From N-substituted thioamides to symmetrical and unsymmetrical 3,4,5-trisubstituted 4H-1,2,4-triazoles: Synthesis and characterisation of new chelating ligands

Article abstract of DOI:10.1002/ejoc.200400184

An improved protocol for the synthesis of N-substituted pyridine-2-thiocarboxamides under the conditions of the Willgerodt-Kindler reaction, employing a catalytic amount of sodium sulfide nonahydrate, has been developed. Following this protocol, eight thioamides carrying aromatic or aliphatic N-substituents have been prepared in good to excellent yields. Condensation of these thioamides or their S-alkylated congeners with hydrazides in refluxing 1-butanol has afforded eight unfused 3,4,5-trisubstituted 4H-1,2,4-triazoles in good yields, including four examples of the otherwise not easily obtainable 4-alkyl-3,5-diaryl-4H-1,2,4-triazoles. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400184

FULL PAPER
From N-Substituted Thioamides to Symmetrical and Unsymmetrical 3,4,5-
Trisubstituted 4H-1,2,4-Triazoles: Synthesis and Characterisation of New
Chelating Ligands
Marco H. Klingele[a] and Sally Brooker*[a]
Keywords: 1,2,4-Triazoles / Thioamides / N ligands / NMR spectroscopy / X-ray diffraction
An improved protocol for the synthesis of N-substituted pyr-
idine-2-thiocarboxamides under the conditions of the
Willgerodt−Kindler reaction, employing a catalytic amount of
sodium sulfide nonahydrate, has been developed. Following
this protocol, eight thioamides carrying aromatic or aliphatic
N-substituents have been prepared in good to excellent
yields. Condensation of these thioamides or their S-alkylated
congeners with hydrazides in refluxing 1-butanol has af-
forded eight unfused 3,4,5-trisubstituted 4H-1,2,4-triazoles in
good yields, including four examples of the otherwise not
easily obtainable 4-alkyl-3,5-diaryl-4H-1,2,4-triazoles.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
triazoles, and all three substituents can potentially be varied
over a wide range of choices; (d) the desired 1,2,4-triazole
can be prepared from either of two possible combinations
of an N-substituted thioamide and a hydrazide, i.e. from
either the R3/R4-thioamide and the R5-hydrazide, or the
R5/R4-thioamide and the R3-hydrazide. Santus[24] and sub-
sequently Reiter and Berg[25] have already demonstrated the
convenience and versatility of this method. Of particular
interest to us were the hitherto unknown 4-alkyl-3,5-di(2-
pyridyl)-4H-1,2,4-triazoles with their electron-donating
alkyl groups.[2,10,26] Since the alkylation of N-unsubstituted
1,2,4-triazoles usually occurs at one of the nitrogen atoms
of the N2 unit,[27] the alkylation of 3,5-di(2-pyridyl)-1H-
1,2,4-triazole[28] is not a viable route for accessing 4-alkyl-
3,5-di(2-pyridyl)-4H-1,2,4-triazoles.[29Ϫ31] It was anticipated
that the thioamideϪhydrazide condensation could provide
a solution to these synthetic difficulties. In this paper we
report the synthesis and characterisation of some N-substi-
tuted pyridine-2-thiocarboxamides and unfused 3,4,5-tri-
substituted 4H-1,2,4-triazoles.
Over the last three decades coordination chemists have
developed an ever-increasing interest in 1,2,4-triazole de-
rivatives due to the versatile coordination chemistry of these
ligands[1Ϫ3] and the intriguing magnetic properties of the
resulting transition metal complexes.[4Ϫ7] In the course of
our ongoing investigation of the coordination chemistry of
1,2,4-triazole-based ligands carrying 2-pyridyl groups in the
3- and/or 5-position,[2,8,9] a straightforward and general
synthetic strategy was needed that would make unfused
3,4,5-trisubstituted 4H-1,2,4-triazoles easily accessible and,
at the same time, would allow for the variation of all three
substituents. A survey of the literature[10] revealed that most
of the known compounds of this type have been prepared
by methods involving, as the key step, the cyclisation of N3-
substituted N1-acyl amidrazones.[11Ϫ15] Since such com-
pounds are accessible by a variety of methods (Scheme 1),
the synthesis of 3,4,5-trisubstituted 4H-1,2,4-triazoles via
these intermediates can be considered the most general and
versatile approach. Of all of the possible routes to N3-sub-
stituted N1-acyl amidrazones, the condensation of N-substi-
tuted thioamides with hydrazides was the most appealing
for the following reasons: (a) thioamides are stable and rela-
tively nonhazardous compounds which can be synthesised
in a variety of ways,[16Ϫ20] and whose potential and useful-
Results and Discussion
Preparation of the Hydrazides
The known hydrazides used in this work, namely benzo-
ness for the synthesis of heterocyclic systems is well estab- hydrazide (1) and pyridine-2-carbohydrazide (2), were most
lished;[21,22] (b) hydrazides are easily accessible from the conveniently prepared by the reaction of the corresponding
corresponding esters;[23] (c) there are no obvious restrictions esters with hydrazine monohydrate.[23] Thus, hydrazide 1
with regard to the substitution pattern of the desired 1,2,4- was obtained from methyl benzoate and a slight excess of
hydrazine monohydrate in 79% yield after recrystallisation
[a]
Department of Chemistry, University of Otago,
from benzene/ethanol (5:1). This solvent mixture was used
since the solubility of hydrazide 1 in ethanol was too high,
while it was poorly soluble in benzene alone. The reaction
P. O. Box 56, Dunedin, New Zealand
Fax: (internat.) ϩ64-3-479-7906
E-mail: sbrooker@alkali.otago.ac.nz
3422
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400184
Eur. J. Org. Chem. 2004, 3422Ϫ3434

From N-Substituted Thioamides to Symmetrical and Unsymmetrical 3,4,5-Trisubstituted 4H-1,2,4-Triazoles
FULL PAPER
Scheme 1. Possible routes to N3-substituted N1-acyl amidrazones as intermediates in the synthesis of unfused 3,4,5-trisubstituted 4H-
1,2,4-triazoles; the box highlights the route described in this work
of ethyl pyridine-2-carboxylate with a twofold excess of hy-
drazine monohydrate similarly gave, after evaporation of
the reaction mixture and recrystallisation of the residue
from ethanol, hydrazide 2 in 83% yield.
(Scheme 2). Under these standard conditions the yields are
usually only poor to moderate (Table 1). In the search for
an improved protocol, the use of a catalytic amount of so-
dium sulfide nonahydrate, as mentioned in a Soviet pat-
ent,[37] appeared promising and was therefore further inves-
tigated.
Preparation of the N-Substituted Thioamides
A convenient method for the preparation of N-substi-
The reaction of a 6:1 molar ratio of sulfur and 1,4-pheny-
tuted thioamides is the WillgerodtϪKindler reaction, which lenediamine in the presence of 5 mol % of sodium sulfide
usually employs aromatic ketones as starting materials.[32,33] nonahydrate and a large excess of refluxing 2-methylpyri-
However, it has been shown that this reaction can also be dine afforded N,NЈ-(1,4-phenylene)bis(pyridine-2-thiocar-
applied to 2-methylpyridine.[34,35] Thus, N-substituted pyri- boxamide (3)[34,37Ϫ39] after 72 h in 80% yield (Scheme 3).
dine-2-thiocarboxamides have been prepared by reaction of The yield was much higher than those previously reported
2-methylpyridine with primary amines,[34,35] nitro com- (Table 1). Interestingly, using similar reaction conditions
pounds,[34] or N-substituted formamides[16,36] as amine but with only two equivalents rather than a large excess of
sources in the presence of sulfur at elevated temperatures 2-methylpyridine, Martin[40] had failed to obtain thioamide
3, instead isolating 2,6-di(2-pyridyl)benzo[1,2-d;4,5-dЈ]bis-
(thiazole), formed by the oxidative cyclisation of thioamide
3. Reducing the amount of sulfur and 2-methylpyridine in
the reaction mixture relative to 1,4-phenylenediamine to
2.4:2:1 afforded a different product, which was identified as
the hitherto unknown N-(4-aminophenyl)pyridine-2-thio-
carboxamide (4), with a yield of 58% (Scheme 3).
The conditions successfully employed for the synthesis of
thioamide 3 were then adapted for the preparation of N-(4-
pyridyl)pyridine-2-thiocarboxamide (5).[41] This compound
had previously only been obtained in an acceptable yield of
57% from the reaction of 2-methylpyridine, sulfur and 4-
aminopyridine in a pressure vessel at 200 °C, while carrying
Scheme 2. Possible amine sources for the synthesis of N-substituted
pyridine-2-thiocarboxamides under the conditions of the
WillgerodtϪKindler reaction
Eur. J. Org. Chem. 2004, 3422Ϫ3434
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3423

M. H. Klingele, S. Brooker
FULL PAPER
Table 1. Comparison of literature yields with the yields obtained in this work for N-substituted pyridine-2-thiocarboxamides synthesised
under the conditions of the WillgerodtϪKindler reaction
N-Substituent
Literature yield
This work[a]
1,4-phenylene (3)
19%[b] (from 4-nitroaniline)[34]
21%[b] (from 4-nitroaniline)[38]
40%[b] (from 4-nitroaniline)[39]
47%[a] (from 1,4-phenylenediamine)[37]
14%[b] (from 4-aminopyridine)[41]
57%[c] (from 4-aminopyridine)[41]
30%[b] (from 4-nitrotoluene)[34]
80%
77%
4-pyridyl (5)
4-methylphenyl (6)
55%[b] (from 4-methylaniline)[42]
14%[b] (from 4-methylaniline)[43]
65%[b] (from 2,4,6-trimethylaniline)[44]
17%[b] (from methylamine hydrochloride)[45]
50%[b] (from N-methylformamide)[36]
34%[d] (from N-methylformamide)[46]
79%
74%
2,4,6-trimethylphenyl (7)
methyl (8)
69%
[a]
[b]
Reaction carried out in the presence of a catalytic amount of sodium sulfide nonahydrate with the appropriate amine.
Reaction
[c]
[d]
carried out under standard conditions. Reaction carried out in a pressure vessel. Reaction carried out in the presence of a catalytic
amount of iodine.
Scheme 4. Synthesis of thioamides 5Ϫ11; reagents and conditions:
Scheme 3. Synthesis of thioamides 3 and 4; reagents and con-
ditions: (a) 6 equiv. S8, 5 mol % Na2S·9H2O, large excess 2-methyl-
pyridine, reflux; (b) 2.4 equiv. S8, 5 mol % Na2S·9H2O, 2 equiv. 2-
methylpyridine, 150 °C
(a) S8, cat. Na2S·9H2O, 2-methylpyridine, reflux; (b) NH3, H2S,
EtOH, room temperature; (c) isobutylamine, reflux
out the same reaction at ambient pressure at reflux report-
While in principle not only aromatic but also aliphatic
edly only yielded 14% of the desired product.[41] In contrast, amines can be used in the WillgerodtϪKindler reaction, in
we obtained a 77% yield of thioamide 5 at ambient pressure practice, this is simple only for high-boiling amines since
with 2 mol % of sodium sulfide nonahydrate as a catalyst. the lower alkylamines, especially, are very volatile sub-
To test the general applicability and efficiency of these stances. Thus, reactions involving the lower alkylamines can
modified reaction conditions (i.e. sulfur/amine ratio of 3:1, only be carried out in pressure vessels. However, Schäfer
large excess of 2-methylpyridine, 2 mol % sodium sulfide and Wegler[45] have reported that not only free amines but
nonahydrate, reflux at ambient pressure), the synthesis of also their hydrochloride salts can be reacted under the
another two N-arylpyridine-2-thiocarboxamides, namely N- conditions of the WillgerodtϪKindler reaction. The pos-
(4-methylphenyl)pyridine-2-thiocarboxamide
(6)[34,42,43] sibility of preparing N-methylpyridine-2-thiocarboxamide
and N-(2,4,6-trimethylphenyl)pyridine-2-thiocarboxamide (8)[36,45Ϫ47] from methylamine hydrochloride was therefore
(7),[44] was carried out (Scheme 4). In these two cases the examined next. Initially, the original protocol,[45] that is
modified reaction conditions also proved to be superior to without the addition of sodium sulfide nonahydrate, was
earlier protocols, the yields of the recrystallised products followed exactly, albeit on only one tenth of the scale. Thus,
being 79 and 74%, respectively (Table 1).
the reaction of sulfur, methylamine hydrochloride and 2-
3424
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2004, 3422Ϫ3434

From N-Substituted Thioamides to Symmetrical and Unsymmetrical 3,4,5-Trisubstituted 4H-1,2,4-Triazoles
FULL PAPER
methylpyridine in a 3:1:1 molar ratio at 170 °C gave, after the separation of the relatively small amount of the desired
workup, a 19% yield of pure thioamide 8, which is in good product from the much larger amounts of unchanged start-
agreement with the literature.[45] Subsequently, the reaction ing materials and intermediates proved to be difficult, pyri-
was carried out with the modified reaction conditions, i.e. dine[24] was tried next as the reaction solvent in the hope
using an excess of 2-methylpyridine in the presence of 2 of achieving higher conversion rates due to higher reaction
mol % of sodium sulfide nonahydrate. After workup and temperatures. In this solvent, however, the reaction of
recrystallisation of the crude product, thioamide 8 was ob- thioamide 5 with hydrazide 1 was much more sluggish, and
tained in a much better yield of 69% (Scheme 4). In the case practically no hydrogen sulfide evolved at room tempera-
of N-benzylpyridine-2-thiocarboxamide (9),[47,48] which to ture, presumably due to the lower solubility of hydrazide 1
the best of our knowledge has never been prepared before in this solvent. Here too, the reaction did not go to com-
under the conditions of the WillgerodtϪKindler reaction, pletion, although conversion seemed to be higher than in
the yield was only moderate (44%). For the preparation of ethanol. The best results were obtained when thioamide 5
N-isobutylpyridine-2-thiocarboxamide (10),[47,48] a different was treated with a slight excess of hydrazide 1 in refluxing
approach was taken. First, pyridine-2-thiocarboxamide (11) 1-butanol,[25] the solvent which has also been used in the
was synthesised in 86% yield by the hydrosulfanylation of synthesis
of
3,3Ј-diphenyl-5,5Ј-di(2-pyridyl)-4,4Ј-(1,4-
pyridine-2-carbonitrile.[49] Thioamide 11 was then reacted phenylene)bis(4H-1,2,4-triazole).[8] Under these conditions,
with an excess of isobutylamine at reflux to give thioamide triazole 12 crystallised in analytically pure form and in 78%
10 in 81% yield as a golden liquid (Scheme 4). Interestingly, yield upon cooling. The reaction of thioamide 5 with hydra-
Kluiber[47] has also found thioamide 10 to be a liquid at zide 2 under identical conditions gave pydpt (13) in 69%
room temperature, while Rukhadze[48] has characterised it yield (Scheme 5).
as a low-melting solid.
The conversion of thioamide 6 into the new compound
pmppt (15) and its known but previously uncharacterised
congener pmdpt (16)[50Ϫ53] was explored next. When
thioamide 6 reacted with hydrazide 1 under the conditions
described above for the preparation of triazoles 12 and 13,
only a small amount of triazole 15 was formed, and mainly
unchanged starting materials were recovered. Subsequently,
acetic acid and 1,2-ethandiol were tested as alternative sol-
vents for this reaction but without success. Toluene and xy-
lene were also employed under both normal reflux con-
ditions and in the presence of a catalytic amount of toluene-
4-sulfonic acid monohydrate in a DeanϪStark apparatus.
However, significant improvements were not achieved un-
der any of these conditions. In agreement with the obser-
vation that almost no hydrogen sulfide was produced, it
seemed plausible that it was not the dehydrative cyclisation
of the intermediate N3-substituted N1-acyl amidrazone that
was hampered, but rather the formation of the latter by the
reaction of thioamide 6 with hydrazide 1.
Preparation of the 1,2,4-Triazoles
After the successful condensation of thioamide 3 with hy-
drazide 1 in 1-butanol to give 3,3Ј-diphenyl-5,5Ј-di(2-pyri-
dyl)-4,4Ј-(1,4-phenylene)bis(4H-1,2,4-triazole)
in
48%
yield,[8] the use of this reaction in the synthesis of other
unfused 3,4,5-trisubstituted 4H-1,2,4-triazoles was exam-
ined. Thus, when thioamide 5 was allowed to react with
hydrazide 1 in ethanol at room temperature,[24] evolution of
hydrogen sulfide was noticeable, and the appearance of the
yellow-orange suspension changed, thus indicating the for-
mation of a new solid. Analysis of an impure sample of this
1
initial product by H and 13C NMR spectroscopy revealed
that it was not the desired 1,2,4-triazole but the intermedi-
ate N3-substituted N1-acyl amidrazone (Scheme 5). This is
in agreement with the findings by Santus.[24] On heating the
initially obtained suspension, a clear orange solution was
obtained which was refluxed for several hours. Monitoring
of the reaction by TLC showed the formation of a second
A common way to increase the susceptibility of thioam-
product, which was subsequently identified as pyppt (12). ides to nucleophilic attack is S-alkylation.[22] Most thioam-
However, when ethanol was used as the solvent, the reac- ides can be readily S-alkylated by simply heating them with
tion could not be driven to completion even with prolonged an excess of the alkylating agent. In the present case, how-
heating, use of a large excess of hydrazide 1 or removal of ever, the use of these conditions was expected to lead to
the hydrogen sulfide formed in the reaction by bubbling a unwanted overalkylation and quaternisation of the pyridine
steady stream of nitrogen through the reaction mixture. As ring. Deprotonation of the thioamide prior to alkylation
Scheme 5. Synthesis of triazoles 12 and 13; reagents and conditions: (a) BuOH, reflux
Eur. J. Org. Chem. 2004, 3422Ϫ3434
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3425

M. H. Klingele, S. Brooker
FULL PAPER
Scheme 6. Synthesis of triazoles 15, 16, 18, 19, 21 and 22; reagents and conditions: (a) NaOEt, EtOH, room temperature; (b) EtBr,
EtOH, 50 °C; (c) hydrazide 1, BuOH, reflux; (d) hydrazide 2, BuOH, reflux
and the use of only a slight excess of the alkylating agent prior S-alkylation. The latter compounds exhibited very
therefore seemed advisable. A search of the literature re- good solubility in all organic solvents, which resulted in
vealed that S-alkylation of pyridine-derived thioamides has losses during their purification by recrystallisation. In the
been reported only once; the reaction conditions involve the case of triazoles 21 and 22 recrystallisation was particularly
use of iodomethane and potassium tert-butoxide in tetra- unsatisfactory, and purification was instead best achieved
hydrofuran.[54] With the use of slightly different conditions, by column chromatography.
S-alkylation of thioamide 6 was achieved by its reaction
with sodium ethoxide in ethanol at room temperature, fol-
lowed by the addition of bromoethane and refluxing of the
reaction mixture. This afforded impure ethyl N-(4-methyl-
phenyl)pyridine-2-carboximidothioate (14) in almost
quantitative yield as an orange oil. This material, as well
as the other S-alkylated thioamides that were subsequently
prepared, have a very unpleasant odour reminiscent of rot-
ten garlic. Condensation of this crude material with hydra-
zides 1 and 2 readily occurred in 1-butanol at reflux and
afforded triazoles 15 and 16 in 65 and 71% yield, respec-
tively. Using this S-alkylationϪcondensation sequence the
compounds meppt (18) and medpt (19), as well as ibppt
(21) and ibdpt (22), all hitherto unknown and carrying alkyl
groups on N4, were similarly prepared in moderate to good
yields via ethyl N-methylpyridine-2-carboximidothioate (17)
and ethyl N-isobutylpyridine-2-carboximidothioate (20),
respectively (Scheme 6). Thioamides 8 and 10 could not be
converted into triazoles 18, 19, 21 and 22 directly without
NMR Spectroscopy
In 2-substituted pyridines each of the four protons
couples with the other three. Consequently, four doublets
of doublets of doublets (ddd) should be observed in the H
NMR spectra of these systems. In the present work the
spectra of all compounds incorporating such a moiety show
the expected four resonances, three of which were indeed
doublets of doublets of doublets, while the signal for 4-PyH
appears as a doublet of triplets (dt) due to the magnitude
1
3
3
of the coupling constants J3,4 and J4,5 (Figure 1).
The chemical shifts for the individual pyridine protons of
the N-substituted thioamides 3Ϫ10 differ only very slightly
from one another and were practically unaffected by the
nature of the N-substituent. In the case of the N-benzyl-
substituted thioamide 9, the signal for 4-PyH coincides with
the multiplet observed for the five protons of the phenyl
ring; this prevented the exact determination of the chemical
shift of this proton. The pyridine resonances for the parent
thioamide 11 are all observed within the narrow ranges
given in Figure 2. In contrast, as might be expected, the
chemical shifts for the protons of the thioamido groups in
compounds 3Ϫ11 vary over a wide range. No concentration
dependence of these signals was observed. For the N-alkyl-
substituted thioamides 8Ϫ10, the resonance for the CSNH
proton appears at δ ϭ 10.21Ϫ10.38 ppm, while for the N-
aryl-substituted thioamides 3Ϫ6 this signal is observed at
δ ϭ 11.91Ϫ12.23 ppm. This downfield shift on changing
the substituent from an electron-donating alkyl group to an
electron-withdrawing aryl group was taken to be a direct
consequence of the electronic effect of the respective sub-
stituent. Thioamide 7, with its 2,4,6-trimethylphenyl group,
shows an intermediate chemical shift of δ ϭ 11.29 ppm for
its CSNH proton, presumably due to some cancellation of
the electron-withdrawing effect of the phenyl group by the
three electron-donating methyl groups. The presence of two
thioamido protons in the parent thioamide 11 gives rise to
Figure 1. Coupling constants observed for the 2-pyridyl groups in
1
the H NMR spectra (CDCl3) of compounds 2Ϫ22
3426
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3422Ϫ3434

From N-Substituted Thioamides to Symmetrical and Unsymmetrical 3,4,5-Trisubstituted 4H-1,2,4-Triazoles
FULL PAPER
two CSNH resonances, which are observed as broad sing-
lets at δ ϭ 7.90 and 9.54 ppm. The former signal is assigned
to the proton trans to the pyridine nitrogen atom, while the
latter is assigned to the cis proton, its relative downfield
shift is a result of a hydrogen bond interaction with the
pyridine nitrogen atom in solution.
Figure 4. Chemical shifts observed in the 1H NMR spectra
(CDCl3) of triazoles 12, 13, 15, 16, 18, 19, 21 and 22
In the 13C NMR spectra of the triazoles 12, 13, 15, 16,
18, 19, 21 and 22 (Figure 5), the resonances for 2-, 3-, 4-
and 5-PyC are shifted slightly upfield relative to the corre-
sponding signals in the spectra of thioamides 3Ϫ11; the sig-
nal for 3-PyC displays the largest shift. In contrast, the sig-
nal for 6-PyC in the triazole spectra is shifted downfield
quite significantly relative to that in the thioamide spectra.
The chemical shift of the signal for the triazole carbon atom
that carries the 2-pyridyl group is in the same range for
both the 4-substituted 3-phenyl-5-(2-pyridyl)-4H-1,2,4-tria-
zoles 12, 15, 18 and 21 and the 4-substituted 3,5-di(2-pyri-
dyl)-4H-1,2,4-triazoles 13, 16, 19 and 22. There is, however,
a noticeable tendency for this signal to appear at the slightly
higher values of δ ϭ 153.99Ϫ154.63 ppm for the symmetri-
cal triazoles, while in the spectra of their unsymmetrical
congeners it is observed at δ ϭ 153.15Ϫ154.04 ppm. Within
the latter group of compounds, in all cases the triazole car-
bon atom adjacent to the phenyl group resonates downfield
(δ ϭ 155.43Ϫ157.25 ppm) from the triazole carbon atom
that carries the 2-pyridyl group. In general terms it was
found that in both the 1H and 13C NMR spectra, the chemi-
cal shifts of the pyridine system are not affected by the nat-
ure of the N4-substituent of the triazole. This is also true
for the triazole carbon atoms whose chemical shifts are in-
fluenced by the substituent directly attached to them only.
Figure 2. Chemical shifts observed in the 1H NMR spectra
(CDCl3) of thioamides 3Ϫ11
Figure 3 shows the chemical shift ranges for the pyridine
and thioamido carbon atoms observed in the 13C NMR
spectra of thioamides 3Ϫ11. Apart from the chemical shifts
for the CSNH carbon atoms, which vary over a range of
almost 10 ppm, the resonances for the 6-PyC atoms show
the largest variation, ranging over about 2 ppm, while the
signals for the remaining carbon atoms are influenced by
the nature of the N-substituent to a lesser extent.
Figure 3. Chemical shifts observed in the 13C NMR spectra
(CDCl3) of thioamides 3Ϫ11
In comparison with the chemical shifts observed for the
pyridine protons in the 1H NMR spectra of thioamides
3Ϫ11, the signals of the corresponding protons in the spec-
tra of triazoles 12, 13, 15, 16, 18, 19, 21 and 22 (Figure 4)
are shifted upfield. This shift is rather small and is practi-
cally negligible for the signals for 4-, 5- and 6-PyH, whereas
it is quite significant for the 3-PyH resonance. As a result
of this, the positions of the 3- and 6-PyH signals relative to
each other in the spectra of the triazoles are inverted with
respect to their positions in the spectra of the thioamides.
Figure 5. Chemical shifts observed in the 13C NMR spectra
(CDCl3) of triazoles 12, 13, 15, 16, 18, 19, 21 and 22
X-ray Diffraction
Single crystals of ibdpt (22) were grown by slow evapor-
ation of a solution of this compound in ethyl acetate/cyclo-
Eur. J. Org. Chem. 2004, 3422Ϫ3434
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3427

M. H. Klingele, S. Brooker
FULL PAPER
hexane (2:1). A specimen was studied by X-ray diffraction, sors. The investigation of the coordination chemistry of
which unambiguously confirmed the structural assignment these new chelating ligands will be reported in due
made on the basis of the spectroscopic data. The molecular course.[9,10,26]
structure of ibdpt (22) is shown in Figure 6. As in the struc-
tures of all other 4-substituted 3,5-di(2-pyridyl)-4H-1,2,4-
triazoles,[2] the pyridineϪtriazoleϪpyridine moiety is not
planar, but the N(1)- and N(4)-pyridine rings are tilted with
respect to the triazole mean plane by 39.9(1) and 26.5(1)°,
respectively. Here too, the two pyridine rings adopt the
usual conformation; the pyridine nitrogen atoms point away
from the N2 unit of the central triazole ring and are on
opposite sides of the triazole mean plane.
Experimental Section
General Remarks: All reagents were commercially available and
were used as received. Unless stated otherwise, all solvents used
were laboratory reagent grade. Dry ethanol required for some reac-
tions was obtained by distillation from magnesium turnings. Col-
umn chromatography was carried out under gravity on Merck silica
gel 60 (200Ϫ400 mesh, 40Ϫ63 µm). For thin-layer chromatographic
analyses MachereyϪNagel Alugram SIL G/UV254 aluminium
sheets were used. Visualisation was achieved with ultraviolet light
(254 nm). Melting points were determined with a Gallenkamp
melting point apparatus in open glass capillaries and are uncor-
rected. Elemental analyses were performed by the Campbell Micro-
analytical Laboratory at the University of Otago. H and 13C nu-
1
clear magnetic resonance spectra were recorded with a Varian IN-
OVA-500 spectrometer at 25 °C. Chemical shifts are given relative
to tetramethylsilane with the residual solvent signals as secondary
reference (chloroform: δH ϭ 7.26 ppm, δC ϭ 77.16 ppm; dimethyl
sulfoxide: δH ϭ 2.50 ppm, δC ϭ 39.52 ppm).[55] Peak assignments
were made on the basis of chemical shifts, integration patterns and
coupling constants, as well as two-dimensional correlation experi-
ments where necessary. Infrared spectra were recorded with a
PerkinϪElmer Spectrum BX FT-IR spectrophotometer over the
range 4000Ϫ400 cmϪ1. All solid samples were measured as potass-
ium bromide pellets, while liquid samples were measured as films
between sodium chloride plates. Mass spectra were run on a Shim-
adzu LCMS-QP8000α spectrometer with acetonitrile as the solvent.
X-ray data were collected with a STOE IPDS diffractometer using
Figure 6. View of the molecular structure of triazole 22 (50%
thermal ellipsoids)
Conclusion
˚
graphite-monochromated Mo-Kα radiation (λ ϭ 0.71073 A). The
structure was solved by direct methods with SHELXS-97[56,57] and
refined against F2 by full-matrix least-squares techniques with
SHELXL-97.[58]
The use of a catalytic amount of sodium sulfide nona-
hydrate in combination with an excess of 2-methylpyridine
provides a convenient, efficient and widely applicable proto-
col for the preparation of N-substituted pyridine-2-thiocarb-
oxamides by means of the WillgerodtϪKindler reaction.
Since the excess 2-methylpyridine can be recovered during
workup, this process is also economical. Low-boiling vol-
atile amines can be used in this reaction as their hydrochlo-
ride salts, which removes the need to use a pressure vessel
for the preparation of the respective thioamides. This proto-
col is therefore an efficient way to conveniently prepare
these lower alkyl-substituted compounds in particular. With
this method it has been possible to increase the yields of
the respective thioamides significantly relative to previously
reported protocols. The condensation of N-substituted pyri-
dine-2-thiocarboxamides, or in some cases preferably the
corresponding ethyl carboximidothioates, i.e. their S-ethyl-
ated congeners, with hydrazides has afforded a range of new
unfused 3,4,5-trisubstituted 4H-1,2,4-triazoles in good
yields. Along with the findings by other authors, these re-
sults demonstrate that the thioamideϪhydrazide conden-
sation is a very versatile and efficient method for the prep-
aration of 3,4,5-trisubstituted 4H-1,2,4-triazoles in particu-
lar, but also for other substituted 1,2,4-triazoles that carry
any type of substituent. It seems that the only limitation of
Benzohydrazide (1): A heterogeneous mixture of methyl benzoate
(34.1 g, 0.25 mol) and hydrazine monohydrate (15.0 g, 0.30 mol)
was refluxed for 18 h during which time a clear colourless solution
was obtained. After cooling, all volatiles were evaporated under
reduced pressure, and the resulting colourless crystalline solid was
dried in vacuo. Recrystallisation from benzene/ethanol (5:1) gave
27.1 g (79%) of analytically pure benzohydrazide (1) as colourless
needles. M.p. 111Ϫ113 °C. C7H8N2O (136.15): calcd. C 61.75, H
5.92, N 20.57; found C 61.66, H 6.12, N 20.38. 1H NMR
(500 MHz, [D6]DMSO): δ ϭ 4.56 (br. s, 2 H, CONHNH2),
7.42Ϫ7.46 (m, 2 H, 3- and 5-PhH), 7.48Ϫ7.52 (m, 1 H, 4-PhH),
7.82Ϫ7.84 (m, 2 H, 2- and 6-PhH), 9.78 (br. s, 1 H, CONHNH2)
ppm. 13C{1H} NMR (125 MHz, [D6]DMSO): δ ϭ 126.96 (2- and
6-PhC), 128.31 (3- and 5-PhC), 131.06 (4-PhC), 133.33 (1-PhC),
165.94 (CONHNH2) ppm. IR (KBr): ν˜ ϭ 3299, 3206, 3019, 2874,
1661, 1616, 1566, 1487, 1446, 1349, 1289, 1121, 1004, 992, 919,
884, 802, 685, 674, 517, 414 cmϪ1. APCI-MS (pos., MeCN): m/z ϭ
137 [M ϩ H]ϩ. TLC (SiO2, EtOAc): Rf ϭ 0.23.
Pyridine-2-carbohydrazide (2): Hydrazine monohydrate (10.0 g,
0.20 mol) was added dropwise to ethyl pyridine-2-carboxylate
(15.1 g, 0.10 mol). A moderately exothermic reaction took place.
The resulting clear solution was refluxed for 18 h. After cooling,
all volatiles were evaporated under reduced pressure, and the
colourless crystalline solid thus obtained was dried in vacuo.
this method is the availability of suitably substituted precur- Recrystallisation from ethanol gave 11.4 g (83%) of analytically
3428  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 3422Ϫ3434

From N-Substituted Thioamides to Symmetrical and Unsymmetrical 3,4,5-Trisubstituted 4H-1,2,4-Triazoles
FULL PAPER
3
3
4
pure pyridine-2-carbohydrazide (2) as colourless needles. M.p.
(ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 1 H, 5-PyH), 7.84 (d,
100Ϫ102 °C. C6H7N3O (137.14): calcd. C 52.55, H 5.14, N 30.64; 3J ϭ 8.5 Hz, 2 H, 2- and 6-PhH), 7.87 (dt, J3,4
ϭ
3J4,5 ϭ 7.7,
3
found C 52.49, H 5.18, N 30.71. 1H NMR (500 MHz, [D6]DMSO):
4J4,6 ϭ 1.8 Hz, 1 H, 4-PyH), 8.53 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8,
3
4
3
3
3
4
δ ϭ 4.53 (br. s, 2 H, CONHNH2), 7.56 (ddd, J4,5 ϭ 7.7, J5,6
ϭ
5J3,6 ϭ 0.9 Hz, 1 H, 6-PyH), 8.81 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2,
4
4.8, J3,5 ϭ 1.2 Hz, 1 H, 5-PyH), 7.94Ϫ8.00 (m, 2 H, 3- and 4-
5J3,6 ϭ 0.9 Hz, 1 H, 3-PyH), 11.91 (br. s, 1 H, CSNH) ppm.
PyH), 8.60 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 1 H, 6- 13C{1H} NMR (125 MHz, CDCl3): δ ϭ 115.06 (3- and 5-PhC),
3
4
5
PyH), 9.87 (br. s, 1 H, CONHNH2) ppm. 13C{1H} NMR 124.44 (2- and 6-PhC), 124.92 (3-PyC), 125.90, (5-PyC), 130.27 (1-
(125 MHz, [D6]DMSO): δ ϭ 121.73 (3-PyC), 126.24 (5-PyC),
PhC), 137.55 (4-PyC), 145.26 (6-PyC), 146.66 (4-PhC), 151.80 (2-
137.64 (4-PyC), 148.50 (6-PyC), 149.85 (2-PyC), 162.65 PyC), 186.38 (CSNH) ppm. IR (KBr): ν˜ ϭ 3384, 3300, 3088, 1619,
(CONHNH2) ppm. IR (KBr): ν˜ ϭ 3308, 3212, 1675, 1651, 1594, 1585, 1524, 1501, 1460, 1434, 1356, 1280, 1266, 1210, 1171, 1095,
1570, 1522, 1473, 1434, 1338, 1303, 1247, 1149, 1125, 1085, 1046,
1050, 1003, 995, 924, 831, 775, 734, 701, 617, 498 cmϪ1. APCI-MS
999, 975, 819, 751, 703, 643, 621, 485, 446, 410 cmϪ1. APCI-MS (pos., MeCN): m/z ϭ 230 [M ϩ H]ϩ. APCI-MS (neg., MeCN):
(pos., MeCN): m/z ϭ 138 [M ϩ H]ϩ. TLC (SiO2, EtOAc): Rf ϭ
m/z ϭ 228 [M Ϫ H]Ϫ. TLC (SiO2, EtOAc): Rf ϭ 0.62.
0.19.
N-(4-Pyridyl)pyridine-2-thiocarboxamide (5): A mixture of 4-amino-
pyridine (9.31 g, 0.10 mol), sulfur (9.62 g, 0.30 mol) and sodium
sulfide nonahydrate (0.48 g, 2 mol %) in 2-methylpyridine (60 mL)
was refluxed for 48 h. After cooling and removal of all volatiles in
N,NЈ-(1,4-Phenylene)bis(pyridine-2-thiocarboxamide) (3): A mixture
of 1,4-phenylenediamine (2.70 g, 25.0 mmol), sulfur (4.81 g, 0.15
mol) and sodium sulfide nonahydrate (0.30 g, 5 mol %) in 2-meth-
ylpyridine (25 mL) was refluxed for 72 h. After cooling, all volatiles vacuo, the dark solid residue was taken up in 2  aqueous sodium
were removed in vacuo. The dark solid residue was suspended in hydroxide (200 mL), and the mixture was filtered. The filtrate was
ethanol (50 mL), and the mixture was refluxed for 1 hour. The diluted with water (400 mL) and acidified to pH 5 by dropwise
resulting suspension was filtered whilst hot. The orange micro-
crystalline solid thus obtained was washed with ethanol and dis-
solved in refluxing 2  aqueous sodium hydroxide (150 mL). The
dark solution was filtered whilst hot and, after cooling, was acidi-
fied to pH 5 by dropwise addition of concd. hydrochloric acid. The
resulting yellow precipitate was filtered off and washed thoroughly
with water. Drying in vacuo gave 7.04 g (80%) of essentially pure
addition of concd. hydrochloric acid. The resulting very volumin-
ous yellow precipitate was filtered off and washed thoroughly with
water. Drying in vacuo gave 16.7 g (77%) of analytically pure N-
(4-pyridyl)pyridine-2-thiocarboxamide (5) as a yellow powder. M.p.
130Ϫ132 °C. C11H9N3S (215.27): calcd. C 61.37, H 4.21, N 19.52,
S 14.89; found C 61.37, H 4.18, N 19.61, S 14.71. 1H NMR
3
3
4
(500 MHz, CDCl3): δ ϭ 7.52 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5
ϭ
3
3
4
N,NЈ-(1,4-phenylene)bis(pyridine-2-thiocarboxamide) (3) as
a
1.2 Hz, 1 H, 5-PyH), 7.91 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz,
1 H, 4-PyH), 8.15Ϫ8.17 (m, 2 H, 3Ј- and 5Ј-PyH), 8.56 (ddd,
3J5,6 ϭ 4.8, 4J4,6 ϭ 1.8, 5J3,6 ϭ 0.9 Hz, 1 H, 6-PyH), 8.66Ϫ8.68 (m,
bright yellow powder. This material could be used for subsequent
reactions without further purification. An analytically pure sample
was obtained as brown lustrous needles by recrystallisation from 2 H, 2Ј- and 6Ј-PyH), 8.73 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6
3
4
5
ϭ
1,4-dioxane. M.p. 213Ϫ215 °C. C18H14N4S2 (350.47): calcd. C
0.9 Hz, 1 H, 3-PyH), 12.23 (br. s, 1 H, CSNH) ppm. 13C{1H} NMR
61.68, H 4.03, N 15.99, S 18.30; found C 61.59, H 3.97, N 15.99,
S 18.00. H NMR (500 MHz, CDCl3): δ ϭ 7.49 (ddd, J4,5 ϭ 7.7,
(125 MHz, CDCl3): δ ϭ 115.47 (3Ј- and 5Ј-PyC), 124.90 (3-PyC),
126.65 (5-PyC), 137.90 (4-PyC), 145.58 (4Ј-PyC), 146.72 (6-PyC),
150.96 (2Ј- and 6Ј-PyC), 151.13 (2-PyC), 189.66 (CSNH) ppm. IR
1
3
4
3
3J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 2 H, 2 ϫ 5-PyH), 7.90 (dt, J3,4
ϭ
4
3J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 2 H, 2 ϫ 4-PyH), 8.25 (s, 4 H, 4 ϫ (KBr): ν˜ ϭ 3170, 1598, 1576, 1519, 1462, 1441, 1408, 1358, 1330,
3
4
5
PhH), 8.57 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 2 H, 2 ϫ
1301, 1256, 1227, 1158, 1100, 1043, 998, 989, 841, 815, 778, 737,
6-PyH), 8.81 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 2 H, 2 622, 562, 529 cmϪ1. APCI-MS (pos., MeCN): m/z ϭ 216 [M ϩ
3
4
5
ϫ 3-PