An approach to 2,3-diaminosuccinic acid derivatives-synthesis of 2-thioxo-1,3-imidazolidines by a Mannich reaction

Article abstract of DOI:10.1071/CH11463

The article deals with a new synthesis of 2-thioxo-1,3-imidazolidine derivatives, masked 2,3-diaminosuccinic acids. The described procedure leads to the designed products by an intermolecular Mannich reaction between aldimine (ethyl iminoacetate) and enolates derived from 2-isothiocyanatocarboxylic esters. The prepared heterocyclic products having two stereogenic centers can be easily separated into cis- and trans- diastereoisomers. The reactivity of titanium(iv), lithium, and potassium enolates and the influence of ester groups on the yields and diastereoselectivities of the Mannich reactions are discussed.

Full text of DOI:10.1071/CH11463

CSIRO PUBLISHING
Aust. J. Chem. 2012, 65, 333–342
Full Paper
http://dx.doi.org/10.1071/CH11463
An Approach to 2,3-Diaminosuccinic Acid
Derivatives—Synthesis of 2-Thioxo-1,3-Imidazolidines
by a Mannich Reaction
A B
,
A
A
Dariusz Ciez,
Justyna Kalinowska-Tłus´cik, and Jakub Marchewka
˙
A
Faculty of Chemistry, Jagiellonian University, 30-060 Krako´w, Poland.
Corresponding author. Email: ciez@chemia.uj.edu.pl
B
The article deals with a new synthesis of 2-thioxo-1,3-imidazolidine derivatives, masked 2,3-diaminosuccinic acids. The
described procedure leads to the designed products by an intermolecular Mannich reaction between aldimine (ethyl
iminoacetate) and enolates derived from 2-isothiocyanatocarboxylic esters. The prepared heterocyclic products having
two stereogenic centers can be easily separated into cis- and trans- diastereoisomers. The reactivity of titanium(IV),
lithium, and potassium enolates and the influence of ester groups on the yields and diastereoselectivities of the Mannich
reactions are discussed.
Manuscript received: 7 December 2011.
Manuscript accepted: 30 January 2012.
Published online: 20 March 2012.
Introduction
synthetic methods are limited to transformation of L-aspartic
acid[9,12] and oxidative dimerization of glycinates,[13] that
furnish unsubstituted derivatives of 2,3-diaminosuccinic acid.
The synthesis of substituted 2,3-diamino-2-methylsuccinates is
represented by only one article, which describes the aza-Henry
reaction of 2-nitropropanoate catalyzed by chiral copper
complexes combined with chiral Lewis acids.[14] In this context
the preparation of 2,3-diaminosuccinic acid derivatives seems
to be an open problem in the chemistry of diamino acids. Two
years later we reported a new method for the preparation of
masked, 2,3-disubstituted-2,3-diaminosuccinates in the simple
way of the oxidative coupling of 2-isothiocyanatocarboxylic
esters.[15] The developed procedure gave symmetrical, disubsti-
tuted D,L-2,3-diisothiocyanatosuccinates, that can be later
transformed into 2,3-diamino acids in several steps.
The biological significance and the therapeutic applications of
non-proteinogenic 2,3-diaminoacids have attracted great
interest in the chemical and pharmacological industries. 2,3-
Diaminoacids have been found in nature not only in insects[1]
and plants[2] but also in the Murchison meteorite,[3] supporting
the theory of an early nucleic acid formation from diaminoacids
in the way of polycondensation reactions. Modified peptides
incorporating a 2,3-diaminoacid moiety show a substantial
resistance against proteolytic enzymes, so their biological
behaviour can be significantly modulated by replacement of a
natural 2-aminoacid with any 2,3-diaminoacid. The 2,3-
diaminoacid structure can be observed in several peptidic
antibiotics,[4] antibacterial agents belonging to a peptide
family,[5] and other bioactive compounds.[6] Application of
2,3-diaminoacids considerably exceeds the pharmacological
field, they also serve as convenient chelating agents for transi-
tion metals.[7] The prepared complexes, especially with radio-
active technetium and rhenium isotopes, are used in clinical tests
as non-invasive imaging probes in nuclear medicine.[8] New
chelating ligands derived from enantiopure 2,3-diaminoacids
can be employed in enantioselective organic synthesis as chiral
catalysts[9] or as building blocks for the synthesis of more
complex molecules.[10]
Although the occurrence and properties of 2,3-diaminoacids
seem to be well documented, one general protocol for the
preparation of 2,3-diaminoacids does not exist and a search
for new and more convenient synthetic methods still remains
a challenge for synthetic organic chemists. Among mono-
carboxylic 2,3-diaminoacids, there is a group of dicarboxylic
2,3-diaminosuccinic acid derivatives. Although the main repre-
sentative of this group, 2,3-diaminosuccinic acid, was one of the
first synthesized diamino acids,[11] the literature concerning
the chemistry of 2,3-diaminosuccinates is very poor. The
Results and Discussion
In a continuation of our research on the design and synthesis of
unsymmetrical 2,3-diaminosuccinates we found that
2-isothiocyanatocarboxylic esters could be very useful in further
investigations. Our experience in the chemistry of
isothiocyanates[15,16] prompted us to develop the Mannich
protocol for the addition of enolates derived from
2-isothiocyanatocarboxylic esters 1 to aldimine 2. We hoped
to obtain 2,3-diaminocarboxylate derivatives in the protected
form, as 2-thioxo-1,3-imidazolidines 4, after addition and
intramolecular cyclization of the formed 3-amino-2-
isothiocyanatocarboxylate 3 (Scheme 1). To the best of our
knowledge, 2-isothiocyanatocarboxylic esters 1 have never
been applied in Mannich reactions. Isothiocyanatoacetate
imides have been used in promising enantioselective Mannich
additions to aldimines but the described experiments only led to
monocarboxylic 2,3-diamino acids.[17,18] Similarly, metallated
Journal compilation Ó CSIRO 2012
www.publish.csiro.au/journals/ajc

334
D. Ciez˙ et al.
O
RЈ
CO2R
NCS
RЈ
CO2R
NCS
OMe
EtO2C
PMP
(i)
1a−h
NCS
1a
O
S
OMe
H
EtO2C
CO2Et
H
NH
(i)
H
N
PMP
N
H
CO2Et
3a−h
N
PMP
2
N
(cis/trans)-4a
MeO
EtO2C
CO2R
EtO2C
RЈ
2
H
N
RЈ
N
H
H
CO2R
H
ϩ
Scheme 1. Mannich addition of isothiocyanatocarboxylic ester into aldi-
mine leading to masked 2,3-diaminosuccinate. Reagents and conditions:
(i): Method A: TiCl4, triethylamine, dichloromethane, ꢀ968C to r.t. then
aq. NH4Cl. Method B: n-BuLi, THF, ꢀ968C to r.t. then AcOH. Method C:
tert-BuOK, THF, ꢀ158C to r.t. then AcOH.
N
N
PMP
PMP
S
S
cis-4a−h
trans-4a−h
Scheme 2. Synthesis of masked 2,3-diaminosuccinate in Mannich addi-
tion of 2-isothiocyanatocarboxylates 1 to ethyl iminoacetate 2. Reagents and
conditions: (i) tert-BuOK, THF, ꢀ158C then AcOH.
Table 1. Outcomes and diastereoselectivities of Mannich addition
reactions measured for different types of enolates derived from methyl
2-isothiocyanato-3-methylbutanoate 1a
Table 2. Diastereoselectivities observed for addition of potassium
enolates of 2-isothiocyanatocarboxylic esters 1a–h to aldimine 2 in
tetrahydrofuran at ꢀ158C
Enolization method
Yield of 4a [%]
cis : trans
A
B
C
15
51
48
56 : 44
68 : 32
71 : 29
Entry
R
R0
cis : trans
4a
4b
4c
4d
4e
CH3–
(CH3)2CH–
CH3–
71 : 29
52 : 48
58 : 42
46 : 54
76 : 24
82 : 18A
43 : 57
66 : 34
70 : 30
C2H5–
D-Menthyl
Endo-(1S)-bornyl
CH3–
CH3–
diethyl isothiocyanatomethylphosphonates were successfully
converted into protected 2,3-diaminoalkylphosphonates
after addition to activated imines.[19] We have divided our
experiment into two parts: at the beginning we focused on the
search for the most efficient method for enolization of
2-isothiocyanatocarboxylates, next we investigated the influ-
ence of some chiral ester groups on the diastereoselectivity
of the reaction. We chose three different enolization systems
for the Mannich addition of methyl 2-isothiocyanato-3-
methylbutanoate 1a to ethyl N-(p-methoxyphenyl)iminoacetate
2. The application of n-buthyllithium and potassium tert-
butoxide in THF gave similar, moderate outcomes (Table 1)
of the desired product 4a whereas enolization of the substrate
1a using titanium(IV) chloride and triethylamine (TEA) in
dichloromethane (DCM) led to 2-thioxoimidazolidine deriva-
tive 4a in a low yield.
