Enolates of 2-isothiocyanatocarboxylic esters: Synthesis of thiazolo[5,4-d]-thiazole derivatives and 2-thioxo-1,3-thiazolidine-4- carboxylates

Article abstract of DOI:10.1055/s-0031-1290825

An oxidative dimerization of titanium(IV) enolates derived from menthyl esters of 2-isothiocarboxylic acids leads to radical coupling followed by cyclization. This cascade reaction gives thiazolo[5,4-d]thiazole derivatives as pure enantiomers. Under simil

Full text of DOI:10.1055/s-0031-1290825

1736▌
PAPER
paper
Enolates of 2-Isothiocyanatocarboxylic Esters: Synthesis of Thiazolo[5,4-d]-
thiazole Derivatives and 2-Thioxo-1,3-thiazolidine-4-carboxylates
Dariusz Cież,* Justyna Kalinowska-Tłuścik
Faculty of Chemistry, Jagiellonian University, ul. Romana Ingardena 3, 30-060 Kraków, Poland
Fax +48(12)6340515; E-mail: ciez@chemia.uj.edu.pl
Received: 19.01.2012; Accepted after revision: 09.03.2012
tions.13 Our investigations on the mechanism of the oxida-
Abstract: An oxidative dimerization of titanium(IV) enolates de-
tive coupling reaction have identified both the scope and
rived from menthyl esters of 2-isothiocarboxylic acids leads to rad-
limitations of this process. The oxidative dimerization of
2-isothiocyanatocarboxylic esters attracted our attention
ical coupling followed by cyclization. This cascade reaction gives
thiazolo[5,4-d]thiazole derivatives as pure enantiomers. Under sim-
ilar conditions, 2-methylbutyl esters of 2-isothiocyanatocarboxylic because the resulting 2,3-diisothiocyanato succinic acid
acids undergo intermolecular oxidative dimerization to give mix-
tures of thiazolo[5,4-d]thiazoles and 2,3-diisothiocyanatosucci-
nates. Application of the soft enolization technique to dimethyl α,α′-
derivatives could be regarded as masked 2,3-diamino
acids.
In continuation of our previous research on the diastereo-
selectivity of the oxidative coupling reaction, we synthe-
sized two novel 2-isothiocyanatocarboxylic esters, L-
menthyl 2-isothiocyanatopropanoate (1a) and D-menthyl
2-isothiocyanatopropanoate (1b), that contain large chiral
ester groups. Soft enolization of L-menthyl 2-isothiocya-
natopropanoate (1a) with the titanium(IV) chloride–diiso-
propyl(ethyl)amine system led exclusively to a single
oxidation product, but analysis of its NMR spectra and
two-dimensional (2-D) NMR studies showed that this
compound was not the expected 2,3-diisothiocyanatosuc-
cinate, but was, in fact the thiazolo[5,4-d]thiazole 6a
(Scheme 1). The titanium(IV) enolates of D-menthyl 2-
isothiocyanatopropanoate (1b) and endo-(1S)-bornyl 2-
isothiocyanatoacetate (1c) also underwent oxidative cou-
pling to give the same fused heterocyclic system in the
products 6b and 6c, respectively.
diisothiocyanatodicarboxylic esters gives novel cyclic 1,2-diiso-
thiocyanato-1,2-dicarboxylates. Sodium enolates of 2-isothiocya-
natocarboxylates, on the other hand, form 5-imino-2-thioxo-1,3-
thiazolidine-4-carboxylic esters by nonoxidative dimerization. The
mechanisms of the two reaction pathways are discussed.
Key words: domino reactions, dimerizations, heterocycles, enols,
titanium, diastereoselectivity
In synthesis, 2-isothiocyanatocarboxylic esters are mainly
used in preparing five-membered heterocycles or acyclic
thioureas. The earliest report on the reaction of ethyl 2-
isothiocyanato-4-methylpentanoate with ammonia to give
2-thioxoimidazolidin-4-one appeared nearly 90 years
ago.1 Later reports on preparations of 2-thioxoimidazoli-
din-4-ones describe reactions with amines,2 hydrazones,3
and aminonitriles.4 Syntheses of 1,2,3,4-thiatriazole5 and
some acyclic thioureas6 have also been described. Thio-
ureas derived from 2-isothiocyanatocarboxylates can
serve as convenient reactants for preparation of chiral iso-
thiazolidines that are potentially useful as antiviral
agents.7 Titanium(IV)-promoted oxidative coupling reac-
tions of 2-isothiocyanatocarboxylic esters have been used
in attempts to synthesize masked symmetric 2,3-
diaminosuccinates8 and 2-thioxoimidazolidine rings.9
More recently, 2-isothiocyanatocarboxylic esters have
been used as substrates in stereoselective Mannich addi-
tions leading to 2-thioxo-1,3-imidazolidines, which are
derivatives of 2,3-diaminosuccinic acid.10
OR
CO2R
i
O
NCS
SCN
2a–c
TiCl3
1a–c
S
N
S
CO2R
RO2C
N
6a–c
a R =
b R =
c R =
Titanium(IV) enolates of carboxylic esters can serve as
very convenient and useful intermediates for C–C bond-
formation reactions.11 Our research in the field of titani-
um(IV) enolates has focused on oxidative coupling reac-
tions to form vicinal 2,3-diisothiocyanatosuccinates8 and
pyrrole derivatives.12 More recently, we found that titani-
Scheme 1 Oxidative dimerization of titanium(IV) enolates of 2-iso-
thiocyanatopropanoates 1a–c to give thiazolo[5,4-d]thiazole deriva-
um(IV) enolates derived from 2-nitrocarboxylic esters tives 6a–c, respectively. Reagents and conditions: (i) TiCl4, CH2Cl2,
argon, –96 °C then DIPEA, CH2Cl2, –96 °C to r.t.
can be quantitatively chlorinated under oxidative condi-
The 13C NMR spectra of both the thiazolo[5,4-d]thiazole
derivatives 6a and 6b exhibited double signals for all the
nonequivalent carbon atoms. This suggested that the prod-
SYNTHESIS 2012, 44, 1736–1744
Advanced online publication: 23.04.2012
DOI: 10.1055/s-0031-1290825; Art ID: SS-2012-Z0069-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

PAPER
Thiazolo[5,4-d]thiazole Derivatives and 2-Thioxo-1,3-thiazolidine-4-carboxylates
1737
ucts might each consist of a mixture of two diastereoiso- of 2-isothiocyanatopropanoate 5g gave DL-2,3-diisothio-
meric forms. However, the two products showed equal but cyanatosuccinate 7g and meso-thiazolo[5,4-d]thiazole 6g
opposite specific rotations, which is typical of enantio- in a 2:3 ratio.
mers rather than diastereoisomers. Indeed, an X-ray crys-
tal structure analysis of 6a showed that the C-2 and C-5
O
O
atoms have absolute configurations of R and S, respective-
i
t-BuO
NH
R2OH
t-BuO
NH
ly (Figure 1), indicating that the oxidative coupling reac-
tions of L- and D-menthyl 2-isothiocyanatopropanoates 1a
and 1b are highly diastereoselective.
+
OR2
R1
R1
CO2H
ii
O
3d–g
NH3
NCS
iii
iv
OR2
OR2
R1
R1
CF3COO
4d–g
O
O
5d–g
O
S
O
R1
NCS
OR2
R1
N
OR2
R2O
SCN
+
R2O
R1
R1
S
N
O
O
6d–g
7d–g
Scheme 2 Titanium(IV) enolates derived from 2-isothiocyanato-
carboxylates bearing medium-sized ester groups underwent oxidative
dimerization to give two oxidation products; d: R2 = (2S)-
CH2CH(Me)Et; R1 = Me, e: R2 = (2S)-CH2CH(Me)Et; R1 = i-Bu, f:
R2 = (2S)-CH2CH(Me)Et; R1 = Bn; g: R2 = Cy; R1 = Me. Reaction
conditions: (i) DCC, DMAP, CH2Cl2; (ii) 5% TFA in CH2Cl2; (iii)
CSCl2, NaHCO3, CH2Cl2/H2O; (iv) TiCl4, CH2Cl2, argon, –96 °C,
then DIPEA, CH2Cl2, –96 °C to r.t.
