 8.01.
N-1’-p-Nitrophenyl-N-3’-ethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione
(6i):
Product 5i, 4 g (10.84 mmol) was reacted with sodium periodate, 2.319 g (10.84 mmol) for 16 h. Two
recrystallizations from aqueous MeOH resulted in 6i as white crystals. Yield: 63.0 %, mp 174-176 ºC.
TLC (70% toluene: 30% MeCN) Rf = 0.85. The IR, 1H-NMR, 13C-NMR, MS and elemental analysis data
of this compound have been reported in our earlier communication1.
N-1’-p-Methoxyphenyl-N-3’-ethyl, 2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-
trione (6j):
Product 5j, 4 g (11.3 mmol) was reacted with sodium periodate, 2.41 g (11.3 mmol) for 16 h. Two
recrystallizations from aqueous MeOH resulted in 6j as white crystals. Yield: 71.0 %, mp 167-169 ºC.
1
TLC (70% toluene: 30% MeCN) Rf = 0.68. IR (KBr) ν: 1801, 1786, 1735 cm-1. H-NMR (DMSO-d6): δ
= 1.011 (t, 3H), 3.110 (sextet, 1H), 3.372 (sextet, 1H), 3.809 (s, 3H), 7.080 (d, 2H), 7.447 (d, 2H), 7.854 (t,
1H), 7.970 (t, 1H), 8.075 (d, 1H), 8.153 (d, 1H). 13C-NMR (DMSO-d6): δ = 14.15, 35.05, 55.34, 92.39,
114.17, 123.44, 125.65, 126.74, 128.20, 132.37, 135.74, 140.77, 153.85, 159.20, 166.13, 166.49. MS:

372
HETEROCYCLES, Vol. 73, 2007
m/z 352 (M·+), 336, 253, 238, 160, 149 (base peak), 134, 104, 76, 50. Anal. Calcd for C19H16N2O5: C,
64.77; H, 4.58; N, 7.95; Found: C, 64.71; H, 4.53; N, 7.95.
N-1’-Methyl-N-3’-propyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6k):
Product, 5k, 2.0 g (7.246 mmol) was reacted with sodium periodate, 1.551 g (7.246 mmol) with stirring
for 18 h. Two recrystallizations from MeOH-water (9:1) resulted in 6k as white crystals. Yield: 82.5 %,
m.p. 142-144 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.75. IR (KBr) ν: 2986, 1792, 1784, 1734, 1604
1
cm-1. H-NMR (DMSO-d6): δ = 0.748 (t, 3H), 1.310 (dodecet, 2H), 2.878 (quintet, 1H), 3.040 (s, 3H),
3.259 (quintet, 1H), 7.834 (t, 1H), 7.934 (t, 1H), 7.961 (d, 1H), 8.054 (d, 1H). 13C-NMR (DMSO-d6): δ =
10.97, 21.94, 25.48, 41.62, 92.78, 124.29, 125.85, 126.81, 132.55, 135.94, 140.87, 155.46, 166.80, 167.13.
MS: m/z 274 (M·+), 259, 245, 230, 201, 189, 174, 160 (base peak), 145, 132, 130, 104, 76, 56. Anal.
Calcd for C14H14N2O4: C, 61.30; H, 5.14; N, 10.21; Found C, 61.08, H, 5.09; N, 10.11.
N-1’-Phenyl-N-3’-propyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione, (6l):
Product 5l, 4 g (11.23 mmol) was reacted with sodium periodate, 2.40 g (11.23 mmol) for 12 h. Two
recrystallizations from hexane: EtOAc (6:4) resulted in 6l as white crystals. Yield: 50.0 %, mp 122-124
1
ºC. TLC (60% n-hexane: 40% EtOAc) Rf = 0.54. IR (KBr) ν: 2970, 1780, 1736, 1598 cm-1. H-NMR
(CD3OD): δ = 0.826 (t, 3H), 1.446 (nonet, 2H), 2.996 (sextet, 1H), 3.356 (sextet, 1H), 7.434 (t, 1H), 7.494
(d, 4H), 7.78-7.91 (m, 3H), 8.023 (d, 1H). 13C-NMR (DMSO-d6): δ =10.93, 21.81, 41.80, 92.46, 124.46,
125.82, 126.76, 126.83, 128.71, 129.01, 131.05, 132.55, 135.91, 140.75, 154.02, 166.05, 166.62. MS:
m/z 336 (M·+), 307, 292, 263, 236, 188, 174, 160 (base peak), 132, 119, 104, 91, 76, 50. Anal. Calcd for
C19H16N2O4: C, 67.72; H, 4.78; N, 8.31; Found: C, 67.51; H, 4.73; N, 8.29.