The product 4a, a protected, cyclic form of 2,3-diaminosuccinic
acid, was formed by intramolecular cyclization of the open-
chain intermediate 3a. Analysis of NMR data showed that the
Mannich addition of isothiocyanatocarboxylate 1a gave a mix-
ture of diastereoisomers 4a-cis and 4a-trans and the ratio
depended on the applied enolization technique. The titanium(IV)
enolate of methyl 2-isothiocyanato-3methylbutanoate 1a gave
the product 4a-cis in a slight excess over the trans diastereo-
isomer, whereas the potassium and lithium enolates formed
mainly the diastereoisomer 4a-cis.
CH3–
(S)-Et–CH(CH3)–
4f
L-Menthyl
L-Menthyl
D-Menthyl
CH3–
4g
4h
(CH3)2CH–CH2–
(CH3)2CH–CH2–
ADiastereoselectivity observed after synthesis at ꢀ968C.
and potassium tert-butoxide as an enolization agent. We
decided to carry out a series of additions using various
2-isothiocyanatocarboxylates derived from a-aminoacids, aldi-
minine 2, and potassium tert-butoxide. Contrary to the reactions
promoted by n-butyllithium, potassium tert-butoxide did not
require such stringent anhydrous conditions and gave outcomes
and diastereoselectivities similar to those observed for lithium
enolates (Scheme 2). The results are summarized in Table 2.
Application of the aldimine 2 derived from ethyl glyoxylate led
to the synthesis of 2,3-diaminosuccinic acid derivatives.
All products 4a–h of the Mannich additions were obtained as
a mixture of cis- and trans-diastereoisomers. TLC analysis of
the crude products 4a–h indicated that the diastereoisomers
were characterized by different Rf values, so the separation of
the cis- and trans-adducts was relatively easy. The isolated cis-
and trans-2-thioxoimidazolidines 4c–h bearing chiral ester or
R0 groups consisted of two different diastereoisomeric forms.
Unfortunately, the resolution of the earlier separated cis and
trans diastereoisomers 4c–h into pure enantiomers was impos-
sible using chromatography techniques. However, we noted that
crystallization could be very helpful for the isolation of pure
Having analyzed preliminary data we found that the
most promising results for the Mannich addition of 2-
isothiocyanatocarboxylates to imines have been achieved for
reactive aldimine, ethyl N-(p-methoxyphenyl)iminoacetate 2,

Mannich Reactions of 2-Isothiocyanatocarboxylates
335
C54a
C54b
C53b
C53a
C43
O52
O51
O42
O41
C40
C12
C11
C5
C3
C4
C16
N1
C13
O16
C44
N3
C46
C47
C14
C15
C17
C45
S1
Fig. 1. A view of the molecular structure of the 4e-cis diastereoisomer, showing the atom-numbering scheme. Displacement
ellipsoids are drawn at the 30 % probability level and H atoms are shown as spheres of arbitrary radii. Visualization made with
ORTEP3.[21]
enantiomers, especially in the presence of a chiral R0 substituent.
Preliminary flash chromatography of 4e followed by preparative
centrifugal thin-layer chromatography using a chromatotron
gave pure diastereoisomers cis-4e and trans-4e. NOESY
experiments of each diastereoisomeric form led us to assign
the proper structure based on each spectrum. Moreover, we
noted that the NMR spectra measured for mixtures of cis and
trans-diastereoisomers displayed two different signals for a
proton at C5 in the range of 4.5 to 5.5 ppm. The chemical shifts
observed for these protons could be correlated with the diaster-
eoisomeric form of 2-thioxoimidazolidine 4 because the signal
of a hydrogen at C5 in the cis-diastereoisomer usually appeared
below 5.0 ppm whereas the signal of the same hydrogen in the
trans-diastereoisomer was shifted downfield and found in the
range 5.00 to 5.50 ppm. Analysis of possible interactions
between substituents located at vicinal C4 and C5 atoms showed
that this phenomenon could be explained by a deshielding effect
of the vicinal, magnetically anisotropic ester group. This effect
became apparent for trans-diastereoisomers where both the
proton at C5 and the ester group at C4 were located very close
to each other, independent of the ring conformations. Contrary
to the trans-diastereoisomers, interactions between the proton in
the C-5 position and the ester group located at C4 in the cis-
diastereoisomer was limited only to one conformer, where
both substituents occupied equatorial positions. The proportion
of the integration values estimated for the singlets assigned to
hydrogens at C5 gave a diestereoisomeric ratio for both forms of
adducts, cis and trans, without separation and purification of
diastereoisomers.
respect to the 2-thioxo-1,3-imidazolidine ring (Fig. 1). There
were three chiral centers present in the molecule. The configu-
ration for C4 was R while for C5 and C44 it was S. The
configuration of the last mentioned atom was already known
from the molecular structure of the reagent chosen for synthesis
(L-isoleucine). The compound crystallized as one enantiomeric
form, in a non-centrosymmetric space group (Flack parame-
ter[20] for the last step of refinement: ꢀ0.03(9)). The main
interactions observed in the crystal structure were strong hydro-
gen bonds N3–H?S1 between two neighbouring molecules
related by a two-fold axis parallel to direction [010]. Molecules
bonded this way have formed dimers. The observed eight-
membered ring (including hydrogen atoms involved in the
interaction) was not planar but twisted ,338. Additional inter-
actions observed in the crystal structure were weak hydrogen
bonds C–H?O or C–H?S and hydrophobic association of
non-polar groups. The disorder of the ethyl substituent in one of
the ester groups was observed in both room temperature and
low-temperature experiments. The reason was probably related
to many weak interactions in which this moiety was involved.
Observed correlations between the structure of the applied
2-isothiocyanatocarboxylic esters and the diastereoselectivity
of the Mannich addition allowed us to consider a stereochemical
aspect of the reaction mechanism. We assumed that the six-
membered cyclic transition state can adopt a boat conformation
5a,b owing to the interaction of the metal ion with the isothio-
cyanate group (Scheme 3). Analysis of this transition state
showed that regardless of which enolate was formed, E or Z,
addition of the isothiocyanatocarboxylate to aldimine would
rather favour formation of the cis-adduct than the trans-adduct.
The reaction leading to trans-adducts proceeded by a less stable
transition state 5b, where the ester group of the aldimine
interacted with an alkyl R0 substituent. cis-Diastereoisomers
were formed from the more stable structure 5a having an ester
group of the aldimine placed opposite to both substituents at C2
of the isothiocyanatocarboxylates. In the presence of medium
Our structural assignments and assumed correlation between
NMR data and diastereoisomeric forms have been confirmed by
X-ray crystal structure determination of the diastereoisomer
cis-4e. Contrary to the amorphous, oily adduct trans-4e, the
diastereoisomer cis-4e precipitated from n-hexane as fine
crystals. The crystal structure of the above mentioned diastereo-
isomer showed cis mutual orientation of both ester groups in

336
D. Ciez˙ et al.
OM
PMP
the diastereoselectivity of the described reactions. High
cis-diastereoselectivities have been observed for additions of
2-isothiocyanatocarboxylates bearing bulky substituents at the
C-2 position. Reactants can be easily prepared from commercial
ethyl glyoxylate, p-anisidine, and esters of the natural
a-aminoacids. Reactions were carried out at ꢀ158C in anhy-
drous THF giving the mixture of diastereoisomeric cis- and
trans-2-thioxo-1,3-imidazolidines in middle to good yields and
middle to good diastereoselectivities. Syntheses carried out at a
lower temperature (ꢀ968C) furnished adducts with better dia-
stereoselectivity but lower yields. The new method provides
wide access to novel 2,3-diaminosuccinic acid derivatives
substituted at C-2 with various groups. The synthesis is very
simply and offers easy isolation of pure cis- and trans-
diastereoisomers, that become precursors of anti-(RS and SR)
and syn-(RR and SS) 2,3-diaminosuccinic acids, respectively.
Transformation of imidazolidine-2-thiones into 2,3-diamino
acids can be realized in a three-step synthesis. The known
procedure involves N-protection of a heterocyclic ring using
di-tert-butyldicarbonate (Boc2O) in the presence of dimethyla-
minopyridine (DMAP),[22] oxidative desulfurization, which
could be achieved in the reaction of the fully protected
imidazolidine-2-thione with mercury(II) acetate,[23,24] and
acidic hydrolysis followed by ring opening using a solution of
hydrochloric acid in methanol.[25,26] Oxidative desulfurization
leading to the imidazolidin-2-one system can be also performed
in ethanol or glacial acetic acid in the presence of yellow
mercury(II) oxide.[27,28]
N
SCN
ϩ
OR
EtO2C
RЈ
RЈ
RЈ
NCS
NCS
H
EtO2C
H
M
M
N
N
EtO2C
RO
O
PMP
O
PMP
RO
5a (favoured)
5b (disfavoured)
H
H
RO2C
RЈ
RO2C
N
N
N
N
RЈ
S
S
H
EtO2C
EtO2C
H
PMP
cis-4 (4S,5R)
PMP
trans-4 (4S,5S)
Scheme 3. A tentative transition state for the Mannich reaction of
2-isothiocyanatocarboxylic esters with ethyl 2-iminoacetate. M ¼ Li, K,
and TiCl3.