Figure 1 Molecular structure of di-L-menthyl (2R,5S)-2,5-dimethyl-
2,5-dihydro[1,3]thiazolo[5,4-d]thiazole-2,5-dicarboxylate (6a) as de-
termined by x-ray crystallographic analysis; the atom displacement
ellipsoids are drawn at the 30% probability level14
Our results suggested that the size of the ester group has a
significant effect on the oxidative coupling of titani-
um(IV) enolates derived from 2-isothiocyanatocarboxyl-
ates and that the reaction can give either a 2,3-
diisothiocyanatosuccinic ester or a fused thiazolo[5,4-
d]thiazole system. To verify this, we prepared chiral (2S)-
2-methylbutyl (2S)-2-isothiocyanatopropanoate (5d) in
three steps from commercial N-(tert-butoxycarbonyl)ala-
nine and (2S)-(–)-2-methylbutan-1-ol. Deprotection of the
ester 3d by trifluoroacetic acid gave the nonisolable ester
of L-alanine 4d, which was transformed into (2S)-2-meth-
ylbutyl (2S)-2-isothiocyanatopropanoate (5d) by the thio-
phosgene method. The designed ester group is smaller
than the menthyl substituent, but is branched. Chiral iso-
thiocyanato ester 5d was transformed into the correspond-
ing titanium(IV) enolate, which underwent dimerization
to give coupling products (Scheme 2). Gas chromatogra-
phy–mass spectrometric analysis of the reaction mixture
showed that the reaction gave two products with the same
molecular mass but different fragmentation patterns.
NMR studies on the isolated products showed that the ox-
idative coupling had produced both the thiazolo[5,4-d]thi-
azole 6d and the 2,3-diisothiocyanatosuccinate derivative
7d. Titanium(IV) enolates of (2S)-2-methylbutyl (2S)-2-
isothiocyanato-4-methylpentanoate (5e) and (2S)-2-meth-
ylbutyl (2S)-2-isothiocyanato-3-phenylpropanoate (5f)
similarly gave DL-2,3-diisothiocyanatosuccinates 7e and
7f, respectively, as the main products. The DL-diastereo-
selectivity of the coupling process was in excess of 95%.
Traces of the meso forms 7e and 7f and of the fused thia-
zolo[5,4-d]thiazole derivatives 6e and 6f were detected by
GC analysis of the reaction mixture. The cyclohexyl ester
An analysis of the competition between the two different
oxidation processes showed that substituents at C-2 had
an opposite effect on the dimerization reaction to that of
the ester group. Branched and bulky ester groups appar-
ently hindered the formation of 2,3-diisothiocyanatosuc-
cinic esters and promoted the oxidative coupling to form
thiazolo[5,4-d]thiazole derivatives, whereas medium-
sized substituents at C-2 promoted the formation of the
corresponding 2,3-isothiocyanatosuccinates. In each case,
however, the final products consisted of equilibrium mix-
tures of the two types of dimer.
The highly diastereoselective oxidative coupling reaction
leading to the thiazolo[5,4-d]thiazole system appears to be
a cascade radical process that commences with oxidation
of the titanium(IV) enolate to a radical 8. This step is me-
diated by titanium(IV) ions that undergo reduction to tita-
nium(III) species. We assume that the dimeric transition
state that Matsumura15 postulated as being typical of oxi-
dative coupling reactions that lead to 2,3-diisothiocya-
natosuccinates is not formed in the presence of large ester
groups because of steric repulsion. The radical 8 under-
goes intermolecular coupling to form a new C–C single
bond between the two isothiocyanate groups, resulting in
intermediate 10. This step initiates a cascade reaction in-
volving double thiolation of the imine function to give 11,
which finally undergoes ring closure to give the thiazo-
lo[5,4-d]thiazole system 6 (Scheme 3). This domino radi-
cal cyclization shows a very high diastereoselectivity in
forming a thiazolo[5,4-d]thiazole core in which the C-2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1736–1744

1738
D. Cież, J. Kalinowska-Tłuścik
PAPER
and C-5 atoms have opposite configurations. This phe- mation of 2,3-diisothiocyanatocarboxylic esters. We
nomenon can be explained in terms of a highly ordered therefore designed some 2-isothiocyanatocarboxylic es-
transition state that forms three-dimensional structures in ters that contained bulky chiral ester groups but which
solution. The titanium(IV) enolates undergo self-assem- were unable to form the thiazolo[5,4-d]thiazole system
bly and self-organization processes in solution as a result because of the presence of a rigid structure that prevented
of the coordination properties of the titanium ions. We the formation of the transition state 9. These reactants,
propose a reaction mechanism based on a dimeric transi- which were diesters of diols with 2-isothiocyanatocarbox-
tion state, as previously suggested for oxidative coupling ylic acids, were prepared in three step from several chiral
of phenylacetate derivatives,15a,b except that in our model, diols [(R)- and (S)-1,1′-binaphthalene-2,2′-diol, and
we assume that two enolate subunits are linked by titani- 1,2;5,6-di-O-cyclohexylidene-D-mannitol] and protected
um(IV) ions and form a three-dimensional transition state amino acids. After esterification and deprotection, the
9 in which the bulky ester substituents are located in the amino groups were transformed into isothiocyanate func-
opposite peripheral parts of the structure. The assumption tions by the thiophosgene method to give the desired dies-
that the bulky ester groups will be located opposite one ters 12–15 (Figure 2). We assumed that the chiral ester
another turns out to be helpful in explaining the diastere- auxiliaries would promote enantioselective oxidative cou-
oselectivity of the reaction. The addition of the sulfur rad- pling of the 2-isothiocyanatocarboxylic fragments to give
ical at the re-face of the enolate 11 is followed by attack the corresponding chiral 2,3-diisothiocyanatosuccinic
of the second sulfur radical at the si-face. In this way, the acid derivatives. However, reactions of diesters 12–15
reaction leads to the fused thiazolo[5,4-d]thiazole system with the titanium(IV) chloride/diisopropyl(ethyl)amine
with opposite configurations at the C-2 and C-5 positions. oxidizing system failed to give any dimerization products.
Although the reactants readily formed double titani-
um(IV) enolates, oxidative coupling was restrained and
RO
RO
RO
•
only the starting material was recovered. As expected, the
recovered reactants 13–15 showed nearly complete race-
mization at the α-positions in the 2-isothiocyanatocarbox-
ylic fragments. The experiment proved that the formation
of 2,3-diisothiocyanatosuccinates and thiazolo[5,4-d]thia-
zole derivatives is markedly dependent on the spatial
structure of the transition state. The structure of the tran-
sition state is determined by interactions of the enolates
derived from the 2-isothiocyanatocarboxylic esters. These
results differ from those previously described by
Periasamy15b for stereoselective oxidative coupling of chi-
ral binaphth-2-yl arylacetates. It is likely that the titani-
um(IV) enolates formed from the isothiocyanatoacetates
underwent isomerization before coupling and that they
formed a complex that was unable to dimerize. Titani-
um(IV) enolates derived from binaphth-2-yl arylacetates,
on the other hand, are more stable and therefore capable
of giving the corresponding oxidative dimerization prod-
O
N
O
N
O
N
C
C
C
Ti
Ti
Ti
S
S
S
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
8
Cl
8
2
Cl
Cl
O
Ti
OR
Cl
S
C N
Cl
Cl
Cl
O
N
C
S
Ti
OR
•
Cl
Ti
S
C N
RO
O
Cl
Cl
N
C
S
9
•
Cl
Ti
RO
O
Cl
Cl
10
– TiCl3
Cl
Ti
Cl
Cl
O
Re face
approach
CO2R
N
OR
S
C N
•
S
S
N
C
+ TiCl3
Si face
approach
Cl
Ti
N
S
RO
O
O
O
NCS
Cl
Cl
RO2C
NCS
NCS
O
O
O
O
6
11
Scheme 3 A tentative reaction mechanism that explains the very
high diastereoselectivity of the oxidation process
NCS
O
O
O
12
13
O
O
Investigations of the competition between two oxidative
coupling processes led us to conclude that 2,3-diisothio-
cyanatocarboxylic esters 7 can be obtained only when the
2-isothiocyanatocarboxylates contain small or medium-
sized ester groups. The presence of bulky or branched es-
ter substituents appears to change the reaction mechanism
and leads to a domino process that gives the thiazolo[5,4-
d]thiazole derivatives 6. This differences in reaction
mechanism appear to arise from the presence of distinct
transition states for each of the two processes and it pre-
cludes the use of chiral auxiliaries for stereoselective for-
O
NCS
NCS
SCN
O
O
i-Pr
O
O
O
i-Pr
O
NCS
O
O
14
15
Figure 2 Chiral diesters of 2-isothiocyanatocarboxylic acids can be
transformed into double enolates by the soft-enolization technique,
but they do not undergo oxidative coupling
Synthesis 2012, 44, 1736–1744
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolo[5,4-d]thiazole Derivatives and 2-Thioxo-1,3-thiazolidine-4-carboxylates
1739
ucts. The labilities of titanium complexes and their stereo- mers. On the basis of the integration data, we
chemical rearrangements are known and have been hypothesized that one diastereoisomer exists as two con-
previously reported.16a,b
formers. Analysis of the possible conformations of cis-
and trans-20a showed that only the trans-diastereoisomer
could have two different conformational energies corre-
sponding to the two ring-flipped forms. These forms dif-
fer in terms of the spatial orientation of the vicinal
isothiocyanate and ester groups, which can be either diax-
ial or diequatorial, respectively.
