Powerful approach to heterocyclic skeletal diversity by sequential three-component reaction of amines, isothiocyanates, and 1,2-diaza-1,3-dienes

Article abstract of DOI:10.1021/jo2021949

By highly efficient, one-pot, three-component reactions, combining one set of 1,2-diaza-1,3-dienes (DDs), primary amines, and isothiocyanates in a different sequential order of addition, heterocyclic skeletal diversity can be achieved. The key feature dis

Full text of DOI:10.1021/jo2021949

Note
pubs.acs.org/joc
Powerful Approach to Heterocyclic Skeletal Diversity by Sequential
Three-Component Reaction of Amines, Isothiocyanates, and 1,2-
Diaza-1,3-dienes
Orazio A. Attanasi,‡ Silvia Bartoccini,‡ Gianfranco Favi,‡ Gianluca Giorgi,† Francesca Romana Perrulli,‡
and Stefania Santeusanio*,‡
‡Dipartimento SteVa, Sezione COSON, Universita
̀
degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy
†Dipartimento di Chimica, Universita
̀
degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
S
* Supporting Information
ABSTRACT: By highly efficient, one-pot, three-component
reactions, combining one set of 1,2-diaza-1,3-dienes (DDs),
primary amines, and isothiocyanates in a different sequential
order of addition, heterocyclic skeletal diversity can be achieved.
The key feature discriminating the different heterocyclic core
formation is the availability of the N or S heteronucleophile to
give the first Michael addition step affording regioselective
substituted 2-thiohydantoins or 2-iminothiazolidinones. The
hydrazone or enehydrazino side chain at the 5-position of both heterocycles represents a valuable functionality to reach
novel 5-hydroxyethylidene derivatives difficult to obtain by other methods.
ive-membered rings containing two heteroatoms are
privileged structures as they belong to a class of
afforded the expected α-aminohydrazone intermediate.6 The
sequential one-pot addition of 4-methoxyphenylisothiocyanate
(3a) successfully gave the 2-thiohydantoin derivative 4a in 86%
yield (Table 1, entry 1).
F
compounds with proven utility in medicinal chemistry. As an
example, 2-thiohydantoin-1 and 2-iminothiazolidin-4-one-
based2 scaffolds can play an important role as synthetic
intermediates with a wide range of applications as therapeu-
tics1b−f and have been found to possess significant pharmaco-
logical activities2c−f as well as fungicides and herbicides.3
Multicomponent reactions (MCRs)4 are well-appreciated
procedures to reach skeletal diversity since they perform
molecular construction in a modular manner in such a way that
the final product incorporates in its structure one or more units
of each module in a precise and determined order.
Within this context, here we report a chemo-/regioselective
approach to heterocyclic skeletal diversity that can be achieved
by sequential three-component reactions involving acyclic
reagents, namely 1,2-diaza-1,3-dienes (DDs),5 primary amines,
and isothiocyanates, as an efficient method for the collection of
2-thiohydantoins and of 2-iminothiazolidin-4-ones simply by
varying the order of the addition of the three reagents taking
into account the mutual reactivity of the components of the
reactions.
In connection with our recent paper describing a synthetic
strategy for selectively trisubstituted hydantoin ring,6 we
envisaged the feasibility to apply the same approach to
tentatively achieve regioselective substituted 2-thiohydantoin
derivatives.
Since the electrophilic nature of the conjugated azo-ene
system of DDs 1 makes it subject to nucleophilic attack, initially
we explored the reaction of 1a (1 mmol) with benzylamine
(2a) (1 mmol) at room temperature in CHCl3 (4 mL) that
From a mechanistic point of view (Scheme 1), the 2-
thiohydantoin 4 core assembly arises from the initial N-
nucleophilic addition of 2 at the high-electrophilic center (C4)
of the conjugated azo-ene system of 1 to produce intermediate
A that rapidly coupled with isothiocyanate 3 affording the
intermediate B in which the unsymmetrical thiourea framework
is directly bonded to the α-carbon of the hydrazone moiety.
Although the contemporary presence in B of S and N
nucleophile centers could give rise to different intramolecular
ring closure, exclusive and spontaneous regioselective heteror-
ing closure by the thioureic nitrogen at the C4 ester function of
the azo-ene system with the loss of an alcohol molecule was
observed.
On the basis of this first result, primary alkylamines 2a−d
were reacted with 1a−g in CHCl3 at room temperature, and
subsequently (after the quickly disappearance of the reagents,
TLC check), isothiocyanates 3a−f were added to afford the
relevant 2-thiohydantoin derivatives 4a−l in good to excellent
yields (54−97%) (Table 1). The structural characterization of
4a−l was achieved by spectroscopic data (1H and 13C NMR,
IR, and MS) and unambiguously confirmed by X-ray crystal
structure analysis of 4h (see the Supporting Information).7
As expected, although primary aromatic amines worked well
in the Michael addition step, the resulting α-aminohydrazone
Received: October 26, 2011
Published: December 22, 2011
© 2011 American Chemical Society
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The Journal of Organic Chemistry
Note
Table 1. One-Pot, Three-Component Synthesis of 2-Thiohydantoins 4a−l
DD 1
R2
amine 2
isothiocyanate 3
2-thiohydantoin 4
a
entry
R1
R3
R4
Bn
R5
yield (%)
1
2
1a
1b
1c
1d
1e
1a
1f
CO2t-Bu
CO2Me
CONH2
CONHPh
CO2Me
CO2t-Bu
CO2t-Bu
CONH2
CONH2
CONH2
CONH2
CONH2
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Et
2a
2b
2c
2a
2c
2b
2a
2d
2b
2a
2c
2a
3a
3b
3c
3c
3a
3c
3a
3b
3d
3e
3d
3f
4-MeO-Ph
4a
4b
4c
4d
4e
4f
86
81
97
90
90
87
75
81
76
77
79
54
n-Bu
All
Ph
3
4-Cl-Ph
4-Cl-Ph
4-MeO-Ph
4-Cl-Ph
Ph
4
Et
Bn
5
Et
All
6
Me
Me
Me
Et
n-Bu
Bn
7
4g
4h
4i
8
1g
1c
1c
1c
1c
Me
Me
Me
Me
Me
n-Pr
n-Bu
Bn
Ph
9
Bn
10
11
12
Et
n-Bu
Bn
4j
Et
All
4k
4l
Et
Bn
All
a
Yield of isolated pure product based on amine 2.