Experimental
and small R0 substituents, the diastereoselectivity of the investi-
gated process was very poor (4b). The presence of bulky chiral
ester groups R exerted a rather weak influence on the diaster-
eoselectivity of the Mannich reaction. We noted that potassium
enolates of L-menthyl 2-isothiocyanatopropanoate (R0 ¼ CH3)
General Experimental
NMR spectra were determined on a Bruker Avance II 300 MHz
spectrometer (using TMS as an internal standard). IR spectra
were measured using a FT-IR spectrometer Nicolet IR200 with a
single-reflection ATR head. Microanalyses were carried out
using a CHNS Vario Micro Cube analyzer and the results were
in good agreement with the calculated values. Gas chromatog-
raphy (GC) was performed using a PerkinElmer Clarus 500
apparatus equipped with an Elite-5MS capillary column.
GC–mass spectrometry (MS) analyses were carried out using
Thermo Scientific ISQ Single Quadrupole GC-MS equipped
with an Elite-5MS capillary column. Column chromatography
was performed using commercial Merck silica gel 60 (230–400
mesh ASTM) and TLC analysis was carried out using Merck
TLC silica gel 60 plates. Preparative TLC was carried out with a
Chromatotron, model 7924T using glass rotor coated with a
2 mm layer of Merck silica gel 60 PF254. Optical rotations were
performed using a Jasco P-2000 polarimeter. Melting points
were measured on an Electrothermal 9100 apparatus.
added to aldimine gave
a
slight excess of the
cis-2-thioxoimidazolidine whereas D-menthyl and endo-(1S)-
bornyl 2-isothiocyanatopropanoates gave, under the same
conditions, trans-adducts (4d and 4f) as predominant diaster-
eoisomers. On the contrary, the large R0 substituents
significantly increased the yields of the cis-diastereoisomers
and limited the influence of the chiral ester groups on the
diastereoselectivity. This effect could be explained by a strong
steric hindrance at C2 observed for the boat conformers.
Repulsion between the aldimine ester group and R0 inhibited
formation of transition state 5b, the precursor to the trans-
diastereoisomer. Substitution of the aldimine ester group with
aryl substituents made the steric repulsions between the aryl and
R0 groups considerably stronger and gave rise to the increase of
the cis-diastereoselectivity.
Methyl (ꢁ)-2-isothiocyanato-3-methyl-butanoate 1a, ethyl
(ꢁ)-2-isothiocyanatopropanoate 1b, and methyl (2S,3S)-2-
isothiocyanato-3-methyl-pentanoate 1e were prepared from
D/L-valine, D/L-alanine, and L-isoleucine esters according to
the described procedures.[29–32] Ethyl N-(p-methoxyphenyl)
iminoacetate 2[33] was obtained from ethyl glyoxylate by
condensation with p-anisidine. 1H and 13C NMR signals of
menthyl and bornyl rings have been assigned with the help of the
SDBS database ( http://riodb01.ibase.aist.go.jp/sdbs/). X-Ray
diffraction data were collected at 110 K using a SuperNova
diffractometer (Oxford Diffraction) with MoKa radiation
Conclusion
The described work is the first example of a practical application
of 2-isothiocyanatocarboxylic esters in Mannich reactions for
the synthesis of masked 2,3-diaminosuccinic acid derivatives.
The developed method gives 2-thioxo-1,3-imidazolidine-
4,5-dicarboxylates in
a one-pot reaction of aldimine,
ethyl N-(p-methoxyphenyl)iminoacetate, with lithium,
potassium, or titanium(IV) enolates derived in situ from
2-isothiocyanatocarboxylic esters. The best outcomes have been
achieved for lithium and potassium enolates. Chiral auxiliaries
placed in ester groups did not exert a significant influence on
Pro
˚
(l ¼ 0.71073A). Data were processed using CRYSALIS
[Oxford Diffraction (2009), CrysAlis PRO, Oxford Diffraction

Mannich Reactions of 2-Isothiocyanatocarboxylates
337
Ltd, Yarnton, England]. The phase problem was solved with
direct methods with SHELXS-97.[34] The model of the structure
was refined by full-matrix least-squares on F2 (SHELXL-97).
All non-hydrogen atoms were refined anisotropically. The
position of the hydrogen atom of the secondary amine was
found in the difference Fourier map and refined in a riding
(4-C), 36.8 (3-C), 28.3 (O–C(CH3)3), 28.0 (5-C), 27.0 (6-C),
19.6 (b-CH3), 18.8 (CH3–C–CH3), 18.7 (CH3–C–CH3), 13.4
(C–CH3). Anal. Calc. for C18H31NO4: C 66.44, H 9.60, N 4.30.
Found: C 66.29, H 9.71, N 4.36 %.
Dry N-Boc-L-alanine endo-(1S)-bornyl ester (1.627 g,
5.00 mmol) was dissolved in DCM (40 mL) in a three-necked
100 mL flask protected against moisture, fitted with an argon
inlet and septum. To the stirred solution was added trifluoroa-
cetic acid (9.1 mL, 13.95 g, 0.122 mol) by a syringe and the
reactants were stirred under argon at room temperature for 2.5 h.
After the deprotection of the N-Boc-L-alanine endo-(1S)-bornyl
ester was complete, the solvent and trifluoroacetic acid were
evaporated under reduced pressure. (Note: the temperature of
evaporation should not exceed 408C.) The remainder was
dissolved in chloroform (30 mL), transferred into a 250 mL
conical flask and water (18 mL) was added to the solution. Next
thiophosgene (0.38 mL, 0.576 g, 5.01mmol) was added drop-
wise to the vigorously stirred reaction mixture and sodium
bicarbonate (1.26 g; 15.00 mmol) was added in several portions.
The reactants were stirred until the thiophosgene was consumed
(30–45 min). The lower organic phase was separated and dried
with anhydrous MgSO4. Crude isothiocyanatocarboxylate 1d
was purified by column chromatography on silica gel (eluent:
cyclohexane/ethyl acetate, 5 : 1) to give 1.050 g of pure endo-
(1S)-bornyl (S)-2-isothiocyanatopropanoate 1d in 79 % yield, as
a yellowish oil. [a]D23 þ168 (c 0.12 in acetone). nmax (ATR)/
cmꢀ1 2981, 2954, 2876, 2048, 1736, 1451, 1384, 1297, 1218,
1148. dH (300 MHz, CDCl3) 4.97 (m, 1H, CH–O), 4.31
(q, J 7.09, 1H, a-CH), 2.40 (m, 1H, 3-CHexo), 1.91 (m, 1H,
6-CHendo), 1.77 (m, 1H, 5-CHexo), 1.72 (m, 1H, 4-CH), 1.59
(d, J 7.09, 3H, b-CH3), 1.30 (m, 2H, 5-CHendo and 6-CHexo),
1.01 (m, 1H, 3-CHendo), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3),
0.86 (s, 3H, CH3). dC (75 MHz, CDCl3) 169.2 (COO), 137.5
(NCS), 82.5 (C–O), 55.0 (a-CH), 48.9 (1-C), 48.0 (CH3–C–
CH3), 44.8 (4-C), 36.7 (3-C), 28.0 (5-C), 27.1 (6-C), 19.6
(b-CH3), 19.5 (CH3–C–CH3), 18.8 (CH3–C–CH3), 13.5
(C–CH3). m/z (GC-MS) 267 (33%, Mþꢂ), 181 (49), 137 (66),
136(67), 121(54), 95(100),81(87). Anal.Calc.for C14H21NO2S:
C 62.88, H 7.92, N 5.24. Found: C 62.95, H 7.79, N 5.30%.
˚
model assuming N–H ¼ 0.88 (2) A and Uiso ¼ 1.2Ueq of the
parent atom with the use of the riding model. The positions of all
other hydrogen atoms were calculated and refined with
Uiso ¼ 1.5Ueq (methylene groups only) or Uiso ¼ 1.2Ueq of the
parent atom. Crystallographic data (excluding structure factors)
for the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 840140. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or
email: deposit@ccdc.cam.ac.uk).
Methyl (ꢁ)-2-Isothiocyanato-3-Methylbutanoate 1a
The title compound was synthesized following literature
procedures.[33,35]
Ethyl (ꢁ)-2-Isothiocyanatopropanoate 1b
The title compound was synthesized following literature
procedures.[29,30]
D-Menthyl (ꢁ)-2-Isothiocyanatopropanoate 1c
The title ester was prepared from D,L-alanine D-menthyl ester
hydrochloride following the literature procedures[33,35] to give
2.295 g of a yellow oil (85 %). m/z (GC-MS) 269 (3 %, Mþꢂ),
183 (19), 139 (88), 86 (53), 83 (100), 69 (68). Anal. Calc. for
C14H23NO2S: C 62.41, H 8.61, N, 5.20. Found: C 62.49, H 8.51,
N 5.33 %.
Synthesis of endo-(1S)-Bornyl
(S)-2-Isothiocyanatopropanoate 1d
Commercial N-Boc-L-alanine (2.271 g, 12.0 mmol) was
dissolved in DCM (75 mL) and the flask was placed in ice-bath
and cooled to 0–58C. Next 1,3-dicyclohexylcarbodiimide
(DCC, 2.476 g, 12.0 mmol) was added and the reaction mixture
was stirred for 30 min. After this time endo-(1S)-(ꢀ)-borneol
(1.542 g; 10.0 mmol) and DMAP (0.147 g; 1.20 mmol) were
added successively to the flask and the ice-bath was removed.