Our next experiment was designed to confirm our obser-
vations concerning the chemo- and regioselectivity of the
oxidative coupling. We investigated the oxidative dimer-
ization of acyclic, enolizable diisothiocyanato esters de-
rived from dicarboxylic acids. The substrates, which were
esters of α,α′-diisothiocyanatosuberic and α,α′-diisothio-
cyanatosebacic acids, (19a and 19b, respectively), were Unlike trans-20a, the second diastereoisomer, cis-20a,
prepared in several steps from the corresponding α,α′-di- shows equivalent conformational energies for the two
bromodicarboxylates 16a and 16b. We expected that the ring-flipped conformers.17 We therefore assigned the dou-
presence of a long hydrocarbon chain would hinder oxida- ble signals to the trans-20a diastereoisomer. Analysis of
tive coupling to form the bicyclic thiazolo[5,4-d]thiazole the NMR data recorded for the eight-membered 1,2-diiso-
(Scheme 4) and would, instead, give the products of intra- thiocyanato-1,2-dicarboxylate 20b showed an excess of
molecular cyclization. Indeed, our experiments showed one diastereoisomer, but the conformational diversity of
that the double titanium(IV) enolates formed from di- the cyclooctane ring prevented us from identifying which
methyl α,α′-diisothiocyanatodicarboxylates 19a and 19b diastereoisomer, cis- or trans-20b, is the main product of
or their diethyl analogues undergo an oxidative dimeriza- the oxidative coupling. An attempt to prepare chiral 1,2-
tion to give the corresponding cyclic 1,2-diisothiocyana- diisothiocyanato-1,2-dicarboxylates failed: oxidative
to-1,2-dicarboxylates 20a and 20b, respectively, which coupling of chiral L-menthyl or (2S)-2-methylbutyl dies-
represent a new group of cyclic dicarboxylic acids . Un- ters of α,α′-diisothiocyanatosebacic acid did not give any
like the oxidative dimerization of simple 2-isothiocya- products, whereas the use of diethyl α,α′-diisothiocya-
natocarboxylates, the degree of diastereoselectivity in the natosuberate or α,α′-diisothiocyanatosebacate led to oxi-
formation of the 1,2-diisothiocyanato-1,2-dicarboxylates dative dimerization. This experiment proved that the size
20a and 20b was low, and nearly equimolar amounts of of the ester group plays a major role in the intramolecular
the cis- and trans-diastereoisomers were obtained. Yields oxidative coupling reactions.
of products 20a and 20b were moderate, but we did not
find any traces of thiazolo[5,4-d]thiazole derivatives. Be-
We also compared our results pertaining to the properties
and reactivities of titanium(IV) enolates with those for the
cause of their similar properties, it was impossible to sep-
corresponding sodium enolates of 2-isothiocyanatocar-
arate the cis- and trans-forms of 1,2-diisothiocyanato-1,2-
boxylates. We chose sodium as a counterion for enolate
formation because the stability of the sodium enolates
should prevent any accidental oxidative coupling process-
dicarboxylates 20a and 20b, and therefore the NMR spec-
tra of these products included data for both diastereoiso-
es. Unlike titanium(IV) enolates, alkali metal enolates
Br
Br
i
tend to undergo oxidative coupling reactions only in the
presence of oxidizing agents.18 2-Isothocyanatocarboxyl-
ates 1 readily gave the sodium enolates 21 on treatment
with sodium hydride in anhydrous N,N-dimethylform-
amide, but the enolates spontaneously underwent inter-
molecular dimerization to give the 5-imino-2-thioxo-1,3-
thiazolidine-4-carboxylic esters 24 in moderate-to-good
yields (Scheme 5). Products 24 were isolated by pouring
the reaction mixture into ice–water and neutralizing the
resultant basic solution. Both the ester groups were stable
and aqueous workup did not cause hydrolysis. The trans-
formation could be described in terms of a two-step mech-
anism (Scheme 5) involving addition of the sodium
enolate 21 to the isothiocyanate group and subsequent cy-
clization of the intermediate 22 after repeated addition of
the sulfur anion to the isothiocyanate function. The 5-im-
ino-2-thioxo-1,3-thiazolidine-4-carboxylic ester product
remains in an anionic form as the disodium salt 23, which
can be readily converted into the desired product 24 by
treatment with an acid. Our suggested mechanism, in
which enolization at the chiral center of the 2-isothiocya-
natocarboxylic ester is followed by racemization, explains
the low stereoselectivity of this reaction. The use of a sub-
stoichiometric amounts of sodium hydride resulted in a
HO2C
CO2H
MeO2C
CO2Me
n
n
ii
16a,b
2Cl
N3
N3
NH3 NH3
CO2Me
18a,b
iii
MeO2C
CO2Me
MeO2C
n
n
17a,b
iv
v
NCS
CO2Me
N
S
Sn
N
X
MeO2C
n
CO2Me
MeO2C
19a,b
v
NCS NCS
CO2Me
NCS NCS
MeO2C
CO2Me
MeO2C
+
n
n
trans-20a,b
cis-20a,b
Scheme 4 Synthesis and oxidative coupling of α,α′-diisothiocyana-
todicarboxylates; a: n = 1, b: n = 2. Reagents and conditions: (i)
SOCl2, Br2, then MeOH; (ii) NaN3, DMF; (iii) Ph3P then aq HCl,
MeOH; (iv) CSCl2, NaHCO3, CHCl3/H2O; (v) TiCl4, CH2Cl2, argon,
–96 °C then DIPEA, CH2Cl2, –96 °C to r.t.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1736–1744

1740
D. Cież, J. Kalinowska-Tłuścik
PAPER
dramatic decrease in the yield. This showed that the first
step of the reaction, enolate attack on the isothiocyanate
group, was only possible when the second reactant was
also present as an enolate. In other cases, the enolate re-
acted with the α-hydrogen atom and did not undergo an
addition to the isothiocyanate function of the 2-isothiocy-
anatocarboxylate.
H
S
CO2Et
CO2Et
H
N
EtO2C
N
EtO2C
H
N
S
N
H
S
S
24h (imine form)
24h (enamine form)
i
H
S
CO2H
R1
OR2
ONa
EtO2C
N
SCN
R1
ONa
OR2
SCN
CO2R2
i
SCN
N
H
R1
S
25h
1h–k
21h–k
Scheme 6 Hydrolysis of 5-imino-2-thioxo-1,3-thiazolidine-4-carbox-
ylic ester 24h to carboxylic acid 25h. Reagents and conditions: (i)
NaOH, EtOH, r.t. then aq HCl (1.0 equiv).
••
O
2Na
R2O2C
SCN
R1
2Na
R2O2C
••
OR2
O
N
S
N
R1
R1
N
failed because the 1,3-thiazolidine ring decomposed un-
der the harsh conditions that were required.