N-1’-Methyl-N-3’-benzyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6m):
Product 5m, 2 g (6.173 mmol) was reacted with sodium periodate, 1.321 g (6.173 mmol) for 16 h. Two
recrystallizations from aqueous MeOH resulted in 6m as white crystals. Yield: 71.0 %, mp 134.5
136 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.77. IR (KBr) ν: 1785, 1725, 1598 cm-1. 1H-NMR
(DMSO-d6): δ = 3.07 (s, 3H), 4.24 (d, 1H), 4.46 (d,1H), 7.04 (m, 2H), 7.18 (t, 3H), 7.74 (m, 3H), 7.96(m,
1H). 13C-NMR (DMSO-d6): δ = 25.51, 43.14, 92.43, 124.37, 125.47, 126.65, 127.39, 127.80, 128.16,
132.14, 135.33, 136.09, 140.48, 155.43, 166.48, 167.02. MS: m/z 322 (M·+), 279, 265, 237, 217, 193, 165,
160, 132 (base peak), 105, 104, 91, 76, 65. Anal. Calcd for C18H14N2O4: C, 67.07; H, 4.37; N, 8.69;
Found: C, 67.00; H, 4.32; N, 8.66.
N-1’-Phenyl-N-3’-benzyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6n):

HETEROCYCLES, Vol. 73, 2007
373
Product 5n, 2 g (6.173 mmol) was reacted with sodium periodate, 1.321 g (6.173 mmol) for 16 h. Two
recrystallizations from aqueous MeOH resulted in 6n as white crystals. Yield: 77.8 %, mp 147-148 ºC.
1
TLC (70% toluene: 30% MeCN) Rf = 0.82. IR (KBr) ν: 1782, 1738, 1597 cm-1. H-NMR (DMSO-d6): δ
= 4.34 (d, 1H), 4.57 (d, 1H), 7.09 (dd, 2H), 7.21 (t, 3H), 7.49 (t, 1H), 7.56 (m, 4H), 7.78 (dt, 2H), 7.96 (d,
1H), 7.99 (d, 1H). 13C-NMR (DMSO-d6): δ = 43.49, 92.22, 124.65, 125.56, 126.66, 126.89, 127.48,
127.94, 128.20, 128.78, 129.02, 131.04, 132.31, 135.46, 135.85, 140.39, 154.16, 166.05, 166.43. MS:
m/z 384 (M·+), 279, 265, 249, 237, 224, 193,174, 165, 160, 132 (base peak), 119, 104, 91, 76, 65. Anal.
Calcd for C23H16N2O4: C, 71.49; H, 4.69; N, 7.25; Found: C, 71.14; H, 4.40; N, 7.27.
N-1’-Phenethyl-N-3’-benzyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6o):
Product 5o, 0.9 g (2.17 mmol) was reacted with sodium periodate, 0.4652 g (2.17 mmol) with stirring for
18 h. Two recrystallizations from MeOH-water (9:1) resulted in 6o as white crystals. Yield: 67.7 %, mp
1
112-114 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.75. IR (KBr) ν: 1798, 1787, 1722, 1603 cm-1. H-
NMR (DMSO-d6): δ = 3.00 (t, 3H), 3.86 (t, 3H), 4.22 (d, 1H), 4.36 (d, 3H), 6.92 (t, 2H), 7.15-7.20
(multiplet, 4H), 7.23 (d, 2H), 7.27 (d, 1H), 7.33 (t, 2H), 7.68 (two triplets, 2H), 7.93 (d, 1H). 13C-NMR
(DMSO-d6): δ = 32.66, 40.31, 42.87, 91.94, 123.68, 125.49, 126.47, 126.58, 127.34, 127.58, 128.12,
128.49, 128.83, 132.09, 135.20, 136.10, 137.65, 140.27, 154.87, 166.34, 166.66. MS: m/z 412 (M·+), 307,
217, 193, 174 (base peak), 165, 160, 132, 105, 104, 91, 77, 65. Anal. Calcd for C25H20N2O4: C, 72.80; H,
4.88; N, 6.79; Found C, 72.73, H, 4.77; N, 6.81.
N-1’-Ethyl-N-3’-isopropyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6p):
Product 5p, 3.0 g (10.345 mmol) was reacted with sodium periodate, 2.213 g (10.345 mmol) for 15 h.
Two recrystallizations from MeOH-water (9:1) resulted in 6p as white crystals. Yield: 74.0 %, m.p. 105-
1
107 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.45. IR (KBr) ν: 2989, 2945, 1780, 1732cm-1. H-NMR
(DMSO-d6): δ = 1.19 (d and t superimposed, 9H), 3.38 (septet, 1H), 3.56 (quartet, 1H), 7.84 (t, 1H), 7.93
(d, 1H), 7.96 (t, 1H), 8.06 (d, 1H). 13C-NMR (DMSO-d6): δ = 13.08, 20.44, 21.00, 34.04, 92.69, 124.02,
125.73, 126.83, 132.37, 135.83, 141.24, 153.85, 166.62, 166.67. MS: m/z 288 (M·+), 287, 273, 245, 230,
189, 174 (base peak), 160, 145, 132, 130, 104, 76, 56. Anal. Calcd for C15H16N2O4: C, 62.48; H, 5.59; N,
9.71; Found C, 62.67, H, 5.57; N, 9.73.
N-1’-Neopentyl-N-3’-isopropyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione
(6q):
Product 5q, 3.0 g (9.036 mmol) was reacted with sodium periodate, 1.933 g (9.036 mmol) for 15 h. Two
recrystallizations from MeOH-water (9:1) gave 6q as white crystals. Yield: 68.3 %, mp 86-88 ºC. TLC

374
HETEROCYCLES, Vol. 73, 2007
1
(70% toluene: 30% MeCN) Rf = 0.82. IR (KBr) ν: 2974, 2935, 1782, 1736cm-1. H-NMR (DMSO-d6): δ
= 0.90 (s, 9H), 1.18 (d,6H), 3.32 (s, 2H), 3.37 (septet, 1H), 7.82 (t, 1H), 7.90 (d, 1H), 7.94 (t, 1H), 8.05 (d,
1H). 13C-NMR (DMSO-d6): δ = 20.41, 20.89, 27.67, 33.34, 45.41, 49.73, 92.74, 123.78, 125.78, 126.87,
132.38, 135.93, 141.29, 154.47, 166.66, 167.51. MS: m/z 330 (M·+), 315, 274, 203, 189, 174 (base peak),
160, 132, 130, 104, 90, 76, 57, 41. Anal. Calcd for C18H22N2O4: C, 65.32; H, 6.70; N, 8.46; Found C,
65.25, H, 6.72; N, 8.57.
N-1’-Phenyl-N-3’-phenethyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-imidazolidine]-2’,3,5’-trione (6r):
Product 5r, 2.0 g (5.00 mmol) was reacted with sodium periodate, 1.07 g (5.00 mmol) with stirring for 19
h. Two recrystallizations from MeOH-water (9:1) resulted in 6r as white crystals. Yield: 60.0 %, mp
1
173-176 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.62. IR (KBr) ν: 1785, 1738, 1596 cm-1. H-NMR
(DMSO-d6): δ = 2.74 (sextet, 1H), 2.83 (sextet, 1H), 3.28 (septet, 1H), 3.60 (septet, 1H), 7.08 (d, 2H),
7.17-7.26 (multiplet, 3H), 7.48 (multiplet, 1H), 7.54 (multiplet, 4H), 7.86 (t, 1H), 7.94 (t, 1H), 8.09 (t, 2H).
13C-NMR (DMSO-d6): δ = 35.37, 42.49, 93.31, 125.27, 126.68, 127.32, 127.61, 127.76, 129.29, 129.37,
129.60, 129.90, 131.87, 133.37, 136.71, 138.75, 141.34, 154.73, 166.68, 167.39. MS: m/z 398 (M·+), 353,
307, 294, 266, 263, 206, 174, 160 (base peak), 119, 104, 91, 77, 76. Anal. Calcd for C24H18N2O4: C,
72.35; H, 4.55; N, 7.03; Found C, 72.18, H, 4.47; N, 7.00.
