Synthesis of unusually substituted ureas starting from bis(l,3,4- thiadiazolo)1,3,5-triazinium halides via oxo-imidothioate zwitterions

Article abstract of DOI:10.1002/ejoc.200900300

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium hal.id.es 1 can be converted into various products such as guanidines or bis(azolyl)alkanes. However, they also react with hydroxide ions in aqueous solution to form novel heterocyclic- substituted ureas 2a-i. The y

Full text of DOI:10.1002/ejoc.200900300

FULL PAPER
DOI: 10.1002/ejoc.200900300
Synthesis of Unusually Substituted Ureas Starting from Bis(1,3,4-thiadiazolo)-
1,3,5-triazinium Halides via Oxo-imidothioate Zwitterions
Martin Schulz,[a] Marion Michnacs,[b] Helmar Görls,[c] and Ernst Anders*[b]
Keywords: Rearrangement / Nitrogen heterocycles / Sulfur heterocycles / Nucleophilic addition
Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides 1 can be con-
verted into various products such as guanidines or bis-
(azolyl)alkanes. However, they also react with hydroxide ions
in aqueous solution to form novel heterocyclic-substituted
ureas 2a–i. The yields were increased from moderate to good
or excellent in the presence of excess guanidine 3. The as-
sumption that hydrogen-bonded intermediate encounter
complexes EC are formed gives a reasonable explanation for
the observed reaction path. The molecular structures of some
of the crystalline products 2 were determined by X-ray
analysis. Furthermore, with copper(II) a dinuclear complex 8
is formed with the two metal ions in a distorted octahedral
environment; a water molecule acts as a bridging ligand be-
tween the CuII ions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
By reaction with primary and secondary amines these
so-called 5/6/5 cationic heterocyclic systems (SNS) can be
converted into a wide variety of highly substituted guan-
idines (G) and bis(azolyl)alkanes (A1 and A2) (Fig-
ure 2).[1,3–7]
Introduction
In 1998 we reported the convenient synthesis of the novel
fused tricyclic ring systems bis(1,3,4-thiadiazolo)-1,3,5-tri-
azinium halides (SNS).[1,2] A subsequent period of extensive
research finally led to novel [1,2,4]triazolo[1,3,4]thiadi-
azolo[1,3,5]triazinium (NNS) and bis(1,2,4-triazolo)-1,3,5-
triazinium halides (NNN) (Figure 1).[3]
Figure 2. Heterocyclic compounds resulting from the reactions of
SNS cations with primary and secondary amines.
Figure 1. Structures of the 5/6/5 heterocycles SNS, NNS and NNN
(X– could be Cl– or Br–).
Detailed investigations of the nucleophilic reactions of
primary and secondary amines with SNS compounds re-
vealed that these conversions proceed on a complicated hy-
persurface and that the reaction paths can be reliably con-
trolled by the reaction conditions. The pronounced electro-
philicity of the C(3a) and C(4a) centers in SNS is responsi-
[a] Institut für Anorganische und Analytische Chemie, Friedrich
Schiller-Universität Jena,
August-Bebel-Str. 2, 07743 Jena, Germany
[b] Institut für Organische Chemie und Makromolekulare Chemie,
Friedrich Schiller-Universität Jena,
Humboldtstr. 10, 07743 Jena, Germany
Fax: +49-3641-948212
ble for the reactivity of these compounds {qC(3a) = qC(4a)
=
E-mail: ernst.anders@uni-jena.de
+0.30e [NPA-B3LYP/6-311++G(d,p) results]}.[7] In the
course of this fast multistep reaction cascade a highly reac-
tive betainic triazinium imidothioate is formed, which is the
key intermediate for the successive reaction.[3,7] The forma-
[c] Institut für Anorganische und Analytische Chemie der Fried-
rich-Schiller-Universität,
Lessingstrasse 8, 07743 Jena, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900300.