The reactants were stirred at the room temperature for 24 h. Next
the solvent was evaporated, ethyl acetate (75 mL) was added to
the flask and the precipitated dicyclohexylurea (DCU) was
separated by filtration. The filtrate containing the ester was
washed with 5 % HCl (25 mL) and brine (20 mL), dried over
MgSO4, and evaporated. The crude product, N-Boc-L-alanine
endo-(1S)-bornyl ester, was obtained as a colourless solid
(2.547 g, 78 % yield), and was pure enough to be used in the next
step without purification (TLC analysis on silica gel: Rf ¼ 0.89;
eluent: CHCl3/MeOH, 10 : 1).
Mp 63–648C. dH (300 MHz, CDCl3) 5.05 (br s, 1H, NH), 4.90
(m, 1H, CH-O), 4.30 (m, 1H, a-CH), 2.35 (m, 1H, 3-CHexo), 1.92
(m, 1H, 6-CHendo), 1.75 (m, 1H, 5-CHexo), 1.72 (m, 1H, 4-CH),
1.44 (s, 9H, CH3), 1.37 (d, J 7.17, 3H, b-CH3), 1.23 (m, 2H,
5-CHendo and 6-CHexo), 0.93 (m, 1H, 3-CHendo), 0.89 (s, 3H,
CH3), 0.87(s, 3H, CH3), 0.83 (s, 3H, CH3). dC (75 MHz, CDCl3)
173.5 (COO), 155.0 (NH–CO), 80.9 (CH–O), 79.7 (O–C
(CH3)3), 49.3 (a-CH), 48.8 (1-C), 47.9 (CH3–C–CH3), 44.8
Methyl (2S,3S)-2-Isothiocyanato-3-Methylpentanoate 1e
The title compound was synthesized following the literature
procedure.[33]
Representative Synthesis of L-Menthyl
(ꢁ)-2-Isothiocyanatopropanoate 1f
An Erlenmayer flask (250 mL) was placed on a magnetic stirrer
and charged with chloroform (45 mL), water (25 mL), and D,L-
alanine L-menthyl ester hydrochloride[36,37] (1.86 g, 7.05 mmol).
To the stirred solution thiophosgene (0.54 mL, 0.814 g,
7.08 mmol) and sodium bicarbonate (1.78 g, 21.19 mmol) were
added in one portion and the reaction mixture was stirred
vigorously until the orange solution turned pale (40–70 min).
After the thiophosgene was consumed, the lower organic layer
was separated and dried over MgSO4. Next the solvent was
removed and the crude oily product was purified using column
chromatography (silica gel, cyclohexane/ethyl acetate, 5 : 1) to
give pure L-menthyl (ꢁ)-2-isothiocyanatopropanoate 1f as a
yellow viscous oil (yield 1.727 g, 91 %). nmax (ATR)/cmꢀ1
2955, 2059, 1741, 1454, 1374, 1289, 1205, 1151. dH (300 MHz,
CDCl3) 4.75 and 4.74 (m, 1H, OCH), 4.28 and 4.27 (2q, J 7.09,
1H, a-CH), 2.02 (m, 1H, 6-CHaHe), 1.86 (m, 1H, CH3–CH–
CH3), 1.72 (m, 1H, 3-CHaHe), 1.68 (m, 1H, 4-CHaHe), 1.58

338
D. Ciez˙ et al.
(d, J 7.09, 3H, b-CH3), 1.46 (m, 2H, 5-CH–CH3 and 2-CH), 1.05
(m, 2H, 3-CHaHe, 6-CHaHe), 0.92 (d, J 6.52, 3H, CH3–CH–
CH3), 0.91 (d, J 7.00, 3H, CH3–CH–CH3), 0.87 (m, 1H,
4-CHaHe), 0.77 and 0.76 (2d, J 6.96, 3H, CH–CH3). NMR data
for the cyclohexane fragment of the menthyl group was attrib-
uted to axial (Ha) and equatorial (He) protons separately.
dC (75 MHz, CDCl3) 168.8 and 168.7 (COO), 137.6 and
137.4 (NCS), 77.2 and 76.9 (C–O), 55.1 and 55.0 (a-CH),
46.9 (2-C), 40.6 (6-C), 34.1 (4-C), 31.4 (5-C), 26.3 and
26.2 (CH3–CH–CH3), 23.4 and 23.3 (3-C), 21.9 (CH–CH3),
20.8 and 20.7 (CH3–CH–CH3), 19.5 (b-CH3), 16.3 and
16.0 (CH3–CH–CH3). Anal. Calc. for C14H23NO2S: C 62.41,
H 8.61, N, 5.20. Found: C 62.35, H 8.60, N 5.28 %.
2 M n-butyllithium in hexane (0.93 mL, 1.86 mmol, 1.0 equiv.)
was added by a syringe to form the lithium enolate. After 20 min
the solution of ethyl N-( p-methoxyphenyl)iminoacetate 2a
(0.385 g, 1.86 mmol, 1.0 equiv.) in THF (2.5 mL) was added
through a septum and the reactants were stirred at ꢀ968C for an
additional 20 min. Next the ice-bath was removed and the
reaction mixture was allowed to reach room temperature. After
24 h of stirring, glacial acetic acid (0.106 mL, 1.86 mmol,
1.0 equiv.) was added, the solution was filtered through a
sintered glass filter (porosity B4) and the solvent was evapo-
rated. The crude oily product was purified using column
chromatography (SiO2; chloroform/methanol, 30 : 1) to give 4a
(0.36 g, 51 %) as an orange oil containing 68 % of the cis- and
32 % of the trans-diastereoisomers.
L-Menthyl (S)-2-Isothiocyanato-4-Methylpentanoate 1g
Representative Synthesis of cis/trans-5-Ethyl 4-Methyl
4-Isopropyl-1-(4-Methoxyphenyl)-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4a by the Titanium(IV) Enolate (Method B)
The title compound was prepared analogously to the above
mentioned 1f from L-leucine-L-menthyl ester hydrochloride[32]
(1.290 g, 4.22 mmol). Yield 0.972 g (74 %), yellowish oil.
[a]D24 þ92 (c 0.12 in acetone); nmax (ATR)/cmꢀ1 2956, 2928,
2871, 2058, 1740, 1456, 1269, 1196. dH (300 MHz, CDCl3) 4.75
(dt, J 4.44 and 10.90, 1H, CH–O), 4.22 (m, 1H, a-CH), 1.98 (m,
1H, 6-CHaHe), 1.82 (m, 3H, CH3–CH–CH3, 3-CHaHe and
4-CHaHe), 1.67 (m, 3H, b-CH2 and g-CH), 1.44 (m, 3H, 5–CH–
CH3, 2-CH and 3-CHaHe), 1.04 (m, 1H, 6-CHaHe), 0.98
(d, J 6.41, 3H, d-CH3), 0.95 (d, J 6.52, 3H, d-CH3), 0.91 (d, J
6.54, 3H, CH3–CH–CH3), 0.91 (d, J 7.02, 3H, CH3–CH–CH3),
0.87 (m, 1H, 4-CHaHe), 0.76 (d, J 6.97, 3H, CH–CH3). dC
(75 MHz, CDCl3) 168.4 (COO), 136.9 (NCS), 76.8 (C–O), 58.2
(a-CH), 46.8 (2-C), 42.0 (b-CH2), 40.6 (6-C), 34.1 (4-C), 31.4
(5-C), 26.2 (CH3–CH–CH3), 25.1 (g-CH), 23.3 (3-C), 22.7
(d-CH3), 21.9 (CH–CH3), 21.1 (d-CH3), 20.7 (CH3–CH–CH3),
16.2 (CH3–CH–CH3). m/z (GC-MS) 311 (6 %, Mþꢂ), 183 (24),
174 (9), 139 (84), 138 (39), 97 (59), 83 (100). Anal. Calc. for
C17H29NO2S: C 65.56, H 9.38, N 4.50. Found: C 65.65, H 9.45,
N 4.61 %.
A three-necked 250 mL flask was protected against moisture,
equipped with an argon inlet and charged with methyl (ꢁ)-2-
isothiocyanato-3-methylbutanoate 1a (0.322 g, 1.86 mmol,
1.0 equiv.) dissolved in DCM (40 mL). The stirred solution was
cooled to ꢀ968C and titanium(IV) chloride (0.205 mL, 0.354 g,
1.0 equiv.) was added in one batch under argon. The yellow
titanium(IV) complex was stirred for 15 min at ꢀ968C and TEA
(0.259 mL, 0.188 g, 1.0 equiv.) was added to form a deep blue
titanium(IV) enolate. The solution was stirred for 15 min and
ethyl N-(p-methoxyphenyl)iminoacetate 2a (0.385g, 1.86mmol,
1.0 equiv.) in DCM (4 mL) was dropped slowly by a syringe to
the enolate. After 15 min the ice-bath was removed and the
reaction mixture was allowed to reach room temperature. The
reactants were stirred for 24 h at room temperature, and then
poured into a saturated solution of ammonium chloride (44 mL),
the lower organic layer was separated and dried using MgSO4.