Scheme 1. Mechanism Pathways for Sequential Three-Component Reaction of DDs, Amines, and Isothiocyanates
derivative proved to be inefficient in the subsequent
thioacylation reaction.6a
Nevertheless, this three-component sequence allows the total
regiocontrol of the aliphatic substitution pattern at N1 and N3
of the 2-thiohydantoin template (Table 1, 4i−l, entries 9−12)
not efficiently achievable through phosphine-catalyzed tandem
umpolung addition/intramolecular cyclization of weakly
asymmetric thioureas on alkynoates8 or by coupling of the
reductive alkylation of α-imino acid esters with isothiocya-
nates.9
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Note
Table 2. One-Pot, Three-Component Synthesis of 5-Hydrazinoethylidene-2-iminothiazolidin-4-ones 5a−g
DD 1
R2
amine 2
isothiocyanate 3
2-iminothiazolidin-4-one 5
a,b
entry
R1
R3
R4
R5
yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1a
1f
CO2t-Bu
CO2Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Et
2e
2f
4-MeO-Ph
Ph
3d
3e
3f
Bn
5a
5b
5c
5d
5e
5f
95
90
91
84
85
88
75
n-Bu
All
CONH2
CONHPh
CO2Me
2g
2g
2e
2g
2f
4-Cl-Ph
4-Cl-Ph
4-MeO-Ph
4-Cl-Ph
Ph
Et
3d
3f
Bn
Et
All
CO2t-Bu
CO2t-Bu
Me
Me
3e
3d
n-Bu
Bn
5g
a
b
Yield of isolated pure product based on amine 2. Yield referred to the mixture of E and Z isomers (approximately 3:1 ratio).
Next, to verify the possibility to perform a “classic” one-pot
according to Ottana
̀
et al.2d) and ready available for the
coupling with DDs 1a−f (0.5−5 h) yielding 5-hydrazinoethy-
lidene-2-iminothiazolidin-4-ones 5a−g (75−95%) (Table 2).
It is noteworthy that the present method is able to install
directly the hydrazinoalkylidene functionality at 5-position that,
at best of our knowledges, is difficult to obtain from the
Knoevenagel condensation of 5-unsubstituted 2-iminothiazoli-
din-4-one derivatives.
three-component reaction, we carried out the reaction by
putting all the reagents 1a, 2a, and 3a in one flask under the
same reaction conditions. After the disappearance of the
starting materials and chromatoraphic purification of the crude,
a mixture of 2-thiohydantoin 4a (30%) and 5-alkylidene-2-
iminothiazolidin-4-one 5a was obtained (23%).
The unexpected formation of the 2-iminothiazolidin-4-one
nucleus can be explained by the initial regioselective S-Michael
addition of the thiourea intermediate C, resulted from the
coupling of 2 and 3, at the electrophilic center of 1 followed by
intramolecular attack of the NH of the resulted isothiourea
derivative D at the ester function on C4 of the hydrazone chain
with a loss of an alcohol molecule (Scheme 1). Since the
formation of two regioisomers was possible, the regiochemistry
of 5a as the unique regioisomer formed was established by
1H{13C} HMBC experiment in which the benzylic protons on
N3 were found to correlate to both the sp2-hybridized carbon
atoms (CO and CN) of the heterocycle. The formation of
5a was in accordance with the results of Patel and co-workers10
who reported that regioselective formation of 5-unsubstituted
2-iminothiazolidin-4-ones is observed for unsymmetrical
thioureas in which the amine attached to the thiourea having
lower pKa is a part of the imino component and the amine
having higher pKa is the contributor to the other heterocyclic
nitrogen.
Both protocols, moreover, offer a valuable point of diversity
at C5 of the two different heterocycles providing directly
hydrazono or enehydrazino functionalities as masked carbonyl
function derived from the conjugated azo-ene system of DDs.
In general, as exemplified in Scheme 2, the simple hydrolytic
cleavage of the hydrazide moiety of 4a,b and 5a,b, under
heterogeneus acid conditions (Amberlyst 15 H), afforded
Scheme 2. Synthesis of 5-Hydroxyethylidene-thiohydantoins
6a,b and -thiazolidinones 7a,b by Hydrolytic Cleavage of
4a,b and 5a,b
The recognition of the predominant isomer with E-geometry
of the exocyclic CC bond of 5a was based on our previous
results.11
Based on these findings and taking into account that 5-
alkylidene-2-iminothiazolidin-4-ones with distinct substitution
patterns on each of the nitrogen atoms are scarcely
represented,2d,e we planned to achieve an array of regiose-
lectively substituted 5-hydrazinoethylidene-2-iminothiazolidin-
4-one derivatives 5 by a sequential one-pot three-component
reaction.
Thus, by addition of alkylisothiocyanates 3d−f (1 mmol) to a
solution of primary aromatic amines 2e−g (1 mmol) in CHCl3
(4 mL) at room temperature, the corresponding unsymmetrical
thiourea derivative C (Scheme 1, Table 2) was formed quickly
(0.2−0.5 h by TLC, checked with authentic sample prepared
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The Journal of Organic Chemistry
Note
402.9 mg (86%). White powder. Mp: 193−195 °C (from CHCl3_-
light petroleum ether). IR (Nujol, ν, cm−1): 3230, 1755, 1715, 1638,
1620, 1592. 1H NMR (400 MHz, DMSO-d6) δ: 1.48 (s, 9H), 1.55 (s,
3H), 3.80 (s, 3H), 4.84 (d, J = 15.2 Hz, 1H), 5.01 (s, 1H), 5.11 (d, J =
15.2 Hz, 1H), 7.04 (d, J = 6.8 Hz, 2H), 7.29−7.39 (m, 7H), 9.98 (s,
1H). 13C NMR (100 MHz, DMSO-d6) δ: 12.5 (q), 28.0 (q), 48.8 (t),
55.4 (q), 69.1 (d), 79.8 (s), 114.1 (d), 126.3 (s), 127.7 (d), 128.4 (d),
128.5 (d), 129.9 (d), 135.3 (s), 142.9 (s), 152.7 (s), 159.4 (s), 170.1
(s), 183.1 (s). MS (EI): m/z = 468 (M+, 5), 412 (15), 368 (17), 352
(25), 311 (9), 277 (12), 165 (100), 106 (40). Anal. Calcd for
C24H28N4O4S (468.56): C, 61.52; H, 6.02; N, 11.96. Found: C, 61.38;
H, 6.14; N, 11.89.
Methyl 2-[1-(3-Butyl-5-oxo-1-phenyl-2-thioxoimidazolidin-4-yl)-
ethylidene]hydrazinecarboxylate (4b). Yield: 293.5 mg (81%).