Eur. J. Org. Chem. 2009, 4143–4148
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4143

M. Schulz, M. Michnacs, H. Görls, E. Anders
FULL PAPER
tion of this betainic intermediate is controlled by the influ- Table 1. Preparation of novel carboxamides 2a–i from bis(1,3,4-
thiadiazolo)-1,3,5-triazinium bromides 1a–i.
ence of negative hyperconjugation [nN(ex.)/σ*C(4a)–S(5) inter-
action].[8]
1, 2
R1
R2
Yield of 2 [%]
However, not only amines could serve as nucleophiles
a
b
c
d
e
f
g
h
i
p-tolyl
p-tolyl
1-naphthyl
1-naphthyl
butyl
methyl
tert-butyl
methyl
tert-butyl
methyl
isopropyl
methyl
ethyl
74
55
41
86
89
74
66
72
66
but also water or the hydroxide ion. The previous investi-
gations of Wermann et al.[3,7] with potassium hydroxide/po-
tassium tert-butoxide prompted us to extend our investi-
gations to the reaction between SNS and the hydroxide ion.
This led to novel heterocyclic-substituted ureas 2. The latter
are suitable ligands for metal complexation.[9]
butyl
o-hydroxyphenyl
o-hydroxyphenyl
o-hydroxyphenyl
tert-butyl
Results and Discussion
Bis(1,3,4-thiadiazolo)-1,3,5-triazinium
halides
1a–i
(SNS) were prepared as described previously from N-(1-
haloalkyl)pyridinium halides and aminothiadiazoles.[1,2]
The N-(1-haloalkyl)pyridinium halides were obtained in
one pot by the reaction of a 1:1:1 molar ratio of aldehyde/
thionyl halide/pyridine (Scheme 1).[10–12]
Scheme 2. Formation of novel carboxamides 2 from SNS cations
1.
within the expected ranges.[14] All structures show a nearly
planar N4–C1(O1)N3–C2–N2–N1–C3 moiety, which indi-
cates a delocalized π system, a fact that is also indicated by
the bond lengths. Furthermore, the space groups are centro-
symmetric, and thus the compounds crystallize as race-
mates.
Scheme 1. Formation of 1 via bromomethylpyridinium bromide.
In our first experiments 1 was allowed to react with po-
tassium hydroxide in water as well as with potassium hy-
droxide in methanol. The result was a mixture of non-iso-
lable products as well as degradation products like tolual-
dehyde. Change of the reaction conditions by using triethyl-
amine led to isolable products 2 in poor yields. Finally, by
replacement of the amine base by guanidine 3 in water/2-
propanol (1:1, v/v), compounds 2 were obtained in excellent
yields of up to 89% (Table 1, Scheme 2). Interestingly, a
double molar amount of guanidine was needed to obtain 2
in such yields. Although 1 and 3 are soluble in water, 2-
propanol was necessary to dissolve the imidothioate inter-
mediates and an excess of water was also necessary. Since
the reaction can be understood as the addition of hydroxide
ions to 1, the consumption of hydroxide ions during the
reaction can be observed by the decrease in the pH from 13
to 9. Experiments with equimolar amounts of water in 2-
propanol or acetonitrile did not lead to the formation of 2. Figure 3. Molecular structure and numbering of 2a. Thermal ellip-
soids are drawn at the 40% probability level. Hydrogen atoms have
been omitted for clarity. Selected bond lengths [pm] and angles [°]:
N2–N3 139.5(3), N1–C2 138.0(3), C1–N1 137.9(3), C1–O1
122.6(3), C1–N4 135.9(3), N4–N5 147.5(3), C1–N1–C2 121.1(2);
Structural assignments of 2 were made on the basis of
NMR investigations, especially by HMQC, HMBC and
DEPT135 experiments, as well as by mass spectrometry, IR
spectroscopy, and X-ray experiments (2a, 2b, 2g, and 2h).
The purity of compounds 2 was confirmed by elemental
analysis of the isolated and crystallized products. Figure 3
O1–C1–N4 121.4(2), O1–C1–N1 123.1(2), N4–C1–N1 115.5(2).
