Reinvestigation of the thiazole synthesis with ethyl 3-amino-2-[5-aryl-1,3, 4-oxadiazol-2(3h)-ylidene]-3-thioxopropanoates and related reactions

Article abstract of DOI:10.1515/znb-2009-0618

Treatment of the 1,3,4-oxadiazoles 3a and 3b with 3-chloropentane-2,4-dione gave the thiazoles 4a and 4b, respectively, which were methylated to furnish compounds 5a and 5b. The formation of 1,3,4-oxadiazoles using the 1,3-dithietane 1 as starting materia

Full text of DOI:10.1515/znb-2009-0618

Reinvestigation of the Thiazole Synthesis with Ethyl 3-Amino-2-
[5-aryl-1,3,4-oxadiazol-2(3H)-ylidene]-3-thioxopropanoates and
Related Reactions
Nico Paepkea,b, Helmut Reinkea, Klaus Pesekea, and Christian Vogela
a Department of Organic Chemistry, Institute of Chemistry, University of Rostock,
Albert-Einstein-Straße 3a, 18059 Rostock, Germany
b Current address: Schreiner Group GmbH & Co. KG, Bruckmannring 22, 85764 Oberschleißheim,
Germany
Reprint requests to Prof. Dr. Christian Vogel. Fax: +49-381-498-6412.
E-mail: christian.vogel@uni-rostock.de
Z. Naturforsch. 2009, 64b, 719 – 726; received April 21, 2009
Dedicated with great appreciation to Professor Gerhard Maas on the occasion of his 60th birthday
Treatment of the 1,3,4-oxadiazoles 3a and 3b with 3-chloropentane-2,4-dione gave the thiazoles
4a and 4b, respectively, which were methylated to furnish compounds 5a and 5b. The formation
of 1,3,4-oxadiazoles using the 1,3-dithietane 1 as starting material, and the consecutive reactions
mentioned above were transferred into sugar chemistry to provide the corresponding derivatives 6 – 9
in good yields. The reaction of 5a with benzyl amine, ethylene diamine and o-phenylene diamine
afforded compounds 10, 11, and 12, respectively, which possess better stabilized push-pull systems
than 5a. The structures of 3a, 4a, 5a, 10, 11, and 12 were compared with the previously proposed
structures I – VI, respectively. The structures of compounds 1, 3b, and 11 were confirmed by X-ray
diffraction studies.
Key words: Diethyl (1,3-Dithietane-2,4-diylidene)bis(2-cyanoacetate), Push-pull Chemistry,
Hydrogen Sulfide Migration, Consecutive Ring Closure Reaction, Structural
Reinvestigation
Introduction
In previous papers published in the 1970ies we
reported the smooth reaction of (2E,2ꢀE)-diethyl
2,2ꢀ-(1,3-dithietane-2,4-diylidene)bis(2-cyanoacetate)
(1) (Fig. 1) with carboxylic acid hydrazides (2a,
2b) [1]. The state-of-the-art NMR and IR technique at
that time gave only limited data which, for example,
suggested the proposed structure I (Fig. 2) for the
product of the reaction of 1 with benzohydrazide. In
1995, Neidlein et al. repeated this type of reaction,
and their X-ray structure analysis has shown that
instead of the dihydropyrazole I the oxadiazole 3a
Fig. 1. Molecular structure of 1 in the crystal (ORTEP plot;
displacement ellipsoids at the 50 % probability level; H
was formed (Scheme 1), obviously by an unusual atoms with arbitrary radii).
migration of hydrogen sulfide to the cyano group [2].
It is noteworthy that during the reaction no smell of
hydrogen sulfide was observed.
fore, we decided to repeat the formerly described
reactions [3], and to reinvestigate the structures of
The alleged dihydropyrazole I had been sub- these compounds. Furthermore, we report the ex-
jected to several secondary reactions, and it was tension of the 1,3-dithietane chemistry by using
feared now that the structures proposed for the re- a sugar hydrazide instead of an aromatic hydr-
sulting compounds II – VI are not correct. There- azide.
c
0932–0776 / 09 / 0600–0719 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access

720
N. Paepke et al. · Reinvestigation of the Thiazole Synthesis
Results and Discussion
In a typical experiment the 1,3,4-oxadiazoles3a and
3b were furnished by the reaction of 1,3-dithietane
1 with the aromatic hydrazides 2a and 2b, respec-
tively [1].
The reaction was conducted in ethanol-chloroform
solution at 60 ◦C, and after 30 min at r. t. the crystalline
products were isolated. Analytical samples were ob-
tained by crystallization from chloroform or ethanol.
The constitution of the 1,3,4-oxadiazole 3b was con-
firmed by X-ray diffraction studies (Fig. 3), and all the
other analytical data of 3a and 3b confirmed the struc-
tural discussion of Neidlein et al. [2].
Now, it was interesting to examine the reaction of 3a
and 3b with 3-chloropentane-2,4-dioneas a 1,2-dielec-
trophile. As previously shown [4], the reaction under
basic conditions gave a mixture of two products which
were converted into the products 4a and 4b, respec-
tively, by heating under reflux with acetic anhydride
for 15 min (Scheme 2). On the basis of the structure
Fig. 2. Previously published, alleged structures of com-
pounds 3a, 4a, 5a, 10, 11, and 12.