OR2
S
R1
••
S
In summary, we found that the reactivity of 2-isothiocya-
natocarboxylates is markedly dependent on their struc-
ture, permitting their use in syntheses of novel
heterocyclic systems or vicinal diisothiocyanates. Titani-
um(IV) enolates of 2-isothiocyanatocarboxylic esters
bearing bulky esters groups gave the previously unknown
fused thiazolo[5,4-d]thiazole system in good yields. We
proposed a mechanism for this transformation that in-
volves three consecutive steps initiated by titanium(IV)
ions. From the mechanistic point of view, the cyclization
can be considered as a radical domino reaction. Steric re-
pulsions between ester substituents resulted in the forma-
tion of thiazolo[5,4-d]thiazole derivatives in which the
two ester groups were located on opposite sides of the
molecule. The structure of the product reflected the struc-
ture of the transition state. Oxidative dimerization to give
2,3-diisothiocyanates occurred when the ester groups
were small or medium-sized. An interesting result was ob-
tained during enolization of dimethyl esters of α.α′-diiso-
thiocyanatodicarboxylic acids; intramolecular cyclization
led to derivatives of 1,2-diisothiocyanato-1,2-dicarboxyl-
ic acids, in agreement with Matsumura’s model of the
transition state. Unfortunately, the diastereoselectivity of
this process was very poor. Unlike titanium(IV) enolates,
sodium enolates prepared from 2-isothiocyanatocarboxyl-
ates underwent dimerization followed by cyclization to
give 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic es-
ters in moderate-to-good yields. The resulting 2-thioxo-
1,3-thiazolidines represent a new group of thiazolidine de-
rivatives.
••
22h–k
23h–k
CO2R2
R1
R2O2C
N
R1
R2
Et
R1
N
ii
S
h
i
H
H
L-menthyl
H
j
endo-(1S)-bornyl
S
Me
k
Et
24h–k
Scheme 5 A tentative reaction mechanism suggested for the inter-
molecular cyclization of sodium enolates. Reagents and conditions:
(i) NaH, DMF, r.t.; (ii) AcOH, H2O.
NMR spectra of the 1,3-thiazolidine-4-carboxylic esters
24h–j derived from ethyl isothiocyanoacetates 1h–j, re-
spectively, showed that the 2-thioxo-1,3-thiazolidines
24h–j exist mainly as the enamine tautomers formed by a
1,3-hydrogen shift from C-4 to the imine group (Scheme
6). Unlike the dimers derived from isothiocyanatoace-
tates, 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic es-
ter 24k, prepared from ethyl 2-isothiocyanatopropanoate
(1k) existed exclusively as the imine. Moreover, the dimer
24k consisted of an equimolar mixture of diastereoiso-
mers because the stereoselectivity of the intermolecular
dimerization was poor. The pure enantiomers of 2-thioxo-
1,3-thiazolidine-4-carboxylates 24i and 24j were obtained
by dimerization of sodium enolates of L-menthyl and
endo-(1S)-bornyl isothiocyanoacetates 1i and 1j, respec-
tively.
The transformation of 5-imino-2-thioxo-1,3-thiazolidine-
4-carboxylic esters 24 into carboxylic acids 25 was possi-
ble under basic or acidic conditions, but only one ester
group underwent hydrolysis. Analysis of the MS/MS
spectra of 25h proved that the 4-ethoxycarbonyl group
was stable and remained unchanged whereas the N-amino
acid fragment of the 1,3-thiazolidine ring was hydrolyzed
(Scheme 6). An attempt to hydrolyze both ester groups
NMR spectra were recorded on a Bruker Avance II 300-MHz spec-
trometer with TMS as an internal standard. IR spectra were record-
ed on a Nicolet IR200 FT-IR spectrometer with a single-reflection
attenuated total reflectance (ATR) head. Microanalyses were car-
ried out by using a Vario MICRO Cube CHNS analyzer and the re-
sults were in good agreement with the calculated values. Column
chromatography was performed on commercial Merck silica gel 60
(230–400 mesh ASTM). TLC analysis was carried out on Merck
Synthesis 2012, 44, 1736–1744
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolo[5,4-d]thiazole Derivatives and 2-Thioxo-1,3-thiazolidine-4-carboxylates
endo-(1S)-Bornyl Isothiocyanatoacetate (1j)
1741
TLC silica gel 60 plates. GC was performed by using a Perkin-
Elmer Clarus 500 chromatograph equipped with an Elite-5ms cap-
illary column. GC/MS analyses were performed on a Thermo Sci-
entific ISQ Single Quadrupole GC/MS equipped with an Elite-5ms
capillary column, whereas EI-MS spectra were recorded on a Finni-
gan MAT 95S spectrometer. Optical rotations were measured by us-
ing a Jasco P-2000 polarimeter. Melting points were measured on
an Electrothermal 9100 apparatus. X-ray diffraction data were col-
lected at 110 K on a SuperNova diffractometer (Oxford Diffraction)
with MoKα radiation (λ = 0.71073 Å).
24
Yield: 1.55 g (51%); colorless oil; [α]D –29.4 (c 0.007, CHCl3);
Rf = 0.41 (cyclohexane–EtOAc, 5:1).
IR (ATR): 2956, 2882, 2083, 1752, 1454, 1350, 1270, 1211 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.86 (s, 3 H, CH3), 0.89 (s, 3 H,
CH3), 0.91 (s, 3 H, CH3), 1.01 (m, 1 H, 3-CHendo), 1.32 (m, 2 H, 5-
CHendo and 6-CHexo), 1.72 (m, 1 H, 4-CH), 1.76 (m, 1 H, 5-CHexo),
1.93 (m, 1 H, 6-CHendo), 2.40 (m, 1 H, 3-CHexo), 4.22 (s, 2 H, α-
CH2), 5.00 (m, 1 H, ABX spin system, OCH).
13C NMR (75 MHz, CDCl3): δ = 13.5, 18.8, 19.7, 27.1, 28.0, 36.6,
44.8, 46.6, 48.0, 48.9, 82.9, 137.5, 166.4.
endo-(1S)-Bornyl (2S)-2-isothiocyanatopropanoate (1c)10 and cy-
clohexyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate (3g)19
were prepared by the procedures described in the literature.
Anal. Calcd for C13H19NO2S: C, 61.63; H, 7.56; N, 5.53. Found: C,
61.73; H, 7.36; N, 5.59.
L-Menthyl (2R/2S)-2-Isothiocyanatopropanoate (1a); Typical
Procedure
(2S)-2-Methylbutyl (2S)-2-[(tert-Butoxycarbonyl)amino]pro-
panoate (3d); Typical Procedure
A 250-mL Erlenmeyer flask was placed on a magnetic stirrer and
charged with CHCl3 (45 mL), H2O (25 mL), and L-menthyl DL-al-
aninate hydrochloride1 (1.86 g, 7.05 mmol). To the stirred soln were
added Cl2C=S (0.54 mL, 0.814 g, 7.08 mmol) and NaHCO3 (1.78 g,
21.19 mmol) in one portion and the mixture was stirred vigorously
until the orange soln became pale (40–70 min). When the Cl2C=S
had been consumed, the lower organic layer was separated, dried
(MgSO4), and concentrated. The crude oily product was purified by
column chromatography [silica gel, cyclohexane–EtOAc (5:1)] to
give a yellow oil; yield: 1.727 g (91%).
A 100-mL Erlenmeyer flask was charged with CH2Cl2 (50 mL), N-
Boc-L-alanine (2 g, 10.57 mmol), and DCC (2.177 g, 10.57 mmol),
and the mixture was stirred at r.t. for 30 min. (2S)-(–)-2-Methylbu-
tan-1-ol (1.20 mL, 0.983 g, 11.14 mmol) and DMAP (0.123 g, 1.01
mmol) were added and the mixture was stirred overnight then con-
centrated under reduced pressure. The residue was dissolved in
EtOAc(80 mL), and the soln was filtered and washed successively
with 5% aq HCl (36 mL) and brine (30 mL). The organic layer was
dried (MgSO4) and concentrated to give a crude product that was
purified by column chromatography [silica gel, CHCl3–MeOH
IR (ATR): 2955, 2928, 2870, 2059, 1741, 1454, 1374, 1289, 1205,
1151 cm–1.
24
(30:1)] to give a colorless oil; yield: 1.96 g (72%); [α]D –4.1 (c
0.011, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.77 and 0.76 (2d, J = 6.96 Hz, 3
H, CH-CH3), 0.87 (m, 1 H, 4-CHaHe), 0.91 (d, J = 7.00 Hz, 3 H,
CH3-CH-CH3), 0.92 (d, J = 6.52, 3 H, CH3-CH-CH3), 1.05 (m, 2 H,
3-CHaHe, 6-CHaHe), 1.46 (m, 2 H, 5-CH-CH3 and 2-CH), 1.58 (d,
J = 7.09 Hz, 3 H, β-CH3), 4.75 and 4.74 (m, 1 H, ABX spin system,
OCH), 1.68 (m, 1 H, 4-CHaHe), 1.72 (m, 1 H, 3-CHaHe), 1.86 (m, 1
H, CH3-CH-CH3), 2.02 (m, 1 H, 6-CHaHe), 4.28 and 4.27 (2q,
J = 7.09 Hz, 1 H, α-CH).