Some guanidines are known as strong bases, sometimes
shows as an example the molecular structure of 2a. For the referred to as superbases. But they are also able to react as
X-ray structures of compounds 2b, 2g, and 2h, see ref.[13] nucleophiles. The aforementioned reactions are promoted
The bond lengths and angles of the examined molecules are by guanidines in which they behave predominantly as bases
4144
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4143–4148

Synthesis of Unusually Substituted Ureas
but not as nucleophiles. We carried out the reactions with
the easy-to-make guanidine 3, which was prepared accord-
ing to ref.[15] by stirring isopropylcarbodiimide in pyrrol-
idine at reflux for 1 h followed by distillation.
In analogy to the results of the mechanistic investigations
of Wermann et al.[3,7,16] and Lill et al.[8] with nitrogen nu-
cleophiles, the hydroxide ion is the nucleophilic reagent in
the described reaction. Owing to the highly basic properties
of guanidine, the acid–base equilibrium is shifted to the side
of the non-nucleophilic guanidinium hydrohalide. The sub-
sequently formed hydroxide ions then attack the electro-
philic centers C(3a) or C(4a), which is followed by ring-
opening of the five-membered thiadiazole ring. The re-
sulting imidothioate sulfur atom now attacks C(9) (cf. Fig-
ure 1), and the six-membered triazine ring opens to form 2
(Scheme 3).
In the course of the described ring transformation, which
can be interpreted as an example of an SNANRORC
mechanism (addition of the nucleophile, ring-opening, and
ring closure),[17] the pro-stereogenic carbon atom C(9) (cf.
Figure 1) becomes a stereocenter. The products 2 are ob-
tained as racemates. Although ring-opening of the central
triazine ring after the addition of the hydroxide at C(3a) or
C(4a) is possible too (as described in ref.[3]), no such prod-
ucts were observed. This might be due to interactions with
the guanidinium, the role of which during the reaction is
not fully understood but its indispensability has been
shown. We hypothesized the existence of hydrogen-bonding
interactions between a guanidinium ion and the O(11)–C–
Scheme 3. Proposed mechanism for the formation of 2 by the
SNANRORC mechanism.
ure 4) stabilizing the central ring of this intermediate. Sim-
ilar interactions are well known between guanidinium ions
and carboxylates, amidinates, and other substrates.[18,19]
Figure 4. Proposed structure of the hydrogen-bonded stabilized en-
counter complex EC formed between the guanidinium cation and
N(4) moiety (formation of encounter complexes EC, Fig- the betainic intermediate 4.
Figure 5. Molecular structure and numbering of 8. Thermal ellipsoids are drawn at the 40% probability level. Hydrogen atoms and
solvent molecules have been omitted for clarity. Selected bond lengths [pm] and angles [°]: CuA–O1 205.1(3), CuB–O1 206.3(3), CuA–
N1A 207.7(4), CuB–N1D 208.0(4), CuA–N1B 205.4(4), CuB–N1C 205.5(4), CuA–N2C 212.6(4), CuB–N2B 212.3(4), CuA–N5A 212.2(4),
CuA–N5B 217.7(5), CuB–N5C 217.1(4), CuB–N5D 213.7(5); CuA–O1–CuB 116.58(16).
Eur. J. Org. Chem. 2009, 4143–4148
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4145

M. Schulz, M. Michnacs, H. Görls, E. Anders
FULL PAPER
The heterocyclic-substituted ureas obtained are suitable
as ligands for metal complexation. Deprotonation of the
ligand’s amidic moiety can be achieved by the use of acetyl-
acetonate compounds in anhydrous THF. Stirring of Cu-
(acac)2 with 2a in anhydrous THF for 24 h afforded the
dinuclear complex 8, in which the two copper centers are in
a distorted octahedral environment (Scheme 4). Two li-
gands are arranged terminally, whereas two others act as
bridging moieties between the metal ions. In addition, a
bridging water molecule occupies the sixth coordination site
(Figure 5). This water molecule stems from Cu(acac)2,
which was prepared in aqueous solution according to stan-
dard procedures. However, water-containing THF did not
lead to the formation of the described copper complex. The
Cu–N bond lengths and angles lie within the expected
range, whereas the CuA–O1–CuB angle [116.18(16)°] is
rather large. Large gaps between the complex molecules
host solvent molecules, which are disordered, thus hamper-
ing the quality of the structure determination.
Experimental Section
General Methods: All manipulations were performed under atmo-
spheric conditions. Solvents other than water were purchased from
commercial sources and were used as received. Anhydrous THF
was prepared according to standard procedures with sodium/
benzophenone. Melting points were measured with a Büchi B-549
instrument and are uncorrected. IR experiments were carried out
with a Nicolet Impact 400 (ATR) spectrometer. NMR spectra were
obtained with Bruker DRX 400 and Avance 250 spectrometers by
using the solvent as the internal standard. H and 13C NMR spec-
1
tra were recorded at 250/400 and 62.5/100 MHz, respectively. For
1H and 13C NMR, [D6]DMSO (H: δ = 2.49 ppm; C: δ = 39.5 ppm)
and CDCl3 (H: δ = 7.24 ppm; C: δ = 77.0 ppm) were used as sol-
vents. Mass spectrometric investigations were conducted with a
Finnigan MAT SSQ 710 spectrometer, and elemental analyses
(CHNS) were performed with a Leco CHNS-932 instrument. New
compounds were named according to IUPAC Naming on I-Lab
via ACD/ChemSketch (www.acdlabs.com).
General Procedure for the Preparation of Substituted N-(1,3,4-Thia-
diazol-2-yl)-1,3,4-thiadiazol-3(2H)-carboxamides 2a–i: Guanidine 3
(0.02 mol) was added to a solution of 1 (0.01 mol) in an equal vol-
ume of water and 2-propanol (total: 100 mL). The mixture was
stirred at room temperature for 12 h before the white precipitate
was collected. The remaining solution was acidified to pH = 6 by
using half-concentrated hydrochloric acid, and again the precipi-
tated compound was removed by filtration. The combined precipi-
tates were dried in vacuo and crystallized from ethyl acetate or
methanol to yield white to colorless crystals. The starting guanidine
3 was recovered from the acidic solution by adding KOH up to pH
= 14 and extraction with chloroform.
Scheme 4. Formation of CuII complex 8 from 2a and Cu(acac)2.
5-Methyl-2-(4-methylphenyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)-
1,3,4-thiadiazol-3(2H)-carboxamide (2a): Yield: 2.47 g (74%); m.p.
183 °C. 1H NMR (CDCl3): δ = 2.26 (s, 3 H, CH3), 2.36 (s, 3 H,
CH3), 2.63 (s, 3 H, CH3), 6.88 (s, 1 H, CH sp3), 7.14–7.49 (dd, 4
H, CHarom.), 9.54 (s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 15.3,
16.4, 21.2, 70.0, 125.8, 129.7, 137.3, 150.6, 159.7, 159.8 ppm. IR
Conclusions
Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides (SNS) 1
are the starting compounds for a wide variety of ring trans-
formation reactions mostly induced by reactions with ali-
phatic or aromatic amines. However, with hydroxide ions
as the nucleophilic reactants novel heterocyclic-substituted
carboxamides 2 were prepared. High yields were obtained
when an excess of water and a double molar amount of
guanidine 3 were used. This reaction can be explained by
hydrogen-bonding interactions between the carboxamide or
zwitterionic intermediate and the guanidinium cation,
which in this case is the determining step that favors the
formation of compounds 2. In addition, the novel com-
pounds 2 can be used as ligands for metal complexation, as
shown by the reaction with copper(II).
Ring transformation reactions of SNS with amines are
dependent to a significant extent on the nature of the amine
(aromatic or aliphatic) and its ability to influence the reac-
tion pathways by negative hyperconjugation. The contri-
bution of oxygen lone-pairs to negative hyperconjugation is
smaller, and thus other influences such as the hydrogen-
bonding effects discussed above can become determining.