Evaporation of the solvent gave a crude product that was puri-
fied by column chromatography (SiO2; chloroform/methanol,
30 : 1) leading to 4a (0.11 g, 15 %) as an orange oil containing
56 % of the cis- and 44 % of the trans-diastereoisomers.
D-Menthyl (S)-2-Isothiocyanato-4-Methylpentanoate 1h
The title compound was prepared from L-leucine-D-menthyl
ester hydrochloride[32] (1.038 g, 3.39 mmol) in the same way as
1f to give 0.856 g (81 %) of a yellow oil. [a]2D4 þ204 (c 0.10 in
acetone). nmax (ATR)/cmꢀ1 2959, 2931, 2871, 2118, 1736,
1457, 1276, 1196. dH (300 MHz, CDCl3) 4.74 (dt, J 4.44 and
10.90, 1H, CH–O), 4.22 (m, 1H, a-CH), 2.04 (m, 1H, 6-CHaHe),
1.86 (m, 3H, CH3–CH–CH3, 3-CHaHe and 4-CHaHe), 1.68
(m, 3H, b-CH2 and g-CH), 1.46 (m, 3H, 5-CH–CH3, 2-CH and
3-CHaHe), 1.08 (m, 1H, 6-CHaHe), 0.95 (d, J 6.45, 3H, d-CH3),
0.94 (d, J 4.08, 3H, d-CH3), 0.91 (d, J 6.51, 3H, CH3-CH-CH3),
0.91 (d, J 7.05, 3H, CH3-CH-CH3), 0.87 (m, 1H, 4-CHaHe), 0.75
(d, J 6.99, 3H, CH–CH3). dC (75 MHz, CDCl3) 168.6 (COO),
136.9 (NCS), 76.7 (C–O), 58.5 (a-CH), 47.0 (2-C), 42.1
(b-CH2), 40.7 (6-C), 34.2 (4-C), 31.6 (5-C), 26.3 (CH3–CH–
CH3), 25.3 (g-CH), 23.3 (3-C), 22.9 (d-CH3), 22.1 (CH–CH3),
21.3 (d-CH3), 20.9 (CH3–CH–CH3), 16.1 (CH3–CH–CH3).
Anal. Calc. for C17H29NO2S: C 65.56, H 9.38, N 4.50. Found:
C 65.61, H 9.26, N 4.57 %.
Representative Synthesis of cis/trans-5-Ethyl 4-Methyl
4-Isopropyl-1-(4-Methoxyphenyl)-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4a by the Potassium Enolate (Method C)
A three-necked 100 mL flask protected against moisture was
charged under argon with anhydrous THF (10 mL) and potas-
sium tert-butoxide (0.211 g, 1.89 mmol, 1.2 eq). The solution
was cooled to ꢀ158C and a mixture of methyl (ꢁ)-2-
isothiocyanato-3-methylbutanoate 1a (0.272 g, 1.57 mmol,
1.0 equiv.) with ethyl N-(p-methoxyphenyl)iminoacetate 2a
dissolved in THF (4 mL) was added through septum into flask.
Reactants were stirred at ꢀ158C for 2 h, next the ice-bath was
removed and the reaction mixture was allowed to warm to room
temperature. After 24 h the reaction was complete. The solution
was neutralized using glacial acetic acid (0.107 mL, 0.113 g,
1.89 mmol, 1.2 equiv.), filtered through a sintered glass filter
(porosity B4) and evaporated. Crude oily product was purified
using column chromatography (SiO2, chloroform/methanol,
30 : 1) to give 4a (0.29 g, 48 %) as an orange oil containing 71 %
of cis and 29 % of trans-diastereoisomers. Partial NMR data for
the cis and trans-diastereoisomers 4a were determined from the
mixture.
Representative Synthesis of cis/trans-5-Ethyl 4-Methyl
4-Isopropyl-1-(4-Methoxyphenyl)-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4a by the Lithium Enolate (Method A)
Methyl (ꢁ)-2-isothiocyanato-3-methylbutanoate 1a (0.322 g,
1.86 mmol 1.0 equiv.) was dissolved under argon in anhydrous
THF (25 mL) and cooled to ꢀ968C. To the stirred solution of 1a,
The following compounds were all synthesized by
Method C.

Mannich Reactions of 2-Isothiocyanatocarboxylates
339
cis/trans-5-Ethyl 4-Methyl 4-Isopropyl-
1-(4-Methoxyphenyl)-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4a
(5-CH), 62.6 (OCH2), 61.9 (OCH2), 55.4 (OCH3), 20.3 (CH–
CH3), 14.1 (CH3), 13.9 (CH3). Anal. Calc. for C17H22N2O5S:
C 77.73, H 6.05, N 7.64. Found: C 77.63, H 6.11, N 7.65 %.
The title compound was obtained as an orange oil with a yield of
0.29 g (48 %).
Application of preparative TLC, which was carried out using
a Chromatotron (2 mm layer of Merck silica gel 60 PF254;
CHCl3/MeOH, 50 : 1), led to pure trans-4a (first fraction; TLC
Rf ¼ 0.70) and cis-4a (second fraction; TLC Rf ¼ 0.65).
cis/trans-5-Ethyl 4-D-Menthyl 1-(4-Methoxyphenyl)-4-
Methyl-2-Thioxoimidazolidine-4,5-Dicarboxylate 4c
The title compound was obtained as an orange oil. Yield 0.31 g
(44 %).
Application of preparative, thin-layer chromatography,
which was carried out using a Chromatotron (2 mm layer of
Merck silica gel 60 PF254; CHCl3/MeOH, 50 : 1), led to pure
trans-4c (first fraction; TLC Rf ¼ 0.65) and cis-4c (second
fraction; TLC Rf ¼ 0.60).
trans-4a
Yield 0.19 g (34 %), orange oil. nmax (ATR)/cmꢀ1 3182,
2967, 2837, 1738, 1512, 1245, 1182, 1025. dH (300 MHz,
CDCl3) 7.32 (d, J 9.11, 2H, meta-ArH), 6.88 (d, J 9.11, 2H,
ortho-ArH), 6.65 (s, 1H, NH), 5.35 (s, 1H, 5-CH), 4.13 (m, 2H,
OCH2), 3.87 (s, 3H, CO2CH3), 3.79 (s, 3H, OCH3), 2.12 (CH3–
CH–CH3), 1.16 (m, 6H, CH2CH3 and CH3–CH–CH3), 0.97 (d, J
6.84, 3H, CH3–CH–CH3). dC (75 MHz, CDCl3) 183.6 (C¼S),
170.5 (CO2Me), 167.1 (CO2Et), 158.8 (Ar), 130.8 (Ar), 128.5
(Ar), 114.1 (Ar), 72.3 (4-C), 71.6 (5-CH), 62.0 (OCH2), 55.4
(OCH3), 53.2 (CO2CH3), 37.3 (CH3–CH–CH3), 17.0 (CH3),
15.9 (CH3), 13.9 (CH3). Anal. Calc. for C18H24N2O5S: C 56.82,
H 6.36, N 7.36. Found: C 56.88, H 6.30, N 7.41 %.
trans-4c
Yield 0.16 g (23 %), orange oil. nmax (ATR)/cmꢀ1 3178,
2955, 2872, 1730, 1511, 1448, 1241, 1179, 1135, 1033. dH
(300 MHz, CDCl3) 7.34 (d, J 9.05, 2H, meta-ArH), 6.90 (d, J
9.05, 2H, ortho-ArH), 6.70, 6.69 (s, 1H, NH), 4.61, 4.60 (s, 1H,
5-CH), 4.72 (m, 1H, CH-O), 4.08 (2 ꢃ dq, J 7.36, 1H, OCH2),
3.80 (s, 3H, OCH3), 1.98 (m, 1H, 6-CHaHe), 1.77, 1.76 (s, 3H,
4C–CH3), 1.71 (m, 3H, CH3–CH–CH3, 3-CHaHe and 4-CHaHe),
1.14 (t, J 7.14, 3H, CH3), 1.08 (m, 2H, 3-CHaHe, 6-CHaHe),
0.91 (m, 6H, CH3–CH–CH3), 0.88 (m, 1H, 4-CHaHe), 0.77
(m, 3H, CH–CH3). dC (75 MHz, CDCl3) 183.1 (C¼S), 169.5
(CO2-L-Ment), 167.2 (CO2Et), 159.0 (Ar), 130.9 (Ar), 128.7
(Ar), 114.3 (Ar), 77.1 (CH–O), 74.0 (4-C), 71.5 (5-C), 61.8
(OCH2), 55.4 (OCH3), 46.8, 46.7 (C-2), 40.3 (C-6), 34.0 (C-4),
31.5 (C-5), 26.4 (CH3–CH–CH3), 23.1 (C-3), 21.9 (CH–CH3),
20.8 (CH3–CH–CH3), 15.9 (CH3–CH–CH3). Anal. Calc. for
C25H36N2O5S: C 63.00, H 7.61, N 5.88. Found: C 63.08, H 7.66,
N 5.95 %.