IR (ATR): 3361, 2967, 2935, 2880, 1712, 1505, 1455, 1366, 1248,
1160, 1064 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 7.42 Hz, 3 H,
CH2CH3), 0.91 (d, J = 6.75 Hz, 3 H, CHCH3), 1.18 (m, 1 H,
CHaHb), 1.37 (d, J = 7.20 Hz, 3 H, CHCH3), 1.41 (m, 1 H, CHaHb),
1.43 (s, 9 H, CH3), 1.70 (m, 1 H, CHCH3), 3.94 (dd, J = 6.61 and
10.8 Hz, 1 H, OCHaHb), 3.98 (dd, J = 6.05 and 10.8 Hz, 1 H,
OCHaHb), 4.30 (m, 1 H, CHNH), 5.05 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 16.3, 16.0, 19.5, 20.8, 20.7, 21.9,
23.4, 23.3, 26.3, 26.2, 31.34, 34.1, 40.6, 46.9, 55.1, 55.0, 77.2, 76.9,
137.6, 137.4, 168.8, 168.7.
13C NMR (75 MHz, CDCl3): δ = 11.2, 16.3, 18.8, 25.9, 28.3, 34.1,
49.3, 69.8, 79.7, 155.1, 173.4.
Anal. Calcd for C14H23NO2S: C, 62.41; H, 8.61; N, 5.20. Found: C,
62.35; H, 8.60; N, 5.28.
Anal. Calcd for C13H25NO4: C, 60.21; H, 9.72; N, 5.40. Found: C,
60.15; H, 9.75; N, 5.51.
D-Menthyl (2R/2S)-2-Isothiocyanatopropanoate (1b)
(2S)-2-Methylbutyl (2S)-2-[(tert-Butoxycarbonyl)amino]-4-
methylpentanoate (3e)
Yield: 2.29 g (85%); yellow oil.
Yield: 2.39 g (75%); colorless oil; [α]D24 –3.2 (c 0.004, CHCl3).
GC-MS (EI, 70 eV): m/z (%) = 69 (68), 83 (100), 86 (53), 139 (88),
183 (19), 269 (3) [M]+.
IR (ATR): 3352, 2961, 2933, 2875, 1712, 1505, 1462, 1366, 1249,
1160, 1047, 1048 cm–1.
Anal. Calcd for C14H23NO2S: C, 62.41; H, 8.61; N, 5.20. Found: C,
62.49; H, 8.51; N, 5.33.
1H NMR (300 MHz, CDCl3): δ = 0.87 (d, J = 7.42 Hz, 3 H,
CHCH3), 0.91 (t, J = 5.30 Hz, 3 H, CH2CH3), 0.92 (2d, J = 5.16 Hz,
6 H, CHCH3), 1.17 (sept, 1 H, CHMe2), 1.42 (s, 9 H, CH3), 1.46 (m,
1 H, CHaHb), 1.48 (m, 1 H, CHaHb), 1.71 (m, 3 H, CHCH3 and CH2-
i-Pr), 3.94 (dd, J = 6.76 and 10.8 Hz, 1 H, OCHaHb), 3.99 (dd,
J = 5.88 and 10.8 Hz, 1 H, OCHaHb), 4.28 (m, 1 H, CHNH), 4.92
(br d, 1 H, NH).
L-Menthyl Isothiocyanatoacetate (1i)
Yield: 2.50 g (76%); yellowish oil; [α]D24 –75.9 (c 0.011, CHCl3);
Rf = 0.51 (cyclohexane–EtOAc, 5:1).
IR (ATR): 2957, 2928, 2871, 2073, 1748, 1455, 1370, 1271, 1210,
981, 958 cm–1.
13C NMR (75 MHz, CDCl3): δ = 11.1, 16.3, 21.9, 22.7, 24.8, 25.9,
28.3, 34.1, 41.9, 52.1, 66.7, 79.7, 155.3, 173.5.
1H NMR (300 MHz, CDCl3): δ = 0.77 (d, J = 6.90 Hz, 3 H, CH-
CH3), 0.86 (m, 1 H, 4-CHaHe), 0.90 (d, J = 6.92 Hz, 3 H, CH3-CH-
CH3), 0.91 (d, J = 6.30 Hz, 3 H, CH3-CH-CH3), 1.05 (m, 2 H, 3-
CHaHe, 6-CHaHe), 1.50 (m, 2 H, 5-CH-CH3 and 2-CH), 1.69 (m, 2
H, 3-CHaHe and 4-CHaHe), 1.83 (m, 1 H, CH3-CH-CH3), 2.03 (m, 1
H, 6-CHaHe), 4.18 (s, 2 H, CH2NCS), 4.78 (td, J = 4.41 and 10.1 Hz,
1 H, OCH).
Anal. Calcd for C16H31NO4: C, 63.76; H, 10.37; N, 4.65. Found: C,
63.65; H, 10.52; N, 4.69.
(2S)-2-Methylbutyl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-
phenylpropanoate (3f)
Yield: 2.52 g (71%); colorless oil; [α]D24 +32.3 (c 0.004, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 16.3, 20.7, 21.9, 23.4, 26.9, 34.0,
IR (ATR): 3367, 2965, 2932, 2878, 1712, 1496, 1455, 1364, 1249,
1162, 1053, 1018 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.88 (m, 6 H, CHCH3 and
CH2CH3), 1.14 (m, 1 H, CHaHb), 1.38 (m, 1 H, CHaHb), 1.41 (s, 9
31.4, 40.7, 46.5, 46.9, 77.2, 138.6, 165.7.
Anal. Calcd for C13H21NO2S: C, 61.14; H, 8.29; N, 5.48. Found: C,
61.21; H, 8.22; N, 5.55.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1736–1744

1742
D. Cież, J. Kalinowska-Tłuścik
PAPER
H, CH3), 1.68 (m, 1 H, CHCH3), 3.08 (m, 2 H, CH2Ph), 3.86 (dd,
J = 6.74 and 10.8 Hz, 1 H, OCHaHb), 3.99 (dd, J = 5.96 and 10.8
Hz, 1 H, OCHaHb), 4.58 (m, 1 H, CHNH), 4.98 (br d, 1 H, NH), 7.13
(m, 2 H, ArH), 7.25 (m, 3 H, ArH).
J = 8.12 and 13.8 Hz, 1 H, PhCHaHb), 3.26 (dd, J = 4.95 and 13.8
Hz, 1 H, PhCHaHb), 3.97 (dd, J = 6.61 and 10.5 Hz, 1 H, OCHaHb),
4.07 (dd, J = 5.93 and 10.5 Hz, 1 H, OCHaHb), 4.46 (m, 1 H, ABX
spin system, CHNCS), 7.24 (m, 2 H, ArH), 7.32 (m, 3 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 11.1, 16.3, 25.9, 28.2, 33.9, 38.4,
13C NMR (75 MHz, CDCl3): δ = 11.1, 16.3, 25.8, 34.0, 39.7, 60.9,
54.4, 69.9, 79.8, 126.9, 128.5, 129.2, 136.1, 155.0, 171.9.
71.0, 127.6, 128.7, 129.3, 135.1, 137.9, 168.0.
Anal. Calcd for C19H29NO4: C, 68.03; H, 8.71; N, 4.18. Found: C,
67.95; H, 8.58; N, 4.22.
Anal. Calcd for C15H19NO2S: C, 64.95; H, 6.90; N, 5.05. Found: C,
65.04; H, 6.78; N, 5.12.
(2S)-2-Methylbutyl (2S)-2-Isothiocyanatopropanoate (5d);
Typical Procedure
Cyclohexyl (2S)-2-Isothiocyanatopropanoate 5g
Yield: 1.12 g (77%); yellow oil.