In fact, the interesting reactions of these classes of com-
pounds can be precisely controlled by small changes of the
(ATR): ν = 1531 (vs), 1673 (vs), 3121 (br., NH) cm–1. MS (DCI):
˜
m/z (%) = 334 (100) [C14H15N5OS2 + 1]+. C14H15N5OS2 (333.4):
calcd. C 50.43, H 4.53, N 21.00, S 19.23; found C 50.54, H 4.79,
N 20.77, S 18.73.
5-tert-Butyl-N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2-(4-methylphen-
yl)-1,3,4-thiadiazol-3(2H)-carboxamide (2b): Yield: 2.30 g (55%);
1
m.p. 153 °C. H NMR (CDCl3): δ = 1.33 [s, 9 H, (CH3)3], 1.42 [s,
9 H, (CH3)3], 2.32 (s, 3 H, CH3), 6.83 (s, 1 H, CH sp3), 7.14–7.26
(dd, 4 H, CHarom), 9.25 (s, 1 H, NH) ppm. 13C NMR (CDCl3): δ
= 21.2, 26.9, 30.8, 35.8, 36.3, 69.3, 125.8, 129.7, 137.6, 139.0, 149.9,
159.1, 164.3, 174.8 ppm. IR (ATR): ν = 1522 (vs), 1672 (vs), 3128
˜
(br., NH) cm–1. MS (DCI): m/z (%) = 418.1 (100) [C20H27N5OS2
+ 1]+. C20H27N5OS2 (417.6): calcd. C 57.53, H 6.52, N 16.77, S
15.36; found C 57.67, H 6.49, N 16.69, S 15.26.
5-Methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-(1-naphthyl)-1,3,4-
thiadiazol-3(2H)-carboxamide (2c): Yield: 1.51 g (41 %); m.p.
232 °C. 1H NMR (CDCl3): δ = 2.26 (s, 3 H, CH3), 2.64 (s, 3 H,
CH3), 7.35–7.92 (m, 7 H, CHarom), 7.65 (s, 1 H, CH sp3), 9.67 (s,
1 H, NH) ppm. 13C NMR (CDCl3): δ = 15.3, 16.5, 67.5, 122.1,
122.3, 125.6, 126.1, 126.9, 128.7, 129.2, 129.6, 134.2, 134.8, 150.1,
152.4, 159.7, 160.2 ppm. IR (ATR): ν = 1523 (vs), 1669 (vs), 3159
˜
(br., NH) cm–1. MS (DCI): m/z (%) = 370 (100) [C17H15N5OS2 +
1]+. C17H15N5OS2 (369.5): calcd. C 55.26, H 4.09, N 18.95, S 17.36;
reaction conditions, thus making such reaction paths an found C 55.02, H 4.36, N 18.90, S 16.98.
ideal subject for high-level DFT investigations. These stud-
ies are underway.
5-tert-Butyl-N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2-(1-naphthyl)-
1,3,4-thiadiazol-3(2H)-carboxamide (2d): Yield: 3.90 g (86%); m.p.
4146
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4143–4148

Synthesis of Unusually Substituted Ureas
1
230 °C. H NMR (CDCl3): δ = 1.23 [s, 9 H, (CH3)3], 2.43 [s, 9 H,
acetylacetonate (72 mg, 0.27 mmol) was dissolved in anhydrous
(CH3)3], 7.32–7.92 (m, 7 H, CHarom.), 7.62 (s, 1 H, CH sp3), 9.41 THF (50 mL). Compound 2a (183 mg, 0.54 mmol) was added as a
(s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 29.2, 30.8, 35.9, 36.4,
solid to this blue solution, and the color changed instantaneously
to green. Upon stirring for 24 h a white precipitate formed, which
66.9, 122.2, 122.4, 125.6, 126.0, 127.6, 128.7, 129.2, 129.5, 134.1,
135.2, 150.1, 159.2, 165.8, 175.0 ppm. IR (ATR): ν = 1524 (vs), was then collected, washed with THF and dried in vacuo. Crystals
˜
1673 (vs), 3147 (br., NH) cm–1. MS (DCI): m/z (%) = 454 (100)
[C23H27N5OS2 + 1]+. C23H27N5OS2 (453.2): calcd. C 60.90, H 6.00,
N 15.44, S 14.14; found C 60.98, H 5.88, N 15.68, S 14.42.