Fig. 3. Molecular structure of 3b in the crystal (ORTEP
plot; displacement ellipsoids at the 50 % probability level;
H atoms with arbitrary radii). There are two intramolecu-
lar hydrogen bonds in the structure. While the NH2 group
at C1 has one H oriented towards O3 with a distance of
261.25(18) pm between N3 and O3, the distance between N2
and S1 is 288.99(12) pm.
of 3a and 3b, the previously described structure II can
be discarded, as the ring closure of the thiocarbamoyl
group obviously gave a 4-methylthiazolyl moiety as a
structural element. Comparing both structural propos-
Scheme 1. Synthesis of the ethyl 3-amino-2-(5-aryl-1,3,4-
oxadiazol-2-yl)-3-thioxopropanoates 3a and 3b. Reagents
and conditions: (i) CHCl3-EtOH, 60 ◦C, 30 min.
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access

N. Paepke et al. · Reinvestigation of the Thiazole Synthesis
721
Scheme 2. Synthesis of the thiazole derivatives 4a and
4b by ring closure of compounds 3a and 3b, respectively,
with 3-chloropentane-2,4-dione, and consecutive methyla-
tion. Reagents and conditions: (i) NaOEt, 20 ◦C, 2 h;
(ii) (AcO)2O, reflux, 15 min; (iii) ethereal CH2N2, CHCl3,
20 ◦C, 10 min.
Scheme 3. Transfer of the reaction protocol described in
Schemes 1 and 2 to the sugar hydrazide 6. Reagents and
conditions: (i) CHCl3-EtOH, reflux, 10 min; (ii) NaOEt,
20 ◦C, 2 h; (ii) (AcO)2O, reflux, 15 min; (iii) ethereal CH2N2,
CHCl3, 20 ◦C, 10 min.
als II and 3a, a remarkable similarity of all the func-
tional groups is obvious.
Fortunately, β-elimination which is a typical side-
reaction of galacturonates under alkaline conditions
was not observed. As expected, short heating under re-
flux of a solution of compounds 1 and 6 in chloroform
gave the 1,3,4-oxadiazole 7 in 75 % yield. Under con-
ditions described for the formation of the thiazoles 4a,
4b and 5a, 5b, the corresponding arabinoyl derivatives
8 and 9 were obtained in 73 % and 89 % yield, respec-
tively (Scheme 3). Unfortunately, all attempts failed to
get crystals of the two compounds for X-ray diffraction
studies.
The tautomeric structures of 3a and 3b discussed by
Neidlein et al. [2] indicated the acidity of the proton
predominantly located at 3-position of the oxadiazol
ring. The ring closure to the thiazoles 4a and 4b should
not have a strong influence on this tautomerism. This
is demonstrated by the fact that in the 1H NMR spectra
of 4a and 4b a broad signal of an N-H proton appeared
in the range of δ = 13.20. Consequently, the reaction of
4a and 4b with an ethereal diazomethane solution pro-
vided the 3-methyl-oxadiazols 5a and 5b, respectively,
in excellent yield (80– 90 %). Again, the differences of
functionalities between both structural proposals, III
and 5a, are small.
To examine the previously reported reaction of al-
leged compound III with primary amines [3], com-
pound 5a was heated under reflux with benzylamine in
EtOH for 1 h. Instead of the originally discussed seven-
The protocol of the formation of 1,2,4-oxadiazol- membered ring IV we now proposed the formation of
es by reaction of 1,3-dithietane 1 with aromatic hy- the 1,2,4-triazole 10 as the product of this reaction. It
drazides was now transferred to sugar hydrazides. For was found by 1H and 13C NMR investigations that nei-
this reason, methyl 1,2;3,4-di-O-isopropylidene-α-D- ther the ester group nor the keto function of 5a was
galactopyranuronate [5] was treated with 85 % aq. hy- attacked by the amine. Obviously, the oxygen atom of
drazine hydrate in EtOH, and the mixture was then the 1,3,4-oxadiazole was replaced by a nitrogen atom
heated under reflux for 2 h to provide the as yet un- providing the triazolylidene fragment which appears
known hydrazide 6 in nearly quantitative yield.
to lend improved stabilization to the push-pull system
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access

722
N. Paepke et al. · Reinvestigation of the Thiazole Synthesis
Fig. 4. Molecular structure of 11 in the crystal (ORTEP
plot; displacement ellipsoids at the 50 % probability level; H
atoms with arbitrary radii). Beside intramolecular hydrogen
bonds between N2 and N1 with a distance of 264.33(18) pm
and between N3 and O2 with a distance of 266.32(17) pm,
there is an intermolecular interaction pattern with a center of
inversion between two symmetry-equivalent molecules. Here
the distance between the donor N3 and the acceptor O2 is
298.51(18) pm.
Scheme 4. Reactions of thiazole 5a with N-nucleophiles.
Reagents and conditions: (i) benzyl amine, EtOH, reflux,
1 h; (ii) 50 % aq. ethylene diamine, EtOH, reflux, 10 min;
(iii) phenylene diamine, EtOH, reflux, 5 h.