A three-necked 100-mL flask equipped with an argon inlet and pro-
tected against moisture was placed on a magnetic stirrer and
charged with a soln of amino ester 3c (1.764 g, 6.80 mmol) in
CH2Cl2 (55 mL). TFA (12.4 mL, 19.03 g, 167 mmol) was added and
the mixture was stirred under argon at r.t. for 2.5 h. When the depro-
tection was completed, the CH2Cl2 and TFA were evaporated under
reduced pressure at 45 °C and residue was transferred into a 250-
mL Erlenmeyer flask and dissolved in CHCl3 (40 mL). Next,
Cl2C=S (0.52 mL, 0.786 g, 6.80 mmol) was added dropwise to the
flask followed by NaHCO3 (1.714 g, 20.4 mmol) and H2O (60 mL),
and the mixture was intensively stirred for 1 h. The lower organic
layer was separated, dried (MgSO4), and concentrated to a crude
oily product that was purified by distillation under reduced pressure
(124–126 °C at 9 mmHg) to give a yellowish oil; yield: 0.75 g
(55%); bp 124–126 °C (9 mmHg); [α]D23 17.8 (c 0.003, CHCl3).
IR (ATR): 2936, 2859, 2058, 1739, 1450, 1287, 1201, 1150, 1010
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.41 (m, 6 H, cyclohexyl), 1.57 (d,
J = 7.09 Hz, 3 H, CH3), 1.73 (m, 2 H, cyclohexyl), 1.83 (m, 2 H, cy-
clohexyl), 4.28 (q, J = 7.09 Hz, 1 H, OCH), 4.86 (m, 1 H, ABX spin
system, CHNCS).
13C NMR (75 MHz, CDCl3): δ = 19.4, 23.4, 25.2, 31.3, 55.0, 75.1,
137.4, 168.4.
Anal. Calcd for C10H15NO2S: C, 56.31; H, 7.09; N, 6.57. Found: C,
56.21; H, 7.20; N, 6.44.
Di-L-menthyl (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thiazo-
lo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6a); Typical Procedure
Ester 1a (1.954 g, 7.23 mmol) was dissolved in anhyd CH2Cl2 (30
mL) under argon and the soln was cooled to –96 °C. A soln of TiCl4
(0.88 mL, 1.522 g, 8.02 mmol) in CH2Cl2 (5 mL) was added drop-
wise and the mixture was stirred for 30 min at –96 °C. When a yel-
low titanium(IV) complex had formed, a soln of DIPEA (1.40 mL,
1.04 g, 8.09 mmol) in CH2Cl2 (4 mL) was added dropwise to give a
deep-blue titanium(IV) enolate. The mixture was stirred for 60 min
at –96 °C then the cooling bath was removed and the soln was al-
lowed to warm to r.t. After 24 h, the brown mixture was quenched
with sat. aq NH4Cl and the organic phase was dried (MgSO4). The
solvent was evaporated and the crude product was purified by col-
umn chromatography [silica gel, CHCl3–MeOH (30:1)]. The prod-
uct was isolated as the first fraction and crystallized (MeOH) to give
IR (ATR): 2964, 2935, 2878, 2059, 1743, 1458, 1379, 1289, 1198,
1149, 1054 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.42 Hz, 3 H,
CH2CH3), 0.95 (d, J = 6.76 Hz, 3 H, CHCH3), 1.22 (m, 1 H,
CHaHb), 1.44 (m, 1 H, CHaHb), 1.59 (d, J = 7.10 Hz, 3 H, CHCH3),
1.77 (m, 1 H, CHCH3), 4.01 (dd, J = 6.62 and 10.5 Hz, 1 H,
OCHaHb), 4.08 (dd, J = 5.94 and 10.5 Hz, 1 H, OCHaHb), 4.33 (q,
J = 7.10 Hz, 1 H, CHNCS).
13C NMR (75 MHz, CDCl3): δ = 11.1, 16.3, 19.5, 25.9, 34.0, 54.9,
70.9, 137.3, 169.0.
GC-MS (EI, 70 eV): m/z (%) = 71 (57), 86 (100), 132 (9), 201 (8)
23
colorless crystals;19 yield: 1.43 g (76%); mp 122–123 °C; [α]D
[M]+.
–72.2 (c 0.01, acetone); Rf = 0.80 (CHCl3–MeOH, 30:1).
Anal. Calcd for C9H15NO2S: C, 53.70; H, 7.51; N, 6.96. Found: C,
53.78; H, 7.65; N, 7.05.
IR (ATR): 3480, 2956, 2932, 2869, 1729, 1620, 1462, 1384, 1372,
1259, 1125 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.75 (d, J = 6.9 Hz, 3 H, CH3-CH-
CH3), 0.73 (d, J = 6.9 Hz, 3 H, CH3-CH-CH3), 0.87 (m, 2 H, 4-CHa-
He), 0.89 (m, 12 H, CH3-CH-CH3 and CH-CH3), 1.05 (m, 4 H, 3-
CHaHe, 6-CHaHe), 1.46 (m, 4 H, 5-CH-CH3 and 2-CH), 1.66 (m, 2
H, 4-CHaHe), 1.70 (m, 2 H, 3-CHaHe), 1.86 (m, 2 H, CH3-CH-CH3),
2.02 (m, 2 H, 6-CHaHe), 2.05 (s, 3 H, β-CH3), 2.01 (s, 3 H, β-CH3),
4.69 (m, 2 H, ABX spin system, CH-O).
13C NMR (75 MHz, CDCl3): δ = 16.2, 16.3, 20.6, 20.7, 21.9, 23.3,
23.5, 26.2, 26.3, 26.6, 27.1, 31.3, 34.1, 40.1, 40.2, 46.9, 77.1, 77.3,
98.9, 99.1, 168.1, 168.3, 177.9, 178.1.
(2S)-2-Methylbutyl (2S)-2-Isothiocyanato-4-methylpentanoate
(5e)
24
Yield: 1.10 g (67%); yellow viscous oil; [α]D –45.6 (c 0.002,
CHCl3).
IR (ATR): 2961, 2933, 2875, 2058, 1744, 1464, 1387, 1316, 1269,
1192, 1149 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.94 (m, 12 H, CH3), 1.22 (m, 1
H, CHaHb), 1.49 (m, 1 H, CHaHb), 1.80 (m, 4 H, CHCH3, CH2-i-Pr,
CHMe2), 4.01 (dd, J = 6.65 and 10.8 Hz, 1 H, OCHaHb), 4.08 (dd,
J = 5.91 and 10.8 Hz, 1 H, OCHaHb), 4.27 (m, 1 H, ABX spin sys-
tem, CHNCS).
13C NMR (75 MHz, CDCl3): δ = 11.2, 16.3, 21.2, 22.7, 25.1, 25.9,
34.0, 42.1, 58.1, 70.9, 136.8, 169.0.
MS (EI, 70 eV): m/z (%) = 83 (97), 139 (17), 171 (100), 216 (16),
261 (17), 399 (23), 537 (22) [M – H]+.
Anal. Calcd for C28H44N2O4S2: C, 62.65; H, 8.26; N, 5.22. Found:
C, 62.33; H, 8.52; N, 5.00.
Anal. Calcd for C12H21NO2S: C, 59.22; H, 8.70; N, 5.76. Found: C,
59.15; H, 8.64; N, 5.86.
Di-D-menthyl (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thiazo-
lo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6b)
Yield: 1.53 g (82%); colorless crystals; mp 122–123 °C; [α]D
(2S)-2-Methylbutyl (2S)-2-Isothiocyanato-3-phenylpropanoate
(5f)
23
Yield: 0.98 g (52%); orange oil; [α]D23 –54.8 (c 0.013, CHCl3).
+71.9 (c 0.01, acetone).
IR (ATR): 2963, 2932, 2877, 2060, 1741, 1457, 1381, 1334, 1268,
1199, 1014 cm–1.
Anal. Calcd for C28H44N2O4S2: C, 62.65; H, 8.26; N, 5.22. Found:
C, 62.36; H, 8.48; N, 5.12.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 7.40 Hz, 3 H,
CH2CH3), 0.90 (d, J = 6.76 Hz, 3 H, CHCH3), 1.18 (m, 1 H,
CHaHb), 1.38 (m, 1 H, CHaHb), 1.78 (m, 1 H, CHCH3), 3.13 (dd,
Di-endo-(1S)-bornyl (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thi-
azolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6c)
Yield: 0.847 g (44%); yellow oil; Rf = 0.90 (CHCl3–MeOH, 30:1).