cis-4a
Yield 0.08 g (14 %), yellow oil. nmax (ATR)/cmꢀ1 3175,
2963, 2831, 1740, 1511, 1240, 1180, 1022. dH (300 MHz,
CDCl3) 7.23 (d, J 9.11, 2H, meta-ArH), 6.89 (d, J 9.11, 2H,
ortho-ArH), 6.79 (s, 1H, NH), 4.69 (s, 1H, 5-CH), 4.13 (m, 2H,
OCH2), 3.75 (s, 3H, CO2CH3), 3.79 (s, 3H, OCH3), 2.29 (CH3–
CH–CH3), 1.16 (m, 6H, CH2CH3 and CH3–CH–CH3), 0.97 (d, J
6.84, 3H, CH3–CH–CH3). dC (75 MHz, CDCl3) 182.7 (C¼S),
169.9 (CO2Me), 168.0 (CO2Et), 159.1 (Ar), 130.5 (Ar), 128.6
(Ar), 114.4 (Ar), 72.0 (4-C), 72.0 (5-CH), 62.0 (OCH2), 55.4
(OCH3), 52.8 (CO2CH3), 37.3 (CH3–CH–CH3), 17.0 (CH3),
15.9 (CH3), 13.9 (CH3). Anal. Calc. for C18H24N2O5S: C 56.82,
H 6.36, N 7.36. Found: C 56.80, H 6.23, N 7.25 %.
cis-4c
Yield 0.15 g (21 %), orange oil. nmax (ATR)/cmꢀ1 3170,
2952, 2871, 1740, 1510, 1444, 1249, 1180, 1142, 1030. dH
(300 MHz, CDCl3) 7.34 (d, J 9.05, 2H, meta-ArH), 6.90 (d, J
9.05, 2H, ortho-ArH), 6.62 (s, 1H, NH), 5.26, 5.22 (s, 1H,
5-CH), 4.81 (m, 1H, CH-O), 4.21 (2dq, J 7.26, 1H, OCH2), 3.80
(s, 3H, OCH3), 1.98 (m, 1H, 6-CHaHe), 1.51, 1.50 (s, 3H, 4C–
CH3), 1.71 (m, 3H, CH3–CH–CH3, 3-CHaHe and 4-CHaHe),
1.24 (t, J 7.14, 3H, CH3), 1.08 (m, 2H, 3-CHaHe, 6-CHaHe),
0.91 (m, 6H, CH3–CH–CH3), 0.88 (m, 1H, 4-CHaHe), 0.77 (m,
3H, CH–CH3). dC (75 MHz, CDCl3) 183.1 (C¼S), 170.8 (CO2-
L-Ment), 167.0 (CO2Et), 158.9 (Ar), 131.1 (Ar), 128.6 (Ar),
114.2 (Ar), 77.2 (CH–O), 74.0 (4-C), 70.8 (5-C), 62.0 (OCH2),
55.4 (OCH3), 46.9 (C-2), 40.4 (C-6), 34.0 (C-4), 31.5 (C-5), 26.4
(CH3–CH–CH3), 23.1 (C-3), 21.9 (CH–CH3), 20.8 (CH3–CH–
CH3), 16.0 (CH3–CH–CH3). Anal. Calc. for C25H36N2O5S:
C 63.00, H 7.61, N 5.88. Found: C 63.05, H 7.55, N 5.84 %.
cis/trans-Diethyl 1-(4-Methoxyphenyl)-4-Methyl-
2-Thioxoimidazolidine-4,5-Dicarboxylate 4b
Yield 0.44 g (48 %), yellow oil. nmax (ATR)/cmꢀ1 3166, 2982,
2838, 1737, 1511, 1442, 1240, 1189, 1109, 1019. Partial NMR
data for the cis and trans diastereoisomers of 4b were deter-
mined from the mixture.
cis-4b
dH (300 MHz, CDCl3) 7.35 (d, J 9.09, 2H, meta-ArH), 6.90
(d, J 9.09, 2H, ortho-ArH), 6.82 (s, 1H, NH), 4.62 (s, 1H, 5-CH),
4.21 (m, 4H, 2 OCH2), 3.80 (s, 3H, OCH3), 1.77, (s, 3H,
4C-CH3), 1.35 (t, J 7.14, 3H, CH3), 1.15 (t, J 7.14, 3H, CH3).
dC (75 MHz, CDCl3) 182.8 (C¼S), 169.9 (CO2Et), 167.2
(CO2Et), 159.0 (Ar), 130.8 (Ar), 128.7 (Ar), 114.3 (Ar), 74.2
(4-C), 70.7 (5-CH), 62.6 (OCH2), 61.9 (OCH2), 55.4 (OCH3),
20.3 (CH–CH3), 14.1 (CH3), 13.9 (CH3).
cis/trans-5-Ethyl 4-[endo-(1S)-Bornyl] 1-
(4-Methoxyphenyl)-4-Methyl-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4d
The title compound was obtained as an orange oil. Yield
0.40 g (45 %). nmax (ATR)/cmꢀ1 3163, 2953, 1735, 1512, 1446,
1243, 1188, 1137, 1018. Partial NMR data for cis and trans-
diastereoisomers of 4d were determined from the mixture.
trans-4b
dH (300 MHz, CDCl3) 7.35 (d, J 9.09, 2H, meta-ArH), 6.90
(d, J 9.09, 2H, ortho-ArH), 6.77 (s, 1H, NH), 5.31 (s, 1H, 5-CH),
4.21 (m, 4H, 2 ꢃ OCH2), 3.80 (s, 3H, OCH3), 1.52 (s, 3H, 4C–
CH3), 1.29 (t, J 7.14, 3H, CH3), 1.23 (t, J 7.14, 3H, CH3). dC
(75 MHz, CDCl3) 182.8 (C¼S), 171.2 (CO2Et), 167.0 (CO2Et),
158.9 (Ar), 131.0 (Ar), 128.7 (Ar), 114.2 (Ar), 74.2 (4-C), 70.7
cis-4d
dH (300 MHz, CDCl3) 7.34 (d, J 9.08, 2H, meta-ArH), 6.90
(d, J 9.08, 2H, ortho-ArH), 6.81 (s, 1H, NH), 4.65 (s, 1H, 5-CH),

340
D. Ciez˙ et al.
4.92 (m, 1H, CH–O), 4.08 (m, 1H, OCH2), 3.80 (2s, 3H, OCH3),
2.33 (m, 1H, 3-CHexo), 1.93 (m, 1H, 6-CHendo), 1.78 (s, 3H, 4C–
CH3), 1.71 (m, 3H, CH3–CH–CH3, 3-CHaHe and 4-CHaHe),
1.61 (m, 1H, 4-CH), 1.33 (m, 2H, 5-CHendo and 6-CHexo), 1.13
(t, J 7.14, 3H, CH3), 1.03 (m, 1H, 3-CHendo), 0.87 (m, 9H, CH3).
dC (75 MHz, CDCl3) 183.0 (C¼S), 170.1 (CO2–(1S)-bornyl),
166.9 (CO2Et), 159.0 (Ar), 130.8 (Ar), 128.7 (Ar), 114.3 (Ar),
82.7 (CH–O), 74.1 (NH–C–CH3), 70.9 (CH–CO2Et), 61.9
(OCH2), 55.4 (OCH3), 49.2 (1-C), 48.0 (CH3–C–CH3), 44.8
(4-C), 36.6 (3-C), 27.9 (5-C), 27.2 (6-C), 19.6 (CH3–C–CH3),
18.8 (CH3–C–CH3), 14.1 and 13.9 (NH–C–CH3), 13.5
(C–CH3).
5-CH), 4.08 and 4.07 (q, J 7.15, 2H, OCH2), 3.79 (OCH3), 3.75
and 3.74 (s, 3H, CO2CH3), 1.28 (m, 1H, CH–C2H5), 1.15 (t, J
7.15, 3H, OCH2–CH3), 1.10 and 0.97 (d, J 6.75, 3H, CH–CH3),
0.96 (m, 5H, CH2–CH3). dC (75 MHz, CDCl3) 182.7 and 182.5
(C¼S), 170.0 and 169.9 (CO2Me), 168.0 (CO2Et), 159.1 (Ar),
130.5 (Ar), 128.6 (Ar), 114.4 (Ar), 72.1 and 72.0 (4-C), 71.9 and
71.8 (5-CH), 62.0 (OCH2), 55.4 (OCH3), 52.8 (CO2CH3), 44.1
and 44.0 (CH–C2H5), 30.9 and 27.6 (CH–CH3), 23.8 and 22.5
(CO2CH2CH3), 13.9 and 13.2 (CH–CH2CH3), 12.1 and 11.8
(CH–CH2CH3). Anal. Calc. for C19H26N2O5S: C 57.85, H 6.64,
N 7.10. Found: C 57.80, H 6.61, N 7.15 %.