White powder. Mp: 180−183 °C (from EtOAc−Et2O). IR (Nujol,
ν, cm−1): 3329, 1749, 1734, 1644, 1507. 1H NMR (400 MHz, DMSO-
d6) δ: 0.89 (t, J = 7.2 Hz, 3H), 1.27−1.36 (m, 2H), 1.53−1.61 (m, 2H)
1.81 (s, 3H), 3.35−3.43 (m, 1H), 3.70 (s, 3H), 3.93−4.01 (m, 1H),
5.15 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.43−7.50 (m, 3H), 10.42 (s,
1H). 13C NMR (100 MHz, DMSO-d6) δ: 12.5 (q), 13.5 (q), 19.3 (t),
28.4 (t), 45.2 (t), 52.1 (q), 68.9 (d), 128.7 (d), 128.8 (d), 133.6 (s),
144.0 (s), 154.4 (s), 169.9 (s), 181.9 (s). MS (EI): m/z = 362 (M+,
38), 288 (100), 247 (20), 171 (61), 135 (42), 115 (46). Anal. Calcd
for C17H22N4O3S (362.44): C, 56.33; H, 6.12; N, 15.46. Found: C,
56.49; H, 5.99; N, 15.37.
unknown 5-hydroxyethylidenethiohydantoins 6a,b and 5-
hydroxyethylidenethiazolidinones 7a,b in excellent yields
(85−98%) both being difficult to access by reacting
imidazoledithioate12 and amino acid esters building
blocks,9,13,14 or by a compatible subsequent condensation
process of 5-unsubstituted thiazolidinone derivative, respec-
tively.15
In summary, by combining a set of acyclic substrates/
reagents, namely 1,2-diaza-1,3-dienes, primary amines, and
isothiocyanates in a different order of addition under the same
reaction conditions, a robust chemo-/regioselective approach to
heterocyclic skeletal diversity can be achieved by means of high-
yielding, one-pot, three-component reactions. The protocols
here described afforded selectively substituted 1,3,5-trisubsti-
tuted 2-thiohydantoins or 2-iminothiazolidin-4-ones bearing a
valuable point of diversity at the 5-position of the heterorings.
Both of the different heterocyclic scaffolds can be easily
transformed into their corresponding 5-acetyl enol form
derivatives. These latter ones, obtained in near-quantitative
yields, are not easy accessible by other methods and could be
useful for further chemical transformations. Moreover, despite
the presence in the literature of many examples of 5-arylidene-
2-iminothiazolidin-4-one of therapeutic interest,2d,e there are no
reports concerning the formation of 5-alkylidene-functionalized
2-iminothiazolidin-4-one. In addition, the mild and simple
reaction conditions of these procedures (no catalyst, no dry
solvents, or inert atmosphere) make them suitable for the
generation of library of functionalized 2-iminothiazolidinone
and 1,3,5-thiohydantoin derivatives.
1-[3-Allyl-1-(4-chlorophenyl)-5-oxo-2-thioxoimidazolidin-4-yl)]-
ethan-1-one Semicarbazone (4c). Yield: 354.8 mg (97%). White
powder. Mp: 182−184 °C (from CHCl3−Et2O). IR (Nujol, ν, cm−1):
3444, 3216, 3159, 1751, 1713, 1688, 1653, 1582. 1H NMR (400 MHz,
DMSO-d6) δ: 1.75 (s, 3H), 4.15 (dd, J = 6.0 Hz, J = 15.6 Hz, 1H),
4.52 (dd, J = 6.0 Hz, J = 15.6 Hz, 1H), 5.02 (s, 1H), 5.23−5.27 (m,
2H), 5.79−5.86 (m, 1H), 6.49 (br s, 2H), 7.40−7.42 (m, 2H), 7.56−
7.59 (m, 2H), 9.65 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 12.4
(q), 47.9 (t), 69.2 (d), 119.2 (t), 129.0 (d), 130.7 (d), 130.8 (d), 132.5
(s), 133.6 (s), 138.3 (s), 156.7 (s), 169.9 (s), 181.6 (s). MS (EI): m/z
= 367 [M+ + 2 (1)], 365 (M+, 2), 306 (100), 265 (11), 225 (46), 169
(33), 111 (22), 100 (35). Anal. Calcd for C15H16ClN5O2S (365.83):
C, 49.25; H, 4.41; N, 19.14. Found: C, 49.18; H, 4.28; N, 19.04.
1-[3-Benzyl-1-(4-chlorophenyl)-5-oxo-2-thioxoimidazolidin-4-yl]-
ethan-1-one N-Phenylsemicarbazone (4d). Yield: 442.8 mg (90%).
White powder. Mp: 207−209 °C (from CHCl3−Et2O). IR (Nujol, ν,
EXPERIMENTAL SECTION
■
General Methods. All chemicals and solvents were purchased
from commercial suppliers and used as received. 1,2-Diaza-1,3-dienes
(DDs) were prepared as reported5,16 and used as EE/EZ isomer
mixtures. Melting points were determined in open capillary tubes and
are uncorrected. FT-IR spectra were obtained as Nujol mulls or neat.