Synthesis 2012, 44, 1736–1744
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiazolo[5,4-d]thiazole Derivatives and 2-Thioxo-1,3-thiazolidine-4-carboxylates
1743
IR (ATR): 2953, 2878, 1736, 1483, 1453, 1377, 1256, 1152, 1116
cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.90 (m, 18 H, 6 CH3), 1.00 (m, 2
H, 3-CHendo), 1.31 (m, 4 H, 5-CHendo and 6-CHexo), 1.61 (m, 2 H, 4-
CH), 1.76 (2 s, 6 H, α-CH3), 1.98 (m, 4 H, 5-CHexo and 6-CHendo),
2.36 (m, 2 H, 3-CHexo), 4.95 (m, 2 H, ABX spin system, CH-O).
13C NMR (75 MHz, CDCl3): δ = 13.4, 13.5, 18.8, 19.6, 19.7, 26.2,
27.1, 27.3, 27.8, 27.9, 36.3, 44.8, 47.9, 48.0, 49.0, 49.1, 82.4, 82.5,
98.9, 99.0, 170.4, 176.6.
mmol) were added to the stirred soln followed by H2O (40 mL) add-
ed carefully in a dropwise manner. The mixture was then stirred for
2.5 h. The organic layer was separated, dried (MgSO4), and concen-
trated under reduced pressure. The crude product was purified by
column chromatography [silica gel, CHCl3– MeOH (30:1)] to give
a yellowish waxy solid; yield: 1.55 g (83%); mp 47–48 °C; Rf (TLC
plates) = 0.90 (CHCl3–MeOH, 30:1).
IR (ATR): 2956, 2935, 2862, 2066, 1745, 1436, 1220, 1168, 986
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.48 (m, 4 H, CH2), 1.92 (m, 4 H,
CH2), 3.81 (s, 6 H, OCH3), 4.29 (m, 2 H, ABX spin system,
CHNCS).
Anal. Calcd for C28H40N2O4S2: C, 63.14; H, 7.60; N, 5.26. Found:
C, 62.98; H, 7.75; N, 5.12.
13C NMR (75 MHz, CDCl3): δ = 24.8, 33.1, 53.2, 59.2, 137.7, 168.7.
Bis[(2S)-2-methylbutyl] (2R,5S)-2,5-Dimethyl-2,5-di-
hydro[1,3]thiazolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6d)
and Bis[(2S)-2-methylbutyl] 2,3-Diisothiocyanato 2,3-dimethyl-
succinate (7d)
Anal. Calcd for C12H16N2O4S2: C, 45.55; H, 5.10; N, 8.85. Found:
C, 45.67; H, 5.20; N, 8.66.
A soln of isothiocyanatopropanoate 5c (0.652 g, 3.24 mmol) in
CH2Cl2 (40 mL) was cooled to –96 °C under argon and TiCl4 (0.39
mL, 0.675 g, 3.56 mmol) was added in one batch. The mixture was
stirred for 20 min at –96 °C then a soln of DIPEA (0.62 mL, 0.463
g, 3.58 mmol) in CH2Cl2 (4 mL) was added dropwise. The soln
turned deep blue owing to the formation of the titanium(IV) enolate.
The mixture was stirred at –96 °C then the cooling bath was re-
moved and soln was allowed to warm to r.t. After 4 h, when the sub-
strate was fully consumed (GC), the mixture was poured into sat. aq
NH4Cl (80 mL). The lower organic phase was separated, dried
(MgSO4), and concentrated to give a crude mixture of dimers 6c and
7c, which were purified by column chromatography [silica gel,
CHCl3–MeOH (50:1)].
Dimethyl 2,9-Diisothiocyanatosebacate (19b)
Yield: 1.524 g (75%); yellow oil; Rf = 0.90 (CHCl3–MeOH, 30:1).
IR (ATR): 2931, 2859, 2059, 1744, 1437, 1331, 1265, 1206, 1176,
986 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.36 (m, 4 H, CH2), 1.43 (m, 4 H,
CH2), 1.88 (m, 4 H, CH2), 3.81 (s, 6 H, OCH3), 4.28 (m, 2 H, ABX
spin system, CHNCS).
13C NMR (75 MHz, CDCl3): δ = 25.3, 28.4, 33.4, 53.1, 59.4, 137.2,
168.9.
Anal. Calcd for C14H20N2O4S2: C, 48.82; H, 5.85; N, 8.13. Found:
C, 48.74; H, 5.90; N, 8.24.
Bis[(2S)-2-methylbutyl] (2R,5S)-2,5-Dimethyl-2,5-di-
hydro[1,3]thiazolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6d)
Yield: 0.235 g (36%); colorless oil. Rf = 0.80 (CHCl3–MeOH, 50:1).
Dimethyl cis- and trans-1,2-Diisothiocyanatocyclohexane-1,2-
dicarboxylate (20a)
A soln of diester 19a (1.451 g, 4.58 mmol) in CH2Cl2 (40 mL) was
cooled to –96 °C under argon and TiCl4 (1.11 mL, 1.920 g, 10.1
mmol) was added in one batch. The mixture was stirred for 20 min
at –96 °C before a soln of DIPEA (1.74 mL, 1.300 g, 10.1 mmol) in
CH2Cl2 (4 mL) was added in a dropwise manner. The soln turned
deep blue as a result of the formation of the titanium(IV) enolate.
The mixture was stirred at –96 °C for 30 min and then the cooling
bath was removed and soln was allowed to warm to r.t. After 5 h,
when the substrate was fully consumed (TLC), the mixture was
poured into sat. aq NH4Cl (80 mL). The lower organic phase was
separated, dried (MgSO4), and concentrated. The resulting crude
product was purified by column chromatography [silica gel,
CHCl3–MeOH (30:1)] to give a yellow solid; yield: 0.88 g (61%;
near equimolar mixture of cis- and trans-diastereoisomers); Rf =
0.85 (CHCl3–MeOH, 30:1).
IR (ATR): 3480, 2960, 2933, 2867, 1730, 1620, 1460, 1383, 1375,
1257, 1120 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 7.70 Hz, 6 H,
CH2CH3), 0.91 (d, J = 5.91 Hz, 6 H, CH3CH), 1.17 (m, 2 H,
CHaHb), 1.38 (m, 2 H, CHaHb), 1.75 (m, 2 H, CH3CH), 2.04 (s, 6 H,
β-CH3), 4.04 (m, 4 H, OCH2).
13C NMR (75 MHz, CDCl3): δ = 11.2, 16.3, 25.9, 26.7, 34.0, 71.0,
98.9, 168.6, 178.2.
Anal. Calcd for C18H28N2O4S2: C, 53.97; H, 7.05; N, 6.99. Found:
C, 53.88; H, 7.15; N, 7.08.
Bis[(2S)-2-methylbutyl] 2,3-Diisothiocyanato 2,3-dimethylsuc-
cinate (7d)
Yield: 0.280 g (43%); colorless oil. Rf = 0.70 (CHCl3–MeOH, 50:1).
IR (ATR): 2936, 2865, 2032, 1741, 1466, 1368, 1233, 1180, 1095,
1015 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.70 (m, 4 H, CH2), 1.96 (m, 2 H,
IR (ATR): 2963, 2933, 2877, 2022, 1740, 1459, 1382, 1257, 1095,
961 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 7.45 Hz, 6 H,
CH2CH3), 0.98 (d, J = 6.77 Hz, 6 H, CH3CH), 1.25 (m, 2 H,
CHaHb), 1.47 (m, 2 H, CHaHb), 1.74 (s, 6 H, β-CH3), 1.79 (m, 2 H,
CH3CH), 4.08 (m, 4 H, OCH2).
CH2), 2.29 (m, 2 H, CH2), 3.91, 3.86 and 3.84 (s, 6 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 22.5, 20.2 and 20.0 (CH2), 33.5,
32.0 and 31.9 (CH2), 54.3, 53.9 and 53.6 (OCH3), 75.2, 73.1, and
69.3 (α-C), 142.2 and 139.4 (NCS), 167.7 (COO).
13C NMR (75 MHz, CDCl3): δ = 11.1, 16.4, 22.5, 25.9, 34.0, 70.5,
72.0, 140.6, 167.9.
Anal. Calcd for C12H14N2O4S2: C, 45.85; H, 4.49; N, 8.91. Found:
C, 45.94; H, 4.67; N, 8.84.
GC-MS (EI; 70 eV): m/z (%) = 71 (100), 130 (33), 200 (24), 201
(31), 401 (2) [M + H]+.
Dimethyl cis- and trans-1,2-Diisothiocyanatocyclooctane-1,2-di-
carboxylate (20b)
Yield: 0.84 g (54%); yellow solid; Rf = 0.85 (CHCl3–MeOH, 30:1).