1,3,4-oxadiazoles described first by Neidlein et al. was
confirmed by X-ray diffraction studies of compound
3b. Subsequent reaction of 3a with 3-chloropentane-
2,4-dione afforded compound 4a, in contrast to the
earlier proposed structure II. Methylation of 4a fur-
nished 5a instead of structure III. The reactions sum-
marized here were successfully applied with the sugar
hydrazide 6, which itself was prepared for the first
time, to afford the corresponding sugar derivatives
7 – 9.
Finally, the nucleophilic attack of 5a by benzyl-
amine, ethylene diamine and o-phenylene diamine
gave the stabilized push-pull structures 10, 11, and 12,
respectively, instead of the earlier postulated structures
IV, V, and VI. Again, the structure of 11 was estab-
lished by X-ray diffraction analysis.
in compound 10 as compared to the oxadiazolylidene
fragment in 5a.
Finally, repetition of the reaction of 5a with ethy-
lene diamine and o-phenylene diamine afforded the
crystalline imidazolidinylidenes 11 and 12 in 76 % and
58 % yield, respectively (Scheme 4). Again, the driv-
ing force of the reaction is the formation of a more
stabilized push-pull system in 11 and 12 than in the
starting material set up by ring closure of the vicinally
constituted binucleophiles. However, the postulation of
structures V and VI as a result of this reaction required
a reductive N–N cleavage of the hydrazide fragment
in compound III which is not very plausible [3]. On
the other hand, V and VI are tautomeric structures of
11 and 12, respectively. The X-ray structure analysis
of compound 11 (Fig. 4) confirms the generation of
the imidazolidin-2-ylidene and methylthiazolyl moi-
eties instead of an imidazolyl and a thiazolin-2-ylidene
residue in the alleged structure V.
Experimental Section
Melting points were determined with a Boetius micro-
heating plate BHMK 05 (Rapido, Dresden) and are not cor-
rected. Optical rotation was measured for solutions in a
2-cm cell with an automatic polarimeter GYROMAT (Dr.
Kernchen Co.). 1H NMR spectra (250.13 MHz, 300.13 MHz,
and 500.13 MHz) and 13C NMR spectra (62.89 MHz,
75.47 MHz, and 125.76 MHz) were recorded on Bruker in-
Conclusion
The reaction of 1,3-dithietane 1 with benzohy-
drazide led to the 1,3,4-oxadiazole 3a instead of the
previously proposed pyrazoline I. The formation of struments AC 250, ARX 300, and Avance 500, respectively,
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access

N. Paepke et al. · Reinvestigation of the Thiazole Synthesis
723
with CDCl3, CD3OD or [D6]DMSO as solvents. The cali-
C
18H17N3O4S (371.41): calcd. C 58.21, H 4.61, N 11.31,
bration of spectra was carried out referring to solvent sig- S 8.63; found C 58.13, H 4.68, N 11.07, S 8.74.
nals (CDCl3: δ 1H = 7.25, δ 13C = 77.0; CD3OD: δ 1H =
4.78, δ 13C = 49.0; [D6]DMSO: δ 1H = 2.50, δ 13C =
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[5-(4-methoxy-
phenyl)-1,3,4-oxadiazol-2(3H)-ylidene]acetate (4b)
39.7). 1H and 13C NMR signals were assigned by DEPT and
two-dimensional 1H,1H COSY and 1H,13C correlation spec-
tra (HMBC and HSQC). Mass spectra were recorded on an
AMD 402/3 spectrometer (AMD Intectra GmbH). Elemental
analyses were performed on a CHNS-Flash-EA-1112 instru-
ment (Thermoquest).
Yield 2.89 g (72 %). – M. p. 203 – 205 ◦C (acetic
acid). – 1H NMR (250.13 MHz, CDCl3): δ = 1.47 (t,
3J = 7.0 Hz, 3 H, OCH2CH3), 2.46 (s, 3 H, COCH3),
2.66 (s, 3 H, CH3), 3.87 (s, 3 H, OCH3), 4.39 (q, 2 H,
OCH2CH3), 7.38, 7.97 (2 m, 4 H, C6H4), 13.20 (br,
1 H, NH). – 13C NMR (75,5 MHz, CDCl3): δ = 15.1
(OCH2CH3), 15.4 (CH3), 30.4 (COCH3), 55.9 (OCH3),
61.1 (OCH2CH3), 80.6 [O(NH)C=C(C2)], 114.9, 117.0,
All washing solutions were cooled to ∼5 ◦C. The
NaHCO3 solution was saturated. Reactions were monitored
by thin-layer chromatography (TLC, Silica Gel 60, F254
,
Merck KGaA). The followings solvents systems (v/v) were
used: (A1) 2 : 1, (A2) 5 : 1, (A3) 6 : 1, (A4) 10 : 1, (A5) 30 : 1,
(A6) 50 : 1, (A7) 80 : 1, (A8) 100 : 1 n-hexane-ethyl acetate;
(B) 10 : 1 ethyl acetate-methanol. The spots were made vis-
ible by dipping the TLC plates into a methanolic 10 %
H2SO4 solution and charring with a heat gun for 3 – 5 min.
Preparative flash chromatography was performed by elution
from columns of slurry-packed Silica Gel 60 (Merck, 63 –
200 µm). All solvents and reagents were purified and dried
according to standard procedures [6]. After classical work-
up of the reactions mixtures, the organic layers were dried
over MgSO4 and then concentrated under reduced pressure
(rotary evaporator).