N-1’-(α,α-Dideutero-2-phenylethyl)-N-3’-benzyl-2’H,3H,5’H-spiro[2-benzofuran-1,4’-
imidazolidine]-2’,3,5’-trione (6s):
Product 5s, 2.0 g (4.95 mmol) was reacted with sodium periodate, 1.05 g (4.95 mmol) with stirring for 18
h. Two recrystallizations from MeOH-water (9:1) resulted in 6s as white crystals. Yield: 72.5 %, mp
1
172-174 ºC. TLC (70% toluene: 30% MeCN) Rf = 0.73. IR (KBr) ν: 1782, 1738, 1599 cm-1. H-NMR
(DMSO-d6): δ = 2.71 (d, 1H), 2.80 (d, 1H), 7.07 (d, 2H), 7.16-7.26 (multiplet, 3H), 7.45-7.57 (multiplet,
5H), 7.86 (t, 1H), 7.94 (t, 1H), 8.08 (d, 1H), 8.10 (d, 1H). 13C-NMR (DMSO-d6): δ = 34.31, 40.88, 92.42,
124.45, 125.83, 126.46, 126.78, 126.89, 128.44, 128.52, 128.76, 129.05, 130.97, 132.52, 135.87, 137.87,
140.46, 153.87, 166.04, 166.56. MS: m/z 400 (M·+), 309, 294, 266, 238, 174, 162 (base peak), 119, 104,
91, 76. Anal. Calcd for C24H16D2N2O4: C, 71.63; H, 4.50; N, 6.96; Found C, 71.83, H, 4.50; N, 7.00.
REFERENCES AND NOTES
1. H. J. Patel, J. Sarra, F. Caruso, M. Rossi, U. Doshi, and R. Stephani, Biorg. Med. Chem. Lett., 2006,
16, 4644.
2. L. C. Raiford and H. B. Freyermuth, J. Org. Chem., 1943, 8, 230.

HETEROCYCLES, Vol. 73, 2007
375
3. R. Shapiro and N. Chatterjee, J. Org. Chem., 1970, 35, 447.
4. J. D. Sarra and R. Stephani, Med. Chem. Res., 2000, 10, 81.
5. L. H. Amundsen and L. S. Nelson, J. Am. Chem. Soc., 1951, 73, 242.
6. I. Lengyel, V. Cesare, H. Karram, and T. Taldone, J. Heterocycl. Chem., 2002, 38, 997.
7. R. K. Hill and T.H. Chan, Tetrahedron, 1965, 21, 2015.
8. R. Stephani, V. Cesare, I. Sadarangani, and I. Lengyel, Synthesis, 2002, 47.
9. K. Mislow and M. Raban, ‘In Topics in Stereochemistry’, ed. by N.L. Allinger and E.L. Eliel, Eds.,
John Wiley & Sons, Inc.: New York, 1967, p. 26.
10. J. B. Lambert, H. F. Shurvell, D. A. Lightner, and R. G. Cooks, ‘Introduction to Organic
Spectroscopy’, Second Edition, Macmillan Publishing Company: New York, 1987, p. 71.
11. R. M. Silverstein and F. X. Webster, ‘Spectrometric Identification of Organic Compounds’, Sixth
Edition, John Wiley & Sons, Inc.: New York, 1998, p. 184.
12. J. K. Snyder and L. M. Stock, J. Org. Chem., 1980, 45, 886.
13. J. Izdebski and D. Pawlak, Synthesis, 1989, 6, 423.
14. H. Martin, E. Nikles, G. Pissiotas, and G. Janiak, Ger. Offen., 1971, DE 2048660.
15. Y. Mido and T. Okuno, J. Mol. Struc., 1982, 82, 29.
16. R. A. Franz, F. Applegath, F. V. Morriss, F. Baiocchi, and L. W. Breed, J. Org. Chem., 1962, 27, 4341.
17. L. C. Martinelli, C. D. Blanton, and J. F. Whidby, J. Am. Chem. Soc., 1971, 93, 5111.
18. K. H. Oh, J. E. Park, D. D. Sung, and I. Lee, J. Org. Chem., 2004, 69, 3150.
19. S. Gastaldi, S. M. Weinreb, and D. Stien, J. Org. Chem., 2000, 65, 3239.
20. S. Bhattacharyya, O. W. Gooding, and J. Labadie, Tetrahedron Lett., 2003, 44, 6099.
21. W. H. Carothers and G. A. Jones, J. Am. Chem. Soc., 1925, 47, 3051.
22. T. Isobe and T. Ishikawa, J. Org. Chem., 1999, 64, 5832.