5-Ethyl 4-Methyl (4R,5S)-1-(4-Methoxyphenyl)-
4-[(1S)-1-Methylpropyl]-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4R,5S-4e
trans-4d
dH (300 MHz, CDCl3) 7.34 (d, J 9.08, 2H, meta-ArH), 6.90
(d, J 9.08, 2H, ortho-ArH), 6.78 (s, 1H, NH), 5.27, 5.24 (s, 1H,
5-CH), 5.06 (m, 1H, CH–O), 4.21 (m, 1H, OCH2), 3.79 (2s, 3H,
OCH3), 2.33 (m, 1H, 3-CHexo), 1.93 (m, 1H, 6-CHendo), 1.54,
1.53 (s, 3H, 4C–CH3), 1.71 (m, 3H, CH3–CH–CH3, 3-CHaHe
and 4-CHaHe), 1.61 (m, 1H, 4-CH), 1.33 (m, 2H, 5-CHendo and
6-CHexo), 1.24 (t, J 7.14, 3H, CH3), 1.03 (m, 1H, 3-CHendo), 0.87
(m, 9H, CH3). dC (75 MHz, CDCl3) 183.0 (C¼S), 171.5 (CO2–
(1S)-bornyl), 166.9 (CO2Et), 158.9 (Ar), 131.0 (Ar), 128.6 (Ar),
114.2 (Ar), 82.9 (CH–O), 74.1 (NH–C–CH3), 70.9 (CH–
CO2Et), 62.0 (OCH2), 55.4 (OCH3), 49.2 (1-C), 48.1 (CH3–
C–CH3), 44.7 (4-C), 36.6 (3-C), 27.9 (5-C), 27.2 (6-C), 19.6
(CH3–C–CH3), 18.8 (CH3–C–CH3), 14.1 and 13.9 (NH–C–
CH3), 13.5 (C–CH3). Anal. Calc. for C25H34N2O5S: C 63.26,
H 7.22, N 5.90. Found: C 63.12, H 7.34, N 5.99 %.
The pure enantiomer was isolated by crystallization of cis-4e
from n-hexane, which gave a white crystalline solid, that was
transparent and stable in the air. Mp 163–1648C. [a]D þ100.2
(c 0.014 in acetone).
Molecular formula C19H26N2O5S, crystal size: 0.2 ꢃ 0.2 ꢃ
0.2 mm3, M ¼ 394.48 g molꢀ1, trigonal, space group P312,
3
˚
˚
˚
a ¼ b ¼ 11.2382(6) A, c ¼ 28.5988(12) A, V ¼ 3128.0(3) A ,
Z ¼ 6, Dc ¼ 1.256 g cmꢀ3, m(MoKa) ¼ 0.19 mmꢀ1, F(000) ¼
1260; theta range: 3.54–28.478, Tmin ¼ 0.852, Tmax ¼ 1.000;
19372 collected reflections, 4910 independent (R(int) ¼ 0.037),
4910 number of reflections included in the refinement. The
refinement parameters are R1 ¼ 0.049 for reflections with
F2 . 2s(F2), wR2 ¼ 0.121, S ¼ 1.02.
cis/trans-5-Ethyl 4-L-Menthyl 1-(4-Methoxyphenyl)-4-
Methyl-2-Thioxoimidazolidine-4,5-Dicarboxylate 4f
cis/trans-5-Ethyl 4-Methyl 1-(4-Methoxyphenyl)-
4-[(1S)-1-Methylpropyl]-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4e
The title compound was obtained as an orange oil. Yield 0.39 g
(52 %). nmax (ATR)/cmꢀ1 3176, 2955, 2870, 1733, 1512, 1447,
1243, 1187, 1138, 1030.
The title compound was obtained as a yellow oil. Yield 0.58 g,
(52 %).
Application of preparative, thin-layer chromatography,
which was carried out using a Chromatotron (2 mm layer of
Merck silica gel 60 PF254; CHCl3 – MeOH 50 : 1), led to pure
trans-4e (first fraction; TLC Rf ¼ 0.65) and cis-4e (second
fraction; TLC Rf ¼ 0.55).
cis-4f
dH (300 MHz, CDCl3) 7.34 (d, J 9.05, 2H, meta-ArH), 6.90
(d, J 9.05, 2H, ortho-ArH), 6.70, 6.69 (s, 1H, NH), 4.61, 4.60
(s, 1H, 5-CH), 4.72 (m, 1H, CH–O), 4.08 (2dq, J 7.36, 1H,
OCH2), 3.80 (s, 3H, OCH3), 1.98 (m, 1H, 6-CHaHe), 1.77, 1.76
(s, 3H, 4C–CH3), 1.71 (m, 3H, CH3–CH–CH3, 3-CHaHe and
4-CHaHe), 1.14 (t, J 7.14, 3H, CH3), 1.08 (m, 2H, 3-CHaHe,
6-CHaHe), 0.91 (m, 6H, CH3–CH–CH3), 0.88 (m, 1H,
4-CHaHe), 0.77 (m, 3H, CH–CH3). dC (75 MHz, CDCl3)
183.1 (C¼S), 169.5 (CO2–L-Ment), 167.2 (CO2Et), 159.0 (Ar),
130.9 (Ar), 128.7 (Ar), 114.3 (Ar), 77.1 (CH–O), 74.0 (4-C),
71.5 (5-C), 61.8 (OCH2), 55.4 (OCH3), 46.8, 46.7 (C-2), 40.3
(C-6), 34.0 (C-4), 31.5 (C-5), 26.4 (CH3–CH–CH3), 23.1 (C-3),
21.9 (CH–CH3), 20.8 (CH3–CH–CH3), 15.9 (CH3–CH–CH3).
trans-4e
Yield 0.08 g (12.5 %), yellow oil. nmax (ATR)/cmꢀ1 3182,
2967, 2931, 2873, 1732, 1512, 1459, 1244, 1223, 1193, 1025. dH
(300 MHz, CDCl3) 7.32 (d, J 9.01, 2H, meta-ArH), 6.88 (d, J
9.01, 2H, ortho-ArH), 6.67 and 6.62 (s, 1H, NH), 5.38 and 5.34
(s, 1H, 5-CH), 4.17 (m, 2H, OCH2), 3.87 and 3.85 (s, 3H,
CO2CH3), 3.79 (OCH3), 1.37 and 1.36 (m, 1H, CH–C2H5), 1.21
and 1.20 (t, J 7.15, 3H, OCH2–CH3), 1.05 and 0.94 (d, J 6.82,
3H, CH–CH3), 0.89 (m, 5H, CH2–CH3). dC (75 MHz, CDCl3)
183.7 and 183.5 (C¼S), 170.6 (CO2Me), 167.2 (CO2Et), 158.8
(Ar), 130.8 (Ar), 128.5 (Ar), 114.1 (Ar), 72.4 and 72.2 (4-C),
71.8 and 71.7 (5-CH), 62.1 and 62.0 (OCH2), 55.4 (OCH3), 53.2
(CO2CH3), 39.0 and 38.6 (CH–C2H5), 25.3 and 24.6 (CH–CH3),
14.7 (CO2CH2CH3), 14.0 and 13.7 (CH–CH2CH3), 12.1 and
11.9 (CH–CH2CH3). Anal. Calc. for C19H26N2O5S: C 57.85,
H 6.64, N 7.10. Found: C 57.92, H 6.72, N 7.06 %.
trans-4f
dH (300 MHz, CDCl3) 7.34 (d, J 9.05, 2H, meta-ArH), 6.90
(d, J 9.05, 2H, ortho-ArH), 6.62 (s, 1H, NH), 5.26, 5.22 (s, 1H,
5-CH), 4.81 (m, 1H, CH–O), 4.21 (2dq, J 7.26, 1H, OCH2), 3.80
(s, 3H, OCH3), 1.98 (m, 1H, 6-CHaHe), 1.51, 1.50 (s, 3H, 4C–
CH3), 1.71 (m, 3H, CH3–CH–CH3, 3-CHaHe and 4-CHaHe),
1.24 (t, J 7.14, 3H, CH3), 1.08 (m, 2H, 3-CHaHe, 6-CHaHe),
0.91 (m, 6H, CH3–CH–CH3), 0.88 (m, 1H, 4-CHaHe), 0.77 (m,
3H, CH–CH3). dC (75 MHz, CDCl3) 183.1 (C¼S), 170.8 (CO2–
L-Ment), 167.0 (CO2Et), 158.9 (Ar), 131.1 (Ar), 128.6 (Ar),
114.2 (Ar), 77.2 (CH–O), 74.0 (4-C), 70.8 (5-C), 62.0 (OCH2),
cis-4e
Yield 0.50 g (40 %), yellowish solid. nmax (ATR)/cmꢀ1 3173,
2965, 2879, 1744, 1511, 1437, 1242, 1170, 1034. dH (300 MHz,
CDCl3) 7.24 (d, J 8.98, 2H, meta-ArH), 6.89 (d, J 8.98, 2H,
ortho-ArH), 6.83 and 6.75 (s, 1H, NH), 4.73 and 4.70 (s, 1H,

Mannich Reactions of 2-Isothiocyanatocarboxylates
341
55.4 (OCH3), 46.9 (C-2), 40.4 (C-6), 34.0 (C-4), 31.5 (C-5), 26.4
(CH3–CH–CH3), 23.1 (C-3), 21.9 (CH–CH3), 20.8 (CH3–CH–
CH3), 16.0 (CH3–CH–CH3). Anal. Calc. for C25H36N2O5S:
C 63.00, H 7.61, N 5.88. Found: C 63.10, H 7.66, N 5.78 %.