120.8, 128.7 (NC=CS, C6H4, three signals are isochronic),
ꢀ
144.2 (NC=CS), 162.2, 162.6 O(NH)C=C(C2), O(N=)C-
ꢁ
C6H5 , 163.9, 166.1 (2 × C=O), 190.3 (C(S)=N). –
C19H19N3O5S (401.44): calcd.
C
56.85,
H
4.77,
N 10.47, S 7.99; found C 56.73, H 4.76, N 10.22,
S 7.91.
Reaction of thiazols 4a and 4b with diazomethane [3]
Thiazole 4a (3.71 g, 10 mmol) or 4b (4.01 g, 10 mmol)
was dissolved in a minimum of chloroform and treated with
an ethereal diazomethane solution. When the reaction was
complete, indicated by a persisting yellow color of the so-
lution, the reaction mixture was treated with acetic acid to
destroy the excess of diazomethane. The solution was then
diluted with the double volume of CHCl3 and the organic
layer washed with water, aq. NaHCO3 (2×), and again wa-
ter, dried, and concentrated. Crystallization from EtOH gave
compounds 5a or 5b as yellow needles.
Reaction of oxadiazols 3a and 3b with 3-chloropentane-2,4-
dione [4]
Sodium (0.23 g, 10 mmol) and oxadiazole 3a (2.91 g,
10 mmol) or 3b (3.21 g, 10 mmol) [1] were dissolved in abs.
EtOH (30 mL), and to the reaction mixture 3-chloropentane-
2,4-dione (1.34 g, 10 mmol) was added. After shaking the
mixture for 2 h at r. t., the released precipitate was filtered
off and washed several times with water. The crude product
was dried and then heated under reflux with 50 mL acetic
anhydride for 15 min. The solution was chilled to r. t., and
the formed crystals were isolated and crystallized from acetic
acid to give compounds 4a or 4b as yellow needles.
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[3-methyl-5-
phenyl-1,3,4-oxadiazol-2(3H)-ylidene]acetate (5a)
Yield 3.51 g (91 %). – M. p. 180 – 181 ◦C (ethanol). –
1H NMR (250.13 MHz, CDCl3): δ = 1.38 (t, 3J =
7.0 Hz, 3 H OCH2CH3), 2.50 (s, 3 H COCH3), 2.66 (s,
3 H CH3), 3.70 (s, 3 H NCH3), 4.34 (q, 2 H OCH2CH3),
7.54, 7.96 (2 m, 5 H C6H5). – 13C NMR (75.5 MHz,
CDCl3): δ = 14.6 (OCH2CH3), 18.3 (CH3), 30.7 (COCH3),
40.1 (NCH3), 60.0 (OCH2CH3), 74.6 [O(NCH3)C=C(C2)],
121.9, 126.1, 126.5, 129.2, 132.7 (NC=CS, C6H5, two
signals are isochronic), 157.5 (NC=CS), 159.2, 163.6
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[5-phenyl-1,3,4-
oxadiazol-2(3H)-ylidene]acetate (4a)
◦
ꢀ
ꢁ
Yield 2.93 g (79 %). – M. p. 193 – 195 C (acetic acid). –
O(NCH3)C=C(C2), O(N=)C-C6H5 , 165.6, 166.1 (2×
3
1H NMR (250.13 MHz, CDCl3): δ = 1.48 (t, J = 7.0 Hz,
C=O), 190.5 (C(S)=N). – C19H19N3O4S (385.44): calcd.
C 59.21, H 4.97, N 10.90, S 8.32; found C 58.93, H 5.13,
N 10.68, S 8.29.
3 H, OCH2CH3), 2.46 (s, 3 H, COCH3), 2.67 (s, 3 H, CH3),
4.41 (q, 2 H, OCH2CH3), 7.50, 8.04 (2 m, 5 H, C6H5),
13.21 (br, 1 H, NH). – 13C NMR (125.8 MHz, CDCl3):
δ = 14.5 (OCH2CH3), 14.8 (CH3), 29.8 (COCH3), 60.6
(OCH2CH3), 80.0 [O(NH)C=C(C2)], 120.4, 124.0, 126.4,
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[3-methyl-5-(4-
methoxyphenyl)-1,3,4-oxadiazol-2(3H)-ylidene]acetate (5b)
128.9, 131.2 (NC=CS, C6H5, two signals are isochronic),
ꢀ
143.6 (NC=CS), 161.7, 162.2 O(NH)C=C(C2), O(N=)C-
Yield 3.36 g (81 %). – M. p. 194 – 196 ◦C (ethanol). –
ꢁ
3
C6H5
,
163.9, 165.6 (2 × C=O), 189.7 (C(S)=N). – 1H NMR (250.13 MHz, CDCl3): δ = 1.38 (t, J = 7.0 Hz,
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access

724
N. Paepke et al. · Reinvestigation of the Thiazole Synthesis
3 H OCH2CH3), 2.50 (s, 3 H COCH3), 2.65 (s, 3 H CH3), CDCl3): δ = 14.2 (OCH2CH3), 24.5, 24.7, 25.8, 26.1
3.60 (s, 3 H NCH3) 3.89 (s, 3 H OCH3), 4.34 (q, 2 H (2 × C(CH3)2), 57.3 (OCH2CH3), 64.3 (C-5), 70.4 (C-2),
OCH2CH3), 7.02, 7.90 (2 m, 4 H C6H4). – 13C NMR 70.7 (C-4), 71.7 (C-3), 83.8 [O(NH)C=C(C2)], 96.5 (C-1),
ꢀ
(75,5 MHz, CDCl3): δ = 14.6 (OCH2CH3), 18.3 (CH3), 30.7 109.5, 110.8 (2 ×C(CH3)2), 157.6, 166.5 O(NH)C=C(C2),
ꢁ
(COCH3), 40.0 (NCH3), 55.5 (OCH3), 59.9 (OCH2CH3), O(N=)C-Ara , 166.7 (C=O), 190.4 (C(S)=N). – MS (ESI):
74.2 [O(NCH3)C=C(C2)], 114.1, 114.8, 125.8, 128.3, m/z ( %) = 444 (100) [M+H]+, 429 (95), 388 (19), 330 (14). –
159.4 (NC=CS, C6H4, two signals are isochronic), 157.6 C18H25N3O4S (443.47): calcd. C 48.75, H 5.68, N 9.48,
ꢀ
(NC=CS), 163.2, 163.4 O(NCH3)C=C(C2), O(N=)C- S 7.23; found C 48.54, H 5.66, N 9.29, S 7.04.