Mass spectra (MS) were carried out by electron impact (EI) at an
1
cm−1): 3392, 3209, 1754, 1713, 1635, 1598, 1544, 1501. H NMR
1
ionizing voltage of 70 eV. H NMR (400 MHz) and 13C NMR (100
(400 MHz, DMSO-d6) δ: 1.51 (s, 3H), 5.00 (d, J = 15.6 Hz, 1H), 5.05
(d, J = 15.6 Hz, 1H), 5.19 (s, 1H), 7.03 (t, J = 7.2 Hz, 1H), 7.29−7.61
(m, 13H), 8.87 (s, 1H), 9.90 (s, 1H). 13C NMR (100 MHz, DMSO-
d6) δ: 12.1 (q), 49.1 (t), 69.4 (d), 119.4 (d), 122.5 (d), 127.7 (d),
128.3 (d), 128.6 (d), 128.9 (d), 130.7 (d), 132.5 (s), 133.6 (s), 135.3
(s), 138.8 (s), 139.8 (s), 152.7 (s), 169.7 (s), 182.3 (s). MS (EI): m/z
= 491 (M+, 3), 398 (10), 315 (8), 241 (31), 176 (87), 169 (80), 119
(100). Anal. Calcd for C25H22ClN5O2S (491.99): C, 61.03; H, 4.51; N,
14.23. Found: C, 60.91; H, 4.59; N, 14.14.
Methyl 2-[1-[3-Allyl-1-(4-methoxyphenyl)-5-oxo-2-thioxoimida-
zolidin-4-yl]ethylidene]hydrazinecarboxylate (4e). Yield: 338.8 mg
(90%). White powder. Mp: 177−180 °C (from EtOAc−Et2O). IR
(Nujol, ν, cm−1): 3205, 1751, 1712, 1649, 1614, 1545, 1524. 1H NMR
(400 MHz, DMSO-d6) δ: 1.79 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 4.15
(dd, J = 6.4 Hz, J = 15.6 Hz, 1H), 4.53 (dd, J = 6.4 Hz, J = 15.6 Hz,
1H), 5.07 (s, 1H), 5.21−5.27 (m, 2H), 5.78−5.87 (m, 1H), 7.01−7.04
(m, 2H), 7.22−7.25 (m, 2H), 10.39 (s, 1H). 13C NMR (100 MHz,
DMSO-d6) δ: 12.8 (q), 48.0 (t), 52.1 (q), 55.3 (q), 68.8 (d), 114.1
(d), 119.2 (t), 126.1 (s), 129.9 (d), 130.9 (d), 143.9 (s), 154.4 (s),
159.3 (s), 170.1 (s), 182.5 (s). MS (EI): m/z = 376 (M+, 10), 302
(100), 261 (11), 247 (13), 220 (49), 165 (67). Anal. Calcd for
C17H20N4O4S (376.43): C, 54.24; H, 5.36; N, 14.88. Found: C, 54.11;
H, 5.44; N, 14.75.
MHz) spectra were recorded in DMSO-d6 or in CDCl3 as specified
below. Chemical shifts (δH) and (δC) are reported in parts per million
(ppm) and were referred to solvent signals as follows: δ = 2.50 ppm
for proton (middle peak) and δ = 39.50 ppm for carbon in DMSO; δ
= 7.26 ppm for proton and δ = 77.00 ppm for carbon (middle peak) in
CDCl3. All coupling constants (J values) are given in hertz (Hz). The
following abbreviations are used to describe peak patterns where
appropriate: s, singlet; d, doublet; dd, double−doublet; t, triplet; q,
quartet; m, multiplet; br, broad. All the NH exchanged with D2O.
Precoated silica gel plates 0.25 mm were employed for analytical thin
layer chromatography and silica gel 35−70 μm for column
chromatography. All new compounds showed satisfactory elemental
analysis. The nomenclature was generated using ACD/IUPACName
(version 3.50, 5 Apr. 1998), Advanced Chemistry Development Inc.,
Toronto, ON, Canada.
General One-Pot, Three-Component Procedure for the
Synthesis of 2-Thiohydantoin Derivatives 4a−l. To a stirred
solution of DD 1a−g (1 mmol) in CHCl3 (4 mL) was added primary
alkyl amine derivative 2a−d (1 mmol) at room temperature. After the
disappearance of the reagents (0.1−0.5 h) (TLC check), isothiocya-
nate derivative 3a−f was added, and the reaction mixture was allowed
to stand at room temperature until completion of the reaction (0.5−18
h). After removal of the reaction solvent, thiohydantoins 4a−f and
4h,i,l were obtained by crystallization from appropriate solvents,
whereas 4g,j,k were achieved after chromatographic purification
(cyclohexane/ethyl acetate mixtures) and subsequent crystallization.
tert-Butyl 2-[1-[3-Benzyl-1-(4-methoxyphenyl)-5-oxo-2-thioxoi-
midazolidin-4-yl]ethylidene]hydrazinecarboxylate (4a). Yield:
tert-Butyl 2-[1-[3-Butyl-1-(4-chlorophenyl)-5-oxo-2-thioxoimida-
zolidin-4-yl]ethylilene]hydrazinecarboxylate (4f). Yield: 351.2 mg
(87%). White powder. Mp: 181−183 °C (from CHCl3−light
petroleum ether). IR (Nujol, ν, cm−1): 3204, 1758, 1752, 1707,
1
1639, 1536. H NMR (400 MHz, DMSO-d6) δ: 0.89 (t, J = 7.2 Hz,
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The Journal of Organic Chemistry
Note
3H), 1.27−1.36 (m, 2H), 1.46 (s, 9H), 1.51−1.63 (m, 2H), 1.80 (s,
3H), 3.35−3.39 (m, 1H), 3.95−4.01 (m, 1H), 5.13 (s, 1H), 7.36−7.39
(m, 2H), 7.54−7.58 (m, 2H), 10.12 (s, 1H). 13C NMR (100 MHz,
DMSO-d6) δ: 12.6 (q), 13.5 (q), 19.3 (t), 28.0 (q), 28.4 (t), 45.1 (t),
69.0 (d), 79.8 (s), 128.9 (d), 130.6 (d), 132.4 (s), 133.5 (s), 143.2 (s),
152.7 (s), 169.8 (s), 181.4 (s). MS (EI): m/z (%) = 438 (M+, 5), 382
(41), 338 (56), 322 (100), 308 (57), 282 (79), 169 (70), 113 (97).
Anal. Calcd for C20H27ClN4O3S (438.97): C, 54.72; H, 6.20; N, 12.76.
Found: C, 54.61; H, 6.29; N, 12.69.
tert-Butyl 2-[(3-Benzyl-5-oxo-1-phenyl-2-thioxoimidazolidin-4-
yl)(phenyl)methylene]hydrazinecarboxylate (4g). Yield: 375.4 mg
(75%). White powder. Mp: 176−179 °C (from Et2O). IR (Nujol, ν,
cm−1): 3357, 1752, 1739, 1710, 1596. 1H NMR (400 MHz, DMSO-d6)
δ: 1.43 (s, 9H), 4.68 (d, J = 15.6 Hz, 1H), 5.24 (s, 1H), 5.41 (d, J =
15.6 Hz, 1H), 6.99 (d, J = 6.0 Hz, 2H), 7.07−7.10 (m, 2H), 7.34−7.50
(m, 11H), 9.60 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 27.9 (q),
48.4 (t), 68.8 (d), 80.2 (s), 127.5 (d), 127.8 (d), 128.3 (d), 128.4 (d),
128.5 (d), 128.9 (d), 129.2 (d), 130.0 (s), 133.5 (s), 134.9 (s), 142.8
(s), 152.2 (s), 169.7 (s), 182.3 (s). MS (EI): m/z = 500 (M+, 6), 444
(34), 400 (46), 384 (100), 309 (35), 281 (43), 241 (14), 160 (40).
Anal. Calcd for C28H28N4O3S (500.61): C, 67.18; H, 5.64; N, 11.19.
Found: C, 67.05; H, 5.81; N, 11.23.
100 (53). Anal. Calcd for C16H19N5O2S (345.42): C, 55.63; H, 5.54;
N, 20.27. Found: C, 55.78; H, 5.47; N, 20.38.