trans-4h
Yield 0.14 g (16 %), orange oil. nmax (ATR)/cmꢀ1 3173,
2952, 2870, 1728, 1514, 1460, 1244, 1187, 1032. dH
(300 MHz, CDCl3) 7.26 (d, J 9.10, 2H, meta-ArH), 6.89 (d, J
9.10, 2H, ortho-ArH), 6.52 (s, 1H, NH), 5.03, 4.99 (s, 1H,
5-CH), 4.86 (m, 1H, CH–O), 4.21 (2dq, J 6.69 and 7.75, 1H,
OCH2), 3.79 (s, 3H, OCH3), 2.04 (m, 1H, 6-CHaHe), 1.88 (m,
3H, CH2–iPr, CH3–CH–CH3), 1.71 (m, 3H, menthyl-CH3–CH–
CH3, 3-CHaHe and 4-CHaHe), 1.25 (t, J 7.75 and 6.69, 3H, CH3),
1.08 (m, 2H, 3-CHaHe, 6-CHaHe), 0.91 (m, 12H, CH3–CH–CH3
and menthyl-CH3–CH–CH3), 0.88 (m, 1H, 4-CHaHe), 0.77
(m, 3H, CH–CH3). dC (75 MHz, CDCl3) 184.5 (C¼S), 171.4
(CO2–L-menthyl), 166.9 (CO2Et), 158.9 (Ar), 131.0 (Ar), 128.5
(Ar), 114.2 (Ar), 77.5 (CH–O), 72.8 (4-C–CH2–iPr), 68.6
(5-CH), 62.1 (OCH2), 55.4 (OCH3), 46.7 (2-C), 41.4 (CH3–
CH–CH3), 40.4 (6-C), 33.9 (4-C), 31.4 (5-C), 26.2 (CH3–CH–
CH3), 25.6 (CH2–iPr), 23.8 (CH3–CH–CH3), 23.3 (CH2CH3),
22.8 (3-C), 21.9 (CH–CH3), 20.9 (menthyl-CH3–CH–CH3),
15.7 (menthyl-CH3–CH–CH3), 14.1 (CH3–CH–CH3). Anal.
Calc. for C28H42N2O5S: C 64.84, H 8.16, N 5.40. Found:
C 64.88, H 8.01, N 5.41 %.
cis/trans-5-Ethyl 4-L-Menthyl 4-Isobutyl-
1-(4-Methoxyphenyl)-2-Thioxoimidazolidine-
4,5-Dicarboxylate 4g
The title compound was obtained as a yellow oil. Yield 0.28 g
(46 %). nmax (ATR)/cmꢀ1 3169, 2955, 2871, 1732, 1512, 1461,
1242, 1185, 1030. Partial NMR data for cis and trans diaster-
eoisomers of 4g were determined from the mixture.
cis-4g
dH (300 MHz, CDCl3) 7.27 (d, J 9.10, 2H, meta-ArH), 6.89
(d, J 9.10, 2H, ortho-ArH), 6.60, 6.55 (s, 1H, NH), 4.64 (s, 1H,
5-CH), 4.70 (m, 1H, CH–O), 4.07 (2dq, J 6.69 and 7.75, 1H,
OCH2), 3.79 (s, 3H, OCH3), 2.04 (m, 1H, 6-CHaHe), 1.88 (m,
3H, CH2-i Pr, CH3–CH–CH3), 1.71 (m, 3H, menthyl-CH3–CH–
CH3, 3-CHaHe, and 4-CHaHe), 1.14 (t, J 7.75 and 6.69, 3H,
CH3), 1.08 (m, 2H, 3-CHaHe, 6-CHaHe), 0.91 (m, 12H, CH3–
CH–CH3 and menthyl-CH3–CH–CH3), 0.88 (m, 1H, 4-CHaHe),
0.77 (m, 3H, CH–CH3). dC (75 MHz, CDCl3) 182.8 (C¼S),
169.5 (CO2–L-menthyl), 167.3 (CO2Et), 159.0 (Ar), 130.8 (Ar),
128.6 (Ar), 114.3 (Ar), 77.5 (CH–O), 74.2 (4-C–CH2–iPr), 68.6
(5-CH), 61.9 (OCH2), 55.4 (OCH3), 46.6 (2-C), 41.4 (CH3–CH–
CH3), 40.3 (6-C), 33.9 (4-C), 31.4 (5-C), 26.2 (CH3–CH–CH3),
25.6 (CH2–iPr), 23.8 (CH3–CH–CH3), 23.3 (CH2CH3), 22.8
(3-C), 21.9 (CH–CH3), 20.9 (menthyl-CH3–CH–CH3), 15.6
(menthyl-CH3–CH–CH3), 13.9 (CH3–CH–CH3).
cis-4h
Yield 0.21 g (37 %), yellow oil. nmax (ATR)/cmꢀ1 3166,
2955, 2873, 1738, 1510, 1458, 1240, 1186, 1027. dH
(300 MHz, CDCl3) 7.26 (d, J 9.10, 2H, meta-ArH), 6.89 (d, J
9.10, 2H, ortho-ArH), 6.60, 6.55 (s, 1H, NH), 4.64 (s, 1H,
5-CH), 4.70 (m, 1H, CH–O), 4.07 (2 ꢃ dq, J 6.69 and 7.75, 1H,
OCH2), 3.79 (s, 3H, OCH3), 2.04 (m, 1H, 6-CHaHe), 1.88
(m, 3H, CH2–iPr, CH3–CH–CH3), 1.71 (m, 3H, menthyl-
CH3–CH–CH3, 3-CHaHe and 4-CHaHe), 1.14 (t, J 7.75 and
6.69, 3H, CH3), 1.08 (m, 2H, 3-CHaHe, 6-CHaHe), 0.91
(m, 12H, CH3–CH–CH3 and menthyl-CH3–CH–CH3), 0.88
(m, 1H, 4-CHaHe), 0.77 (m, 3H, CH–CH3). dC (75 MHz,
CDCl3) 182.8 (C¼S), 169.5 (CO2–L-menthyl), 167.3 (CO2Et),
159.0 (Ar), 130.8 (Ar), 128.6 (Ar), 114.3 (Ar), 77.5 (CH–O),
74.2 (4-C–CH2–iPr), 68.6 (5-CH), 61.9 (OCH2), 55.4 (OCH3),
46.6 (2-C), 41.4 (CH3–CH–CH3), 40.3 (6-C), 33.9 (4-C), 31.4
(5-C), 26.2 (CH3–CH–CH3), 25.6 (CH2–iPr), 23.8 (CH3–CH–
CH3), 23.3 (CH2CH3), 22.8 (3-C), 21.9 (CH–CH3), 20.9
(menthyl-CH3–CH–CH3), 15.6 (menthyl-CH3–CH–CH3),
13.9 (CH3–CH–CH3). Anal. Calc. for C28H42N2O5S: C 64.84,
H 8.16, N 5.40. Found: C 64.80, H 8.15, N 5.47 %.
trans-4g
dH (300 MHz, CDCl3) 7.27 (d, J 9.10, 2H, meta-ArH), 6.89
(d, J 9.10, 2H, ortho-ArH), 6.52 (s, 1H, NH), 5.03, 4.99 (s, 1H,
5-CH), 4.86 (m, 1H, CH–O), 4.21 (2dq, J 6.69 and 7.75, 1H,
OCH2), 3.79 (s, 3H, OCH3), 2.04 (m, 1H, 6-CHaHe), 1.88 (m,
3H, CH2-iPr, CH3–CH–CH3), 1.71 (m, 3H, menthyl-CH3–CH–
CH3, 3-CHaHe and 4-CHaHe), 1.25 (t, J 7.75 and 6.69, 3H, CH3),
1.08 (m, 2H, 3-CHaHe, 6-CHaHe), 0.91 (m, 12H, CH3–CH–
CH3 and menthyl-CH3–CH–CH3), 0.88 (m, 1H, 4-CHaHe), 0.77
(m, 3H, CH–CH3). dC (75 MHz, CDCl3) 184.5 (C¼S), 171.4
(CO2–L-menthyl), 166.9 (CO2Et), 158.9 (Ar), 131.0 (Ar), 128.5
(Ar), 114.2 (Ar), 77.5 (CH–O), 72.8 (4-C–CH2–iPr), 68.6
(5-CH), 62.1 (OCH2), 55.4 (OCH3), 46.7 (2-C), 41.4 (CH3–
CH–CH3), 40.4 (6-C), 33.9 (4-C), 31.4 (5-C), 26.2 (CH3–CH–
CH3), 25.6 (CH2–iPr), 23.8 (CH3–CH–CH3), 23.3 (CH2CH3),
22.8 (3-C), 21.9 (CH–CH3), 20.9 (menthyl-CH3–CH–CH3),
15.7 (menthyl-CH3–CH–CH3), 14.1 (CH3–CH–CH3). Anal.
Calc. for C28H42N2O5S: C 64.84, H 8.16, N 5.40. Found:
C 64.80, H 8.08, N 5.56 %.
Acknowledgements
This work was supported by the Polish Ministry of Science and Higher
Education (Grant no. N N204 310037). The research was carried out with the
equipment purchased thanks to the financial support of the European
Regional Development Fund in the framework of the Polish Innovation
Economy Operational Program (contract no. POIG.02.01.00-12-023/08).
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