ꢁ
C6H5
,
165.6, 166.4 (2 × C=O), 190.4 (C(S)=N). –
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[5-(1,2;3,4-di-O-
isopropylidene-β-L-arabinopyranos-5-yl)1,3,4-oxadiazol-
2(3H)-ylidene]acetate (8)
C20H21N3O4S (415.46): calcd. C 57.82, H 5.09, N 10.11,
S 7.72; found C 58.11, H 5.32, N 9.97, S 7.26.
(1,2;3,4-Di-O-isopropylidene-α-D-galactopyranose)uron-
hydrazide (6)
Sodium (115 mg, 5 mmol) and compound 7 (2.22 g,
5 mmol) were dissolved in abs. EtOH (15 mL), and to the re-
action mixture 3-chloropentane-2,4-dione (0.67 g, 5 mmol)
was added. After shaking it for 2 h at r. t., the reaction
mixture was concentrated, and the residue was dissolved in
CHCl3 (50 mL). The organic layer was washed with water
(2 × 25 mL), dried and concentrated. The residue was dried
under high vacuum and then heated under reflux with 25 mL
acetic anhydride for 15 min. The solution was chilled to r. t.
and poured into ice-water (150 mL). The aqueous layer was
extracted with CHCl3 (3×25 mL), and the combined organic
layers were washed with water (2 × 20 mL), dried and con-
centrated. The crude product was purified by column chro-
matography (chloroform : acetonitrile 5 : 1) to afford com-
pound 8 (1.91 g, 73 % yield) as a colorless foam.
Hydrazine hydrate (85 %, 0.77 g, 22 mmol) was added
to a solution of methyl 1,2;3,4-di-O-isopropylidene-α-D-
galactopyranuronate (2.88 g, 10 mmol) [4] dissolved in a
minimum of EtOH with slight warming to give a clear re-
action mixture. After heating under reflux for 2 h (moni-
tored by TLC, solvent toluene : ethylacetate 2 : 1) the solu-
tion was chilled to r. t. and diluted with chloroform. The
organic layer was washed several times with water, dried
and concentrated. Traces of hydrazine were removed by co-
concentration with toluene. After drying under high vacuum,
compound 6 (2.74 g, 95 % yield) was received.
M. p. 150 – 152 ◦C. – [α]D24 = −121.9 (c = 1.0, CHCl3). –
ꢀ
ꢁ
1H NMR (250.13 MHz, CDCl ): δ = 1.32 s, 6 H C(CH3)2
,
ꢀ
ꢁ3
[α]2D3
=
−123.8 (c
= 1.0, CHCl3). –
1H NMR
1.40, 1.50 2 s, 6 H C(CH3)2 , 4,35 (m, 2 H 2-H, 3-H), 4.64,
3
(250.13 MHz, CDCl3): δ = 1.37 (t, 3J = 7.0 Hz, 3 H
OCH2CH3), 1.33, 1.37, 1.48, 1.58 [4 s, 12 H 2 × C(CH3)2],
4.65 (2 s, 2 H 4-H, 5-H), 5.56 (d, 1 H J = 4.9 Hz, 1-H). –
13C-NMR (75.5 MHz, CDCl3): δ = 24.2, 24.8, 25.9, 26.0
(4 s, 4 × CH3), 68.8 (C-5), 70.3 (C-2), 70.7 (C-4), 71.3 (C-3),
96.2 (C-1), 109.3, 109.6 (2 s, 2 ×C(CH3)2), 168.7 (C=O). –
C12H20N2O6 (288.30): calcd. C 49.99, H 6.99, N 9.72; found
C 50.24, H 7.10, N 9.49.