1-(1-Allyl-3-benzyl-5-oxo-2-thioxoimidazolidin-4-yl)ethan-1-one
Semicarbazone (4l). Yield: 186.5 mg (54%). White powder. Mp:
163−166 °C (from EtOAc−cyclohexane). IR (Nujol, ν, cm−1): 3414,
3287, 3285, 3157, 1750, 1702, 1671, 1628, 1584. 1H NMR (400 MHz,
DMSO-d6) δ: 1.58 (s, 3H), 4.09 (dd, J = 6.0 Hz, J = 15.4 Hz, 1H),
4.49 (dd, J = 6.0 Hz, J = 15.4 Hz, 1H), 4.89−5.01 (m, 3H), 5.16−5.20
(m, 2H), 5.75−5.82 (m, 1H), 6.39 (br s, 2H), 7.26−7.35 (m, 5H),
9.59 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 12.5 (q), 44.7 (t),
47.8 (t), 68.3 (d), 119.0 (t), 127.4 (d), 128.4 (d), 130.9 (d), 136.0 (s),
138.3 (s), 156.5 (s), 170.6 (s), 182.0 (s). MS (EI): m/z = 345 (M+, 2),
328 (7), 286 (100), 270 (43), 245 (17), 205 (52), 106 (27), 100 (58).
Anal. Calcd for C16H19N5O2S (345.42): C, 55.63; H, 5.54; N, 20.27.
Found: C, 55.50; H, 5.66; N, 20.34.
General One-Pot, Three-Component Procedure for the
Synthesis of 2-Iminothiazolidin-4-one Derivatives 5a−g. To a
stirred solution of primary aromatic amine derivative 2e−g (1 mmol)
in CHCl3 (4 mL) was added alkylisothiocyanate 3d−f at room
temperature. After the formation of the corresponding thiourea
derivative (0.2−0.5 h, TLC check with an authentic sample), DD 1a−f
(1 mmol) was added as solid or dissolved in CHCl3 (1 mL), and the
reaction mixture was left at room temperature until the reaction was
complete (0.5−6 h, TLC check). In general, the solvent was removed
under reduced pressure and the crude reaction mixture was purified by
column chromatography (cyclohexane/ethyl acetate mixtures) to
afford 5 as mixture of C5 E/Z isomers (approximately ratio 3:1). In
the case of 5b−e solid compound was obtained by precipitation from
the reaction medium and subsequent recrystallization from the
appropriate solvents.
1-(5-Oxo-1-pheny1-3-propyl-2-thioxoimidazolidin-4-yl)ethan-1-
one Semicarbazone (4h). Yield: 270.0 mg (81%). Colorless crystals.
Mp: 169−171 °C (from EtOH). IR (Nujol, ν, cm−1): 3429, 3285, 3202
1
1742, 1710, 1693, 1678, 1590. H NMR (400 MHz, DMSO-d6) δ:
0.89 (t, J = 7.2 Hz, 2H), 1.57−1.69 (m, 2H), 1.77 (s, 3H), 3.31−3.38
(m, 1H), 3.90−3.96 (m, 1H), 5.07 (s, 1H), 6.51 (br s, 2H), 7.33 (d, J
= 7.2 Hz, 2H), 7.45−7.52 (m, 3H), 9.67 (s, 1H). 13C NMR (100
MHz, DMSO-d6) δ: 11.1 (q), 12.0 (q), 19.9 (t), 47.0 (t), 69.0 (d),
128.8 (d), 128.9 (d), 133.7 (s), 138.5 (s), 156.7 (s), 170.2 (s), 181.9
(s). MS (EI): m/z = 333 (M+, 19), 316 (25), 290 (12), 274 (88), 233
(38), 135 (91), 100 (100). Anal. Calcd for C15H19N5O2S (333.40): C,
54.04; H, 5.74; N, 21.01. Found: C, 54.20; H, 5.87; N, 20.09.
1-(1-Benzyl-3-butyl-5-oxo-2-thioxoimidazolidin-4-yl)ethan-1-one
Semicarbazone (4i). Yield: 274.7 mg (76%). White powder. Mp:
173−176 °C (from EtOAc). IR (Nujol, ν, cm−1): 3396, 3283, 3184,
1748, 1697, 1685, 1671, 1638, 1585. 1H NMR (400 MHz, DMSO-d6)
δ: 0.85−0.90 (m, 3H), 1.24−1.28 (m, 2H), 1.50−1.59 (m, 5H), 3.24−
3.30 (m, 1H), 3.92−3.99 (m, 1H), 4.90 (d, J = 15.2 Hz, 1H), 4.96−
5.01 (m, 2H), 6.44 (br s, 2H), 7.26−7.34 (m, 5H), 9.63 (s, 1H). 13C
NMR (100 MHz, DMSO-d6) δ: 12.1 (q), 13.5 (q), 19.3 (t), 28.4 (t),
44.6 (t), 44.9 (t), 68.2 (d), 127.3 (d), 127.4 (d), 128.4 (d), 136.1 (s),
138.3 (s), 156.6 (s), 170.6 (s), 181.8 (s). MS (EI): m/z = 361 (M+,
17), 344 (22), 302 (51), 261 (26), 111 (62), 100 (100). Anal. Calcd
for C17H23N5O2S (361.46): C, 56.49; H, 6.41; N, 19.38. Found: C,
56.57; H, 6.57; N, 19.30.
1-(3-Benzyl-1-butyl-5-oxo-2-thioxoimidazolidin-4-yl)ethan-1-one
Semicarbazone (4j). Yield: 278.3 mg (77%). White powder. Mp:
138−140 °C (from MeOH). IR (Nujol, ν, cm−1): 3395, 3352, 3201,
1743, 1723, 1648, 1577. 1H NMR (400 MHz, DMSO-d6) δ: 0.89 (t, J
= 7.2 Hz, 3H), 1.25−1.30 (m, 5H), 1.55−1.61 (m, 2H), 3.73−3.78 (m,
2H), 4.83−4.87 (m, 2H), 4.93 (d, J = 15.2 Hz, 1H), 6.41 (br s, 2H),
7.29−7.31 (m, 5H), 9.43 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ:
11.7 (q), 13.5 (q), 19.4 (t), 29.2 (t), 41.4 (t), 48.7 (t), 68.8 (d), 127.6
(d), 128.3 (d), 128.4 (d), 135.5 (s), 138.2 (s), 156.5 (s), 170.5 (s),
182.7 (s). MS (EI): m/z = 361 (M+, 12), 344 (14), 302 (22), 286
(46), 261 (61), 106 (100), 100 (50). Anal. Calcd for C17H23N5O2S
(361.46): C, 56.49; H, 6.41; N, 19.38. Found: C, 56.42; H, 6.52; N,
19.34.