Anal. Calcd for C18H28N2O4S2: C, 53.97; H, 7.05; N, 6.99. Found:
C, 53.85; H, 7.14; N, 6.92.
IR (ATR): 2935, 2863, 2035, 1740, 1465, 1368, 1238, 1183, 1097,
1018 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.11 (m, 2 H, CH2), 1.34 (m, 6 H,
CH2), 1.88 (m, 2 H, CH2), 2.03 (m, 2 H, CH2), 3.87, 3.85, 3.82, and
3.81 (s, 6 H, OCH3).
Dimethyl 2,7-Diisothiocyanatosuberate (19a); Typical Proce-
dure
A 250-mL Erlenmeyer flask was placed on a magnetic stirrer and
charged with a suspension of dimethyl 2,7-diaminosuberate dihy-
drochloride 18a (1.801 g, 5.90 mmol) in CHCl3 (60 mL). Cl2C=S
(0.99 mL, 1.493 g, 12.98 mmol) and NaHCO3 (3.272 g, 38.95
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1736–1744

1744
D. Cież, J. Kalinowska-Tłuścik
PAPER
13C NMR (75 MHz, CDCl3): δ = 25.2, 24.6, and 24.4 (CH2), 28.8
and 28.1 (CH2), 34.1 and 33.4 (CH2), 54.1, 53.9, and 53.1 (OCH3),
75.9 (α-C), 141.1, 140.8, and 140.4 (NCS), 167.8, 167.7 and 167.2
(COO).
References
(1) Kodama, H. Chem. Zentralbl. 1923, 94, 206.
(2) (a) Berlin, A. Ya.; Levi, I. S. J. Gen. Chem. USSR (Engl.
Transl.) 1963, 33, 846. (b) Tsogoeva, S. B.; Hateley, M. J.;
Yalalov, D. A.; Meindl, K.; Weckbecker, C.; Huthmacher,
K. Bioorg. Med. Chem. 2005, 13, 5680. (c) Floch, L.; Uher,
M.; Lesko, J. Collect. Czech. Chem. Commun. 1989, 54, 206.
(d) Dobosz, M.; Pachuta-Stec, A. Acta Pol. Pharm. 1994,
51, 457. (e) Ryczek, J. J. Heterocycl. Chem. 2003, 40, 665.
(f) Chowdhury, A. Z.; Shaifullah, M.; Shibata, Y. Chem.
Pharm. Bull. 2001, 49, 391.
(3) (a) Bates, S. R. E.; Guthrie, D. J. S.; Elmore, D. T. J. Chem.
Res., Miniprint 1993, 2, 0201. (b) Foye, W. O.; Dabade, S.
V.; Kelley, C. J.; Lebrun, E.; Rapenbusch, R. Med. Chem.
Res. 1998, 8, 542.
(4) (a) Masquelin, T.; Sprenger, D.; Baer, R.; Gerber, F.;
Mercadal, Y. Helv. Chim. Acta 1998, 81, 646. (b) Cabon, G.;
Gaucher, B.; Gegout, A.; Heulle, S.; Masquelin, T. Chimia
2003, 57, 248.
(5) Floch, L.; Martvoň, A.; Uher, M.; Leško, J.; Weis, W.
Collect. Czech. Chem. Commun. 1977, 42, 2945.
(6) (a) Dobosz, M.; Pitucha, M.; Wujec, M. Acta Pol. Pharm.
1996, 53, 31. (b) Veverka, M.; Marchalin, M. Collect.
Czech. Chem. Commun. 1987, 52, 113.
Anal. Calcd for C14H18N2O4S2: C, 49.11; H, 5.30; N, 8.18. Found:
C, 48.95; H, 5.43; N, 8.28.
Ethyl 5-[(2-Ethoxy-2-oxoethyl)amino]-2-thioxo-2,3-dihydro-
1,3-thiazole-4-carboxylate (24h)
A 250-mL Erlenmeyer flask, protected from moisture by a CaCl2
guard tube, was placed on a stirrer and charged with anhyd DMF
(90 mL) and ethyl isothiocyanatoacetate (3.77 g, 0.026 mol). The
mixture was cooled to 0 °C on an ice bath. NaH (0.834 g, 0.035 mol)
was carefully added in several portions to the stirred soln and then
the ice bath was removed and the mixture was stirred for 2 h at r.t.
The red-brown soln was poured into cold H2O and acidified to pH
5 with 10% aq HCl aq. The resulting yellow precipitate was filtered
off and crystallized (EtOH) to give the pure pale-yellow product.
The filtrate was extracted with EtOAc (2 × 100 mL), and the organic
layers were washed successively with H2O (80 mL) and brine (50
mL) then dried (MgSO4) and concentrated. The brown residue was
crystallized (EtOH) to give a second portion of the product; total
yield: 2.45 g (65%); mp 188 °C.
IR (ATR): 3362, 3077, 2974, 2913, 1742, 1652, 1592, 1511, 1428,
1211, 1183, 1020 cm–1.
(7) (a) Cież, D.; Szneler, E. Monatsh. Chem. 2005, 136, 2059.
(b) Cież, D.; Szneler, E. J. Chem. Res. 2007, 200.
(8) Cież, D. Tetrahedron 2007, 63, 4510.
(9) Cież, D.; Kalinowska-Tłuścik, J.; Peyrat, S.; Touko, E. P.;
Trzewik, B.; Zwoliński, K. Synthesis 2008, 3261.
(10) Cież, D.; Kalinowska-Tłuścik, J.; Marchewka, J. Aust. J.
Chem 2012, in press; DOI: 10.1071/CH11463.
(11) Periasamy, M. ARKIVOC 2002, (vii), 151.
(12) Cież, D. Org. Lett. 2009, 11, 4282.
(13) Cież, D.; Kalinowska-Tłuścik, J. Synlett 2012, 23, 267.
(14) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(15) (a) Matsumura, Y.; Nishimura, M.; Hiu, H.; Watanabe, M.;
Kise, N. J. Org. Chem. 1996, 61, 2809. (b) Rao, V. D.;
Periasamy, M. Tetrahedron: Asymmetry 2000, 11, 1151.
(16) (a) Weingarten, H.; Miles, M. G.; Edelmann, N. K. Inorg.
Chem. 1968, 7, 879. (b) Ribeiro, N.; Fetzer, L.; Streiff, S.;
Désaubry, L. Synlett 2010, 2928.
1H NMR (300 MHz, CDCl3): δ = 1.31 (t, J = 7.15 Hz, 3 H, CH3),
1.36 (t, J = 7.14 Hz, 3 H, CH3), 3.90 (d, J = 5.78 Hz, 2 H, CH2), 4.27
(q, J = 7.15 Hz, 2 H, OCH2), 4.32 (q, J = 7.14 Hz, 2 H, OCH2), 7.11
(br s, 1 H, NH), 9.77 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 14.4 (CH3), 48.1
(CH2), 61.3 (OCH2), 62.2 (OCH2), 106.2 (C=C), 153.9 (C=C),
158.5 (CO2Et), 168.1 (CO2Et), 176.8 (C=S).
Anal. Calcd for C10H14N2O4S2: C, 41.37; H, 4.83; N, 9.65. Found:
C, 41.45; H, 4.73; N, 9.82.
Acknowledgment
We are grateful to the Polish Ministry of Science and Higher Edu-
cation (Grant No. N N204 310037) and the European Regional De-
velopment Fund in the framework of the Polish Innovation
Economy Operational Program (contract no. POIG.02.01.00-12-
023/08) for financial support.
(17) Penn, J. H.; Plants, R. C.; An, L. Chem. Commun.
(Cambridge) 1999, 2359.
(18) Alvarez-Ibarra, C.; Csákÿ, A. G.; Colmenero, B.; Quiroga,
M. L. J. Org. Chem. 1997, 62, 2478.
(19) Hayashida, O.; Sebo, L.; Rebek, J. J. Org. Chem. 2002, 67,
8291.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinIfatgnonmSorti
i
npfurotIangSiuptor
(20) Crystallographic data for compound 6a have been deposited
with the accession numbers CCDC 862700 and can be
obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk; Web site:
www.ccdc.cam.ac.uk/conts/retrieving.html.
Synthesis 2012, 44, 1736–1744
© Georg Thieme Verlag Stuttgart · New York