2.46 (s, 3 H COCH3), 2.64 (s, 3 H CH3), 4.34 (q, 2 H
OCH2CH3), 4.45 (m, 1 H 2-H), 4.58 (dd, 1 H J3,4
7.4 Hz, 3-H), 4.75 (dd, 1 H J4,5 = 1.8 Hz, 4-H), 5.20
(d, 1 H 5-H), 5.70 (d, 1 H J1,2 = 4.8 Hz, H-1). –
3
=
3
3
13C NMR (125.8 MHz, CDCl3): δ = 14.4 (OCH2CH3),
18.4 (CH3), 24.6, 24.7, 25.9, 26.0 (2 × C(CH3)2), 29.8
(COCH3), 60.5 (OCH2CH3), 64.3 (C-5), 70.5 (C-2), 70.7
(C-4), 72.2 (C-3), 80.0 [O(NH)C=C(C2)], 96.5 (C-1), 109.2,
110.4 (2 ×C(CH3)2), 120.2 (NC=CS), 143.6 (NC=CS),
Ethyl 3-amino -2-[5-(1,2;3,4-di-O-isopropylidene-β-L-
arabinopyranos-5-yl)-1,3,4-oxadiazol-2(3H)-ylidene]-3-
thioxopropanoate (7)
A hot solution of diethyl 2,2ꢀ-(1,3-dithietane-2,4-diylid-
ene)bis(2-cyanoacetate) (1, 1.55 g, 5.0 mmol) [7] in CHCl3
(5 mL) was added to a warm solution of hydrazide 6 (2.88 g,
10 mmol) in CHCl3 (10 mL). The reaction mixture was
heated under reflux for 10 min, then chilled to r. t. and evapo-
rated. The residue was crystallized from ethyl acetate to pro-
vide compound 7 (3.32 g, 75 % yield) as colorless crystals.
ꢀ
ꢁ
159.9, 162.2 O(NH)C=C(C2), O(N=)C-Ara , 164.4, 165.6
(2 × C=O), 189.8 (C(S)=N). – C23H29N3O9S (523.56):
calcd. C 52.76, H 5.58, N 8.03, S 6.12; found C 52.83,
H 5.45, N 7.87, S 6.01.
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[3-methyl-5-
(1,2;3,4-di-O-isopropylidene-β-L-arabinopyranos-5-yl)
1,3,4-oxadiazol-2(3H)-ylidene]acetate (9)
◦
M. p. 145 – 146 C (ethyl acetate). – [α]2D2 = −55.7 (c =
1.03, CHCl3). – 1H NMR (250.13 MHz, CDCl3): δ =
ꢀ
ꢁ
1.33, 1.37, 1.45, 1.57 4 s, 12 H 2 × C(CH3)2 , 1.34 (t,
Compound 8 (524 mg, 1 mmol) was dissolved in a
3J = 7.0 Hz, 3 H OCH2CH3), 4.25 (q, 2 H OCH2CH3), minimum of chloroform and treated with an ethereal di-
3
4.46 (m, 1 H 2-H), 4.53 (dd, 1 H J3,4 = 7.6 Hz, 3-H), azomethane solution. When the reaction was complete, indi-
4.76 (dd, 1 H3J4,5 = 2.1 Hz, 4-H), 5.07 (d, 1 H 5-H), cated by a persisting yellow color of the solution, the reaction
3
5.67 (d, J1,2 = 4.9 Hz, 1-H), 6.94, 10.25 (2 × br, 2 H mixture was treated with acetic acid to destroy the excess of
NH2), 7.76, 8.86 (1 H NH). – 13C NMR (125.8 MHz, diazomethane. The solution was then diluted with the double
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access

N. Paepke et al. · Reinvestigation of the Thiazole Synthesis
725
volume of CHCl3, and the organic layer washed with water, 3 mmol) in EtOH (30 mL), and the resulting reaction mixture
aq. NaHCO3 (2×), and again water, dried, and concentrated. was heated under reflux for 10 min. During heating crystal-
The desired compound 9 (479 mg, 89 %) was obtained ana- lization started. After chilling the mixture to r. t. the crystals
lytically pure as a colorless foam.
were filtered off and washed several times with cold EtOH.
In such a way product 11 (673 mg, 76 %) was obtained in
analytically pure form.