tert-Butyl 2-[1-[3-Benzyl-2-[(4-methoxyphenyl)imino]-4-oxo-1,3-
thiazolidin-5-ylidene]ethyl]hydrazinecarboxylate (5a). Yield: 445.1
mg (95%). Light yellow foam. IR (Nujol, ν, cm−1): 3301, 3278, 1736,
1
1718, 1670, 1618, 1507. H NMR (400 MHz, DMSO-d6) δ: 1.31 and
1.40 (2s, 9H), 1.85 and 2.31 (2s, 3H), 3.71 and 3.72 (2s, 3H), 4.92
and 4.96 (2s, 2H), 6.79 and 6.90 (m, 4H), 7.25−7.36 (m, 5H), 8.80
and 9.77 (br s and s, 1H), 9.28 (s, 1H). 13C NMR (100 MHz, DMSO-
d6) δ: 16.6 (q), 26.3 (q), 27.9 (q), 44.3 (t), 44.6 (t), 55.2 (q), 80.0 (s),
80.1 (s), 84.1 (s), 114.3 (d), 114.6 (d), 122.1 (d), 122.3 (d), 127.1
(d), 127.6 (d), 128.3 (d), 128.4 (d), 136.8 (s), 137.3 (s), 141.7 (s),
142.5 (s), 151.1 (s), 154.9 (s), 155.7 (s), 155.9 (s), 166.3 (s). MS
(EI): m/z = 468 (M+, 3), 368 (3), 275 (50), 197 (100), 122 (51).
Anal. Calcd for C24H28N4O4S (468.56): C, 61.52; H, 6.02; N, 11.96.
Found: C, 61.67; H, 5.91; N, 11.87.
Methyl 2-[1-[3-Butyl-4-oxo-2-(phenylimino)-1,3-thiazolidin-5-
ylidene]ethyl]hydrazinecarboxylate (5b). Yield: 326.2 mg (90%).
White powder (from Et2O−light petroleum ether). IR (Nujol, ν,
1
cm−1): 3337, 3295, 1742, 1729, 1664, 1616, 1587, 1497. H NMR
(400 MHz, DMSO-d6) δ: 0.89−0.94 (m, 3H), 1.26−1.36 (m, 2H),
1.56−1.65 (m, 2H), 1.85 and 2.34 (2s, 3H), 3.56 and 3.63 (2s, 3H),
3.72−3.78 (m, 2H), 6.90−6.95 (m, 2H), 7.04−7.11 (m, 1H), 7.30−
7.36 (m, 2H), 8.74 and 9.85 (br s and s, 1H), 9.51 (s, 1H). 13C NMR
(100 MHz, DMSO-d6) δ: 13.6 (q), 16.7 (q), 19.5 (t), 19.6 (t), 29.0
(t), 41.0 (t), 41.2 (t), 52.3 (q), 84.3 (s), 87.5 (s), 121.1 (d), 121.3 (d),
123.5 (d), 123.9 (d), 129.1 (d), 129.3 (d), 149.0 (s), 149.3 (s), 151.5
(s), 152.1 (s), 154.6 (s), 156.6 (s), 165.7 (s), 166.1 (s). MS (EI): m/z
= 362 (M+, 67), 330 (9), 288 (12), 274 (33), 175 (54), 119 (78), 101
(100). Anal. Calcd for C17H22N4O3S (362.44): C, 56.33; H, 6.12; N,
15.46. Found: C, 56.21; H, 6.22; N, 15.39.
2-[1-[3-Allyl-2-[(4-chlorophenyl)imino]-4-oxo-1,3-thiazolidin-5-
ylidene]ethyl]hydrazinecarboxamide (5c). Yield: 332.9 mg (91%).
White powder (from EtOAc−Et2O). IR (Nujol, ν, cm−1): 3426, 3311,
3252, 3200, 1711, 1677, 1633, 1617, 1588, 1536, 1496. 1H NMR (400
MHz, DMSO-d6) δ: 1.88 and 2.33 (2s, 3H), 4.33−4.38 (m, 2H),
5.07−5.21 (m, 2H), 5.83−5.91 (m, 1H), 6.18 and 6.20 (2s, 2H),
6.91−7.00 (m, 2H), 7.33−7.43 (m, 2H), 8.15 (s, 1H), 8.80 and 9.78
(br s and s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 12.6 (q), 16.8
(q), 43.1 (t), 43.4 (t), 83.5 (s), 85.6 (s), 116.4 (t), 116.7 (t), 123.0 (d),
123.2 (d), 127.3 (s), 129.1 (d), 129.3 (d), 132.3 (d), 147.8 (s), 148.1
(s), 152.1 (s), 153.3 (s), 156.5 (s), 156.7 (s), 158.5 (s), 158.6 (s),
1-(3-Allyl-1-benzyl-5-oxo-2-thioxoimidazolidin-4-yl)ethan-1-one
Semicarbazone (4k). Yield: 272.9 mg (79%). White powder. Mp:
145−147 °C (from EtOAc−cyclohexane). IR (Nujol, ν, cm−1): 3486,
3210, 3157, 1750, 1714, 1638, 1588. 1H NMR (400 MHz, DMSO-d6)
δ: 1.33 (s, 3H), 4.38 (br s, 2H), 4.83−4.96 (m, 3H), 5.10−5.17 (m,
2H), 5.78−5.90 (m, 1H), 6.39 (br s, 2H), 7.23−7.35 (m, 5H), 9.43 (s,
1H). 13C NMR (100 MHz, DMSO-d6) δ: 11.9 (q), 43.7 (t), 48.8 (t),
68.8 (d), 117.1 (t), 127.7 (d), 128.4 (d), 131.4 (d), 135.5 (s), 138.2
(s), 156.5 (s), 170.1 (s), 182.4 (s). MS (EI): m/z = 345 (M+, 14), 328
(11), 286 (18), 270 (22), 245 (17), 204 (48), 111 (42), 106 (100),
1165
dx.doi.org/10.1021/jo2021949 | J. Org. Chem. 2012, 77, 1161−1167

The Journal of Organic Chemistry
Note
165.1 (s), 165.8 (s). MS (EI): m/z = 367 [M+ + 2 (15)], 365 (M+,
43), 348 (100), 307 (8), 292 (13), 225 (35), 193 (45), 130 (79), 101
(97). Anal. Calcd for C15H16ClN5O2S (365.83): C, 49.25; H, 4.41; N,
19.14. Found: C, 49.32; H, 4.29; N, 19.23.
The crude reaction mixture was purified by flash chromatography
eluting with cyclohexane/ethyl acetate mixtures to obtain pure
derivatives 6a,b or 7a,b.