suitable for X-ray analysis were obtained by slow solvent evapora-
tion of a solution of 8 in chloroform/ethanol. Yield: 42 mg (21%);
m.p. 260 °C. IR (ATR): ν = 708, 724 (s), 743, 755, 810, 873, 1122,
˜
1179, 1186, 1337, 1368, 1399, 1459, 1599, 1622 (vs), 2905 (w), 2990
2-Butyl-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1,3,4-thia-
diazol-3(2H)-carboxamide (2e): Yield: 2.66 g (89%); m.p. 115 °C.
1H NMR (CDCl3): δ = 0.89 (t, 3 H, CH3), 1.29 (m, 4 H, CH2),
1.81/1.97 (m, 2 H, CH2), 2.20 (s, 3 H, CH3), 2.65 (s, 3 H, CH3),
5.96 (q, 1 H, CH), 9.41 (s, 1 H, NH) ppm. 13C NMR (CDCl3): δ
= 13.9, 15.3, 16.6, 22.0, 26.6, 36.9, 69.4, 149.9, 151.7, 159.6,
(w), 3052 (w) cm–1. MS (micro-ESI in methanol/THF): m/z (%) =
1479 (2) [C56H56Cu2N20O4S8
+
23]+, 1124 (2), 750 (34)
[C28H28CuN10O2S4 + 23]+, 685(100). C56H58Cu2N20O5S8 (1474.8):
calcd. C 45.61, H 3.96, N 18.99, S 17.39; found C 45.24, H 4.16,
N 18.74, S 17.19.
159.8 ppm. IR (ATR): ν = 1525 (vs), 1663 (vs), 3150 (br., NH)
˜
X-ray Structure Determinations of 2a, 2b, 2g, 2h, and 8: The inten-
sity data for compounds 2a, 2b, 2g, 2h, and 8 were collected with
a Nonius-KappaCCD diffractometer by using graphite-monochro-
mated Mo-Kα radiation. Data were corrected for Lorentzian and
polarization effects but not for absorption effects.[20,21] The struc-
tures were solved by direct methods (SHELXS)[22] and refined by
cm–1. MS (DCI): m/z (%) = 300 (100) [C11H17N5OS2 + 1]+.
C11H17N5OS2 (299.4): calcd. C 44.13, H 5.72, N 23.39, S 21.42;
found C 44.11, H 5.75, N 23.41, S 21.30.
2-Butyl-5-isopropyl-N-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,3,4-thia-
1
diazol-3(2H)-carboxamide (2f): Yield: 2.63 g (74%); m.p. 68 °C. H
2
full-matrix least-squares techniques against Fo (SHELXL-97).[23]
NMR (CDCl3): δ = 0.88 (t, 3 H, CH3), 1.25 (d, 6 H, CH3), 1.33
(m, 4 H, CH2), 1.40 (d, 6 H, CH3), 1.86/1.93 (m, 2 H, CH2), 2.83
(m, 1 H, CH), 3.37 (m, 1 H, CH), 5.95 (q, 1 H, CH), 9.47 (s, 1 H,
NH) ppm. 13C NMR (CDCl3): δ = 14.0, 20.9, 21.0, 21.9, 23.1, 26.6,
For compounds 2a, 2b, and 2h the amine hydrogen atoms, for com-
pound 8 the hydrogen atoms of the water molecule, and for com-
pound 2g all hydrogen atoms were located by difference Fourier
synthesis and refined isotropically. The other hydrogen atoms were
included at calculated positions with fixed thermal parameters. All
non-hydrogen atoms were refined anisotropically.[23] XP (SIE-
MENS Analytical X-ray Instruments, Inc.) was used for structure
representations.
29.7, 30.3, 36.8, 68.3, 125.5, 150.1, 162.2, 171.6 ppm. IR (ATR): ν
˜
= 1527 (vs), 1671 (vs), 3119 (br., NH) cm–1. MS (EI): m/z (%) = 356
(100) [C15H25N5OS2 + 1]+. C15H25N5OS2 (355.4): calcd. C 50.67, H
7.09, N 19.70, S 18.04; found C 50.51, H 6.78, N 20.16, S 18.55.
2-(2-Hydroxyphenyl)-5-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-
1,3,4-thiadiazol-3(2H)-carboxamide (2g): Yield: 2.21 g (66%); m.p.
Supporting Information (see footnote on the first page of this arti-
cle): Crystal data and refinement details.
1
243 °C. H NMR (DMSO): δ = 2.21 (s, 3 H, CH3), 2.79 (s, 3 H,
CH3), 6.73-7.16 (m, 4 H, CHarom), 7.02 (s, 1 H, CH sp3), 10.01 (s,
1 H, OH), 11.31 (br., 1 H, NH) ppm. 13C NMR (DMSO): δ = 14.8,
16.2, 65.0, 115.3, 119.2, 124.3, 126.9, 129.3, 150.6, 153.0, 158.5,
Acknowledgments
160.3 171.1 ppm. IR (ATR): ν = 1457 (vs), 1528 (vs), 1681 (vs),
˜
3121 (br., NH), 3387 (s, OH) cm–1. MS (DCI): m/z (%) = 336 (40)
[C13H13N5O2S2 + 1]+. C13H13N5O2S2 (335.4): calcd. C 46.55, H
3.91, N 20.88, S 19.12; found C 46.44, H 4.02, N 20.77, S 19.05.
Financial support by the Deutsche Forschungsgemeinschaft (DFG
Bonn-Bad Godesberg; SFB 436) and the Fonds der Chemischen
Industrie (Germany) is gratefully acknowledged.
5-Ethyl-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-hydroxyphenyl)-1,3,4-
thiadiazol-3(2H)-carboxamide (2h): Yield: 2.62 g (72 %); m.p.
209 °C. H NMR (DMSO): δ = 1.15 (t, 3 H, CH3), 1.23 (t, 3 H,
[1] E. Anders, K. Wermann, B. Wiedel, W. Günther, H. Görls, Eur.
J. Org. Chem. 1998, 2923–2930.
1
[2] E. Anders, K. Wermann, J. J. Vanden Eynde, Advances in Het-
erocyclic Chemistry: Chemistry of N-(1-Haloalkyl)Heteroaryl-
ium Salts (Ed.: A. R. Katritzky), Academic Press, New York,
2000, vol. 77, pp. 183–219 (Review Article).
[3] K. Wermann, M. Walther, W. Günther, H. Görls, E. Anders,
Eur. J. Org. Chem. 2003, 1389–1403.
CH3), 2.53 (q, 2 H, CH2), 2.91 (q, 2 H, CH2), 6.74 (t)/6.80 (d)/6.87
(d)/7.15 (t, 4 H, CHarom), 7.01 (s, 1 H, CH sp3), 10.08 (s, 1 H, OH),
11.3 (br., 1 H, NH) ppm. 13C NMR (DMSO): δ = 15.3, 16.4, 21.2,
22.1, 70.0, 116.7, 120.0, 124.4, 125.8, 129.7, 137.3, 150.6, 159.7,
159.8, 170.9 ppm. IR (ATR): ν = 1462 (vs), 1538 (vs), 1689 (vs),
˜
3090 (br., NH), 3381 (s, OH) cm–1. MS (DCI): m/z (%) = 364 (30)
[C15H17N5O2S2 + 1]+. C15H17N5O2S2 (363.5): calcd. C 49.57, H
4.71, N 19.27, S 17.64; found C 49.70, H 4.89, N 19.12, S 17.18.
[4] K. Wermann, M. Walther, E. Anders, ARKIVOC 2002, 10, 24–
33.
[5] M. Walther, K. Wermann, H. Görls, E. Anders, Synthesis 2001,
1327–1330.
5-tert-Butyl-N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2-(2-hydroxyphen-
yl)-1,3,4-thiadiazol-3(2H)-carboxamide (2i): Yield: 2.77 g (66%);
[6] K. Wermann, M. Walther, H. Görls, E. Anders, Synlett 2003,
1459–1462.
1
m.p. 254 °C. H NMR (DMSO): δ = 1.22 [s, 9 H, (CH3)3], 1.34 [s,
[7] K. Wermann, M. Walther, W. Günther, H. Görls, E. Anders,
Tetrahedron 2005, 61, 673–685.
9 H, (CH3)3], 6.74 (t)/6.78 (d)/6.83 (d)/7.14 (t, 4 H, CHarom), 7.01
(s, 1 H, CH sp3), 10.03 (s, 1 H, OH), 11.30 (br., 1 H, NH) ppm.
13C NMR (DMSO): δ = 28.8, 30.4, 35.3, 35.7, 64.5, 115.4, 119.2,
124.3, 127.0, 129.2, 150.7, 153.0, 159.8, 162.9, 172.8 ppm. IR
[8] S. O. N. Lill, G. Rauhut, E. Anders, Chem. Eur. J. 2003, 9,
3143–3153.
[9] M. Walther, K. Wermann, M. Lutsche, W. Günther, H. Görls,
E. Anders, J. Org. Chem. 2006, 71, 1399–1406.
[10] E. Anders, K. Wermann, B. Wiedel, J. J. Vanden Eynde, Liebigs
Ann./Recueil 1997, 745–752.
[11] E. Anders, J. G. Tropsch, A. R. Katritzky, D. Rasala, J. J.
Vanden Eynde, J. Org. Chem. 1989, 54, 4808–4812.
[12] E. Anders, A. Opitz, K. Wermann, B. Wiedel, M. Walther, W.
Imhof, H. Görls, J. Org. Chem. 1999, 64, 3113–3121.
(ATR): ν = 1454 (vs), 1522 (vs), 1691 (vs), 3079 (br., NH), 3390
˜
(OH) cm–1. MS (DCI): m/z (%) = 420 (100) [C19H25N5O2S2 + 1]+.
C19H25N5O2S2 (419.6): calcd. C 54.39, H 6.01, N 16.69, S 15.28;
found C 54.42, H 6.04, N 16.40, S 14.98.
[Cu2{5-methyl-2-(4-methylphenyl)-N-(5-methyl–1,3,4-thiadiazol-2-
yl)-1,3,4-thiadiazol-3(2H)-carboxamidato}4(H2O)] (8): Copper(II)
Eur. J. Org. Chem. 2009, 4143–4148
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4147

M. Schulz, M. Michnacs, H. Görls, E. Anders
FULL PAPER
[13] CCDC-719782 (2a), -719783 (2b), -719784 (2g), -719785 (2h)
and -719786 (8) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[14] F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G.
Orpen, J. Chem. Soc. Perkin Trans. 2 1987, 6, S1–S19.
[15] E. W. Thomas, E. E. Nishizawa, D. C. Zimmermann, D. J. Wil-
liams, J. Med. Chem. 1989, 32, 228–236.
[19]
[20]
F. P. Schmidtchen, Coord. Chem. Rev. 2006, 250, 2918–2928.
Z. Otwinowski, W. Minor, “Processing of X-ray Diffraction
Data Collected in Oscillation Mode” in Methods in Enzy-
mology, vol. 276 (Macromolecular Crystallography) (Eds.:
C. W. Carter, R. M. Sweet), Academic Press, San Diego, 1997,
part A, pp. 307–326.
COLLECT, Data Collection Software, Nonius B. V., Nether-
lands, 1998.
[21]
[22] G. M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467–473.
[23] G. M. Sheldrick, SHELXL-97 (Release 97–2), University of
Göttingen, Germany 1997.
[16] K. Wermann, M. Walther, W. Günther, H. Görls, E. Anders,
J. Org. Chem. 2001, 66, 720–726.
[17] N. J. Kos, H. C. Van der Plas, J. Org. Chem. 1980, 4, 2942–
Received: March 20, 2009
Published Online: July 6, 2009
2945.
[18] F. P. Schmidtchen, M. Berger, Chem. Rev. 1997, 97, 1609–1646.
4148
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4143–4148