[α]2D7
=
−134.2 (c
= 1.0, CHCl3). –
1H NMR
(250.13 MHz, CDCl3): δ = 1.34 (t, 3J = 7.0 Hz, 3 H
OCH2CH3), 1.33, 1.36, 1.46, 1.55 (4 s, 12 H 2 × C(CH3)2),
◦
M. p. 184 – 185 C (ethanol). – 1H NMR (250.13 MHz,
3
2.47 (s, 3 H COCH3), 2.62 (s, 3 H CH3), 3.63 (s, 3 H NCH3), CDCl3): δ = 1.41 (t, J = 7.0 Hz, 3 H OCH2CH3), 2.46 (s,
4.29 (q, 2 H OCH2CH3), 4.44 (m, 1 H 2-H), 4.56 (dd, 1 H 3 H COCH3), 2.62 (s, 3 H CH3), 3.78 (s, 4 H NCH2CH2N),
3J3,4 = 7.6 Hz, 3-H), 4.75 (dd, 1 H J4,5 = 1.8 Hz, 4-H), 4.34 (q, 2 H OCH2CH3). – 13C NMR (75.5 MHz, CDCl3):
3
3
5.06 (d, 1 H 5-H), 5.67 (d, 1 H J1,2 = 4.9 Hz, H-1). – δ = 14.7 (OCH2CH3), 18.3 (CH3), 30.5 (COCH3), 43.2
13C NMR (125.8 MHz, CDCl3): δ = 14.4 (OCH2CH3), (NCH2CH2N, one signal is isochronic), 60.0 (OCH2CH3),
18.3 (CH3), 24.4, 24.6, 25.7, 26.0 (2 × C(CH3)2), 29.6 79.1 [NH(NH)C=C(C2)], 124.4 (NC=CS), 156.3 (NC=CS),
(COCH3), 30.7 (NCH3), 60.0 (OCH2CH3), 64.4 (C-5), 70.4 164.5 [NH(NH)C=C(C2)], 164.5, 168.9 (2 × C=O), 190.5
(C-2), 70.5 (C-4), 71.2 (C-3), 74.5 [O(NH)C=C(C2)], 96.5 (C(S)=N). – C13H17N3O3S (295.36): calcd. C 52.86, H 5.80,
(C-1), 109.5, 110.7 (2 ×C(CH3)2), 126.2 (NC=CS), 157.4 N 14.23, S 10.86; found C 52.93, H 5.92, N 13.98, S 10.87.
ꢀ
ꢁ
(NC=CS), 157.9, 164.0 O(NH)C=C(C2), O(N=)C-Ara ,
165.5, 166.0 (2 × C=O), 190.4 (C(S)=N). – C24H31N3O9S
(537.58): calcd. C 53.62, H 5.81, N 7.82, S 5.96; found
C 53.37, H 6.01, N 7.87, S 5.71.
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-{1H-benzo[d]
imidazol-2(3H)-ylidene}acetate (12) [3]
Phenylene diamine (648 mg, 6 mmol) was added to a so-
lution of compound 5a (1.16 g, 3 mmol) in EtOH (30 mL),
and the resulting reaction mixture was heated under reflux
for 5 h. After chilling the mixture to r. t., the crystals were
filtered off and washed several times with cold EtOH. Prod-
uct 12 (721 mg, 70 %) was obtained as yellow needles.
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[4-benzyl-1-
methyl-3-phenyl-1H-1,2,4-triazol-5(4H)-ylidene]acetate
(10) [3]
Benzylamine (643 mg, 6 mmol) was added to a solution of
compound 5a (1.16 g, 3 mmol) in EtOH (25 mL). The result-
ing reaction mixture was heated under reflux for 1 h, chilled
to r. t., and evaporated. The residue was dissolved in chloro-
form (100 mL), and the organic layer was washed with water
(50 mL), aq. 15 % NaHSO4 (3×50 mL), water (50 mL), aq.
NaHCO3 (2×50 mL), and again water, (50 mL), dried, and
evaporated. The yellow residue was purified by column chro-
matography (chloroform : acetonitrile 4 : 1) to furnish com-
pound 10 (1.21 g, 85 %) as a syrup.
M. p. 236 – 238 ◦C (acetonitrile).
–
1H NMR
(250.13 MHz, [D6]DMSO): δ = 1.37 (t, 3J = 7.0 Hz,
3 H OCH2CH3), 2.45 (s, 3 H COCH3), 2.74 (s, 3 H CH3),
4.39 (q, 2 H OCH2CH3), 7.27, 7.68 (2 m, 4 H C6H4),
13.00 (br, 2H, NH). – 13C NMR (75.5 MHz, [D6]DMSO):
δ = 15.0 (OCH2CH3), 18.4 (CH3), 30.3 (COCH3), 59.7
(OCH2CH3), 78.4 [NH(NH)C=C(C2)], 112.1, 123.0,
124.8, 130.3 (NC=CS, C6H4, three signals are isochronic),
150.0 [NH(NH)C=C(C2)], 155.9 (NC=CS), 165.9, 167.8
(2 × C=O), 189.9 (C(S)=N). – C17H17N3O3S (343.40):
calcd. C 59.46, H 4.99, N 12.24, S 9.34; found C 59.18,
H 5.08, N 12.00, S 9.47.
M. p. 89 – 91 ◦C (ethyl acetate–heptane). – 1H NMR
(250.13 MHz, CDCl3): δ = 1.21 (m, 3 H OCH2CH3),
2.44 (s, 3 H COCH3), 2.60 (s, 3 H CH3), 3.86 (s, 3 H
NCH3), 4.16 (m, 2 H OCH2CH3), 5.21 (dd, 2 H 2J =
18 Hz H2CC6H5), 6.71, 7.12, 7.50 (3 m, 10 H H2CC6H5,
C6H5). – 13C NMR (125.8 MHz, CDCl3): δ = 15.1
(OCH2CH3), 18.6 (CH3), 30.7 (COCH3), 38.3 (NCH3),
X-Ray structure determinations
Data collections were performed using an X8Apex
diffractometer system with MoKα radiation and a CCD area
detector. The structures were solved with Direct Methods and
refined against F2 (program system used: Bruker SHELXTL
[8]).
50.6 (H2CC6H5), 58.7 (OCH2CH3), 124.1, 126.9, 128.2,
128.5, 128.9, 129.1, 131.5, 133.6 O(NCH3)C=C(C2),
ꢀ
ꢁ
(NC=CS), 2 × C6H5, six signals are isochronic , 153.0
ꢀ
(NC=CS), 155.0, 158.9 N(NCH3)C=C(C2), N(N=)C-
Crystal structure data of 1: Crystal size: 0.025 × 0.21 ×
ꢁ
3
C6H5
,
164.9, 168.9 (2 × C=O), 190.0 (C(S)=N). –
¯
0.6 mm , triclinic crystal system, space group P1, a =
◦
C26H26N4O3S (474.57): calcd. C 65.80, H 5.52, N 11.81,
˚
4.9450(2), b =◦6.7471(3), c = 10.5470(5) A, α = 82.926(3) ,
◦
3
S 6.76; found C 65.53, H 5.51, N 11.68, S 6.76.
˚
β = 81.722(2) , γ = 84.299(2) , V = 344.38(3) A , Z = 1,
T = 293 K, µ(MoKα ) = 4.0 cm−1, θ range for data collec-
tion 3.93 – 25.00◦, index ranges (h, k, l) = 5, 8, 12,
10317 measured reflections, 1201 independent reflections,
Ethyl 2-(5-acetyl-4-methylthiazol-2-yl)-2-[imidazolidin-2-
ylidene]acetate (11) [3]
Ethylene diamine (50 % aqueous solution, 750 mg, Rint = 0.0301, GOF (F2) = 1.135, R1/wR2 [I ≥ 2σ(I)] =
6 mmol) was added to a solution of compound 5a (1.16 g, 0.0329/0.0871, R1/wR2 (all data) = 0.0376/0.0951, ∆ρfin
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access

726
N. Paepke et al. · Reinvestigation of the Thiazole Synthesis
Crystal structure data of 11: Crystal size: 0.04 × 0.12 ×
(max/min) = 0.0304/−0.0244 e A−3. Remarks: All non-
˚
hydrogen atoms were refined anisotropically. The hydrogen 0.58 mm3, monoclinic crystal system, space group P21/n,
˚
atoms were put into theoretical positions, and these positions a = 10.1322(2), b = 7.3519(2), c = 19.1581(4) A, β =
were then refined with a riding model.
102.032(1)◦, 3.45 – 27.50◦, index ranges (h, k, l) = 13,
9, 24, 27433 measured reflections, 3203 independent re-
flections, Rint = 0.0496, GOF (F2) = 1.022, R1/wR2 [I ≥
2σ(I)] = 0.0345/0.0824, R1/wR2 (all data) = 0.0533/0.0912,
Crystal structure data of 3b: Crystal size: 0.10 × 0.12 ×
3
¯
0.35 mm , triclinic crystal system, space group P1, a =
◦
˚
7.3134(3), b = ◦9.1288(4), c = 11.5577(4) A, α = 85.551(2) ,
∆ρfin (max/min) = 0.283/−0.191 e A−3. Remarks: All non-
◦
3
˚
˚
β = 83.651(2) , γ = 69.2677(2) , V = 718.52(5) A , Z =
2, T = 173 K, µ(MoKα ) = 2.48 cm−1, θ range for data
collection 2.91 – 25.00◦, index ranges (h, k, l) = 8, 10,
13, 22641 measured reflections, 2512 independent reflec-
tions, Rint = 0.0295, GOF (F2) = 1.086, R1/wR2 [I ≥
2σ(I)] = 0.0286/0.0816, R1/wR2 (all data) = 0.0345/0.085,
hydrogen atoms were refined anisotropically. The hydrogen
atoms at N2 and N3 were elucidated from a difference map,
and their positions were refined freely. The other hydrogen
atoms were put into theoretical positions, and these positions
were then refined with a riding model.
∆ρfin (max/min) = 0.197/−0.180 e A−3. Remarks: All non-
˚
CCDC 728522 (1), 728523 (3b), and 728524 (11) con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Center via www.ccdc.cam.ac.
uk/data request/cif.
hydrogen atoms were refined anisotropically. The hydrogen
atoms at N2 and N3 were elucidated from a difference map,
and their positions were refined freely. The other hydrogen
atoms were put into theoretical positions, and these positions
were then refined with a riding model.
[1] K. Peseke, J. Prakt. Chem. 1976, 318, 939 – 954.
[2] M. Jochheim, H. G. Krug, R. Neidlein, C. Krieger, Het-
erocycles 1995, 41, 1235 – 1250.
[3] K. Peseke, C. Vogel, J. Prakt. Chem. 1982, 324, 652 –
658.
[5] S. Kramer, B. Nolting, A.-J. Ott, C. Vogel, J. Carbo-
hydr. Chem. 2000, 19, 891 – 921, and refs. cited therein.
[6] D. D. Perrin, W. L. F. Armarego, Purification of Lab-
oratory Chemicals, 3rd ed., Pergamon Press, Oxford,
1988.
[4] K. Peseke, C. Vogel, J. Blaesche, K.-H. Kollhof,
J. Prakt. Cem. 1982, 324, 639 – 651.
[7] K. Peseke, Z. Chem. 1975, 15, 19 – 20.
[8] G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112 –
122.
- 10.1515/znb-2009-0618
Downloaded from De Gruyter Online at 09/12/2016 06:02:00AM
via free access