1-Benzyl-5-(1-hydroxyethylidene)-3-(4-methoxyphenyl)-2-thio-
xoimidazolidin-4-one (6a). Compound 6a was isolated by column
chromatography (ethyl acetate/cyclohexane 50:50) in 98% yield
(347.3 mg) as a yellow oil. IR (neat, ν, cm−1): 3392, 1766, 1728, 1611,
2-[1-[3-Benzyl-2-[(1-(4-chlorophenyl)imino]-4-oxo-1,3-thiazoli-
din-5-ylidene]ethyl]-N-phenylhydrazinecarboxamide (5d). Yield:
413.3 mg (84%). White crystals (from EtOAc−Et2O−light petroleum
ether). IR (Nujol, ν, cm−1): 3276, 3201, 3099, 1711, 1698, 1652, 1629,
1
1590. H NMR (400 MHz DMSO-d6) δ: 2.38 (s, 3H), 3.80 (s, 3H),
1
5.64 (s, 2H), 7.02 (d, J = 8.8 Hz, 2H), 7.23−7.33 (m, 7H), 12.12 (br s,
1H). 13C NMR (100 MHz, DMSO-d6) δ: 14.0 (q), 49.2 (t), 55.3 (q),
108.6 (s), 113.9 (d), 114.2 (d), 126.4 (d), 126.7 (d), 127.1 (s), 128.1
(d), 128.2 (d), 129.6 (d), 130.0 (d), 137.7 (s), 155.0 (s), 159.0 (s),
163.1 (s), 173.2 (s). MS m/z: 354 (M+, 44), 327 (69), 312 (100), 166
(19), 149 (49), 108 (14). Anal. Calcd for C19H18N2O3S (354.42): C
64.39, H 5.12, N 7.90; Found: C 64.51, H 5.03, N 8.01.
1603, 1573, 1547. H NMR (400 MHz, DMSO-d6) δ: 1.82 and 2.41
(2s, 3H), 4.94 and 4.99 (2s, 2H), 6.96−7.01 (m, 2H), 7.25−7.55 (m,
12H), 8.48 (br s, 1H), 8.85 (s, 1H), 8.94 and 9.99 (br s and s, 1H).
13C NMR (100 MHz, DMSO-d6) δ: 12.5 (q), 16.9 (q), 44.3 (t), 44.6
(t), 84.0 (s), 85.9 (s), 118.7 (d), 119.2 (d), 122.3 (d), 122.7 (d), 123.0
(d), 123.1 (d), 127.3 (d), 127.4 (d), 127.5 (s), 127.6 (d), 127.9 (s),
128.3 (d), 128.4 (d), 128.5 (d), 128.7 (d), 129.0 (d), 129.3 (d), 136.6
(s), 137.1 (s), 139.1 (s), 139.3 (s), 147.6 (s), 147.9 (s), 152.9 (s),
153.4 (s), 155.1 (s), 155.4 (s), 165.3 (s), 166.0 (s). MS (EI): m/z =
493 [M+ + 2 (5)], 491 (M+, 13), 398 (52), 274 (100), 241 (57), 179
(79), 119 (83). Anal. Calcd for C25H22ClN5O2S (491.99): C, 61.03; H,
4.51; N, 14.23. Found: C, 61.12; H, 4.39; N, 14.32.
Methyl 2-[1-[3-allyl-2-[(4-methoxyphenyl)imino]-4-oxo-1,3-thia-
zolidin-5-ylidene]ethyl]hydrazinecarboxylate (5e). Yield: 319.9 mg
(85%). Light gray powder (from EtOAc−Et2O). IR (Nujol, ν, cm−1):
3317, 3290, 1742, 1653, 1616, 1585. 1H NMR (400 MHz, DMSO-d6)
δ: 1.86 and 2.34 (2s, 3H), 3.58 and 3.62 (2s, 3H), 3.73 (s, 3H), 4.33−
4.38 (m, 2H), 5.09−5.17 (m, 2H), 5.84−5.94 (m, 1H), 6.83−6.92 (m,
4H), 8.75 and 9.82 (br and s, 1H), 9.52 (br s, 1H). 13C NMR (100
MHz, DMSO-d6) δ: 16.2 (q), 16.7 (q), 43.4 (t), 43.5 (t), 52.4 (q),
55.2 (q), 84.7 (s), 86.7 (s), 114.4 (d), 114.6 (d), 116.5 (t), 116.7 (t),
122.1 (d), 122.3 (d), 132.0 (d), 132.4 (d), 141.9 (s), 142.1 (s), 150.8
(s), 155.7 (s), 155.9 (s), 156.7 (s), 156.8 (s), 165.4 (s), 165.8 (s). MS
(EI): m/z = 376 (M+, 46), 344 (8), 287 (2), 189 (36), 147 (100), 101
(53). Anal. Calcd for C17H20N4O4S (376.43): C, 54.24; H, 5.36; N,
14.88. Found: C, 54.16; H, 5.49; N, 14.79.
1-Butyl-5-(1-hydroxyethylidene)-3-phenyl-2-thioxoimidazolidin-
4-one (6b). Compound 6b was isolated by column chromatography
(ethyl acetate/cyclohexane 30:70) in 97% yield (281.6 mg) as orange
1
oil. IR (neat, ν, cm−1): 3308, 1759, 1739, 1655, 1599. H NMR (400
MHz DMSO-d6) δ: 0.92 (t, J = 7.2 Hz, 3H), 1.30−1.36 (m, 2H),
1.64−1.68 (m, 2H), 2.45 (s, 3H), 4.33−4.37 (m, 2H), 7.25−7.48 (m,
5H), 11.15 (br s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 13.7 (q),
17.7 (q), 19.4 (t), 30.3 (t), 46.0 (t), 108.5 (s), 128.6 (d), 128.7 (d),
128.9 (d), 134.4 (s), 154.7 (s), 163.1 (s), 171.6 (s). MS m/z: 290 (M+,
66), 263 (88), 248 (100), 234 (11), 215 (75), 136 (57), 119 (33).
Anal. Calcd. for C15H18N2O2S (290.38): C 62.04, H 6.25, N 9.65;
Found: C 62.17, H 6.36, N 9.53.
3-Benzyl-5-(1-hydroxyethylidene)-2-[(4-methoxyphenyl)imino]-
1,3-thiazolidin-4-one (7a). Compound 7a was isolated by column
chromatography (ethyl acetate/cyclohexane 40:60) in 91% yield
(322.5 mg) as a yellow oil. IR (neat): 3284, 1750, 1728, 1635, 1614,
1
1505. H NMR (400 MHz, DMSO-d6) δ: 2.45 (s, 3H), 3.73 (s, 3H),
4.96 and 4.99 (2s, 2H), 6.85−6.92 (m, 4H), 7.26−7.35 (m, 5H), 11.67
(br s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 18.2 (q), 44.7 (t), 55.2
(q), 94.6 (s), 114.6 (d), 122.2 (d), 122.4 (d), 127.2 (d), 127.4 (d),
127.5 (d), 128.3 (d), 136.9 (s), 141.5 (s), 141.7 (s), 151.0 (s), 151.1
(s), 156.0 (s), 162.4 (s), 165.5 (s). MS (EI): m/z = 354 (M+, 38), 310
(5), 263 (3), 238 (10), 197 (100), 165 (10). Anal. Calcd for
C19H18N2O3S (354.42): C, 64.39; H, 5.12; N, 7.90. Found: C, 64.51;
H, 5.20; N, 7.79.
tert-Butyl 2-[1-[3-Butyl-2-[(4-chlorophenyl)imino]-4-oxo-1,3-thia-
zolidin-5-ylidene]ethyl]hydrazinecarboxylate (5f). Yield: 386.3 mg
(88%). Pale yellow foam. IR (Nujol, ν, cm−1): 3298, 3280, 1739, 1734,
1
1718, 1671, 1623, 1617, 1587. H NMR (400 MHz, DMSO-d6) δ:
0.88−0.93 (m, 3H), 1.23−1.63 (m, 13H), 1.85 and 2.31 (2s, 3H),
3.70−3.77 (m, 2H), 6.88−6.97 (m, 2H), 7.32−7.39 (m, 2H), 8.81 and
9.81 (br s and s, 1H), 9.28 (s, 1H). 13C NMR (100 MHz, DMSO-d6)
δ: 13.6 (q), 16.7 (q), 19.5 (t), 19.6 (t), 27.9 (q), 28.9 (t), 29.0 (t), 40.8
(t), 79.9 (s), 84.1 (s), 123.0 (d), 123.3 (d), 127.5 (s), 129.0 (d), 129.3
(d), 147.9 (s), 148.8 (s), 152.0 (s), 154.8 (s), 155.3 (s), 165.6 (s),
166.2 (s). MS (EI): m/z = 440 [M++2 (7)], 438 (M+, 17), 382 (91),
338 (52), 282 (55), 209 (63), 130 (100), 101 (89). Anal. Calcd for
C20H27ClN4O3S (438.97): C, 54.72; H, 6.20; N, 12.76. Found: C,
54.59; H, 6.29; N, 12.83.
tert-Butyl 2-[[3-Benzyl-4-oxo-2-(phenylimino)-1,3-thiazolidin-5-
ylidene](phenyl)methyl]hydrazinecarboxylate (5g). Yield: 375.4 mg
(75%). Yellow foam. IR (neat, ν, cm−1): 3348, 3292, 1731, 1671, 1623,
1591. 1H NMR (400 MHz, CDCl3) δ: 1.29 (s, 9H), 5.10 (s, 2H), 6.18
(br s, 1H), 6.90 (d, J = 7.6 Hz, 2H), 7.27−7.37 (m, 11H), 7.56 (d, J =
6.8 Hz, 2H), 9.88 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 28.0 (q),
45.4 (t), 81.8 (s), 94.8 (s), 121.2 (d), 124.1 (d), 127.6 (d), 127.9 (d),
128.2 (d), 128.4 (d), 128.7 (d), 128.9 (d), 129.2 (d), 132.7 (s), 136.5
(s), 148.6 (s), 152.0 (s), 155.1 (s), 155.8 (s), 167.3 (s). MS (EI): m/z
= 500 (M+, 12), 444 (84), 400 (56), 385 (21), 370 (17), 282 (13), 167
(100). Anal. Calcd for C28H28N4O3S (500.61): C, 67.18; H, 5.64; N,
11.19. Found: C, 67.29; H, 5.77; N, 11.26.
3-Butyl-5-(1-hydroxyethylidene)-2-(phenylimino)-1,3-thiazolidin-
4-one (7b). Compound 7b was isolated by column chromatography
(ethyl acetate/cyclohexane 60:40) in 85% yield (246.8 mg) as yellow-
1
green oil. IR (neat, ν, cm−1): 3280, 1748, 1641, 1625, 1590. H NMR
(400 MHz, DMSO-d6) δ: 0.91 (t, J = 7.6 Hz, 3H), 1.28−1.33 (m, 2H),
1.59−1.63 (m, 2H), 2.44 (s, 3H), 3.74−3.77 (m, 2H), 6.93 (d, J = 8.0
Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 2H), 11.55 (br s,
1H). 13C NMR (100 MHz, DMSO-d6) δ: 13.6 (q), 18.1 (q), 19.5 (t),
29.0 (t), 41.3 (t), 94.8 (s), 121.2 (d), 123.9 (d), 129.2 (d), 148.8 (s),
151.3 (s), 161.9 (s), 165.5 (s). MS m/z: 290 (M+, 93), 273 (5), 257
(6), 247 (24), 234 (100), 198 (66), 173 (12). Anal. Calcd for
C15H18N2O2S(290.38): C 62.04, H 6.25, N 9.65; Found: C 62.19, H
6.17, N 9.56.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of products and X-ray data
for compound 4h (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
General Procedure for the Synthesis of 5-Hydroxyethyli-
dene 1,3-Disubstituted Thiohydantoins 6a,b and of 5-
Hydroxyethylidene-2-iminothiazolidin-4-ones 7a,b. A 1 mmol
portion of 4a,b or 5a,b was refluxed in 10 mL of acetone/water (9:1
mixture) in the presence of Amberlyst 15 H (250 mg) for the
appropriate reaction time (2−8 h, checked by TLC). After the
filtration of the resin, washed twice with acetone, the crude reaction
mixture was concentrated under reduced pressure, and the residue was
extracted with ethyl acetate (3 × 10 mL). The organic phase was dried
on anhydrous sodium sulfate and evaporated under reduced pressure.
AUTHOR INFORMATION
Corresponding Author
*E-mail: stefania.santeusanio@uniurb.it.
■
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione, dell’Uni-
■
versita
̀
e della Ricerca (MIUR)-Roma, and the University of
Urbino “Carlo Bo” is gratefully acknowledged.
1166
dx.doi.org/10.1021/jo2021949 | J. Org. Chem. 2012, 77, 1161−1167

The Journal of Organic Chemistry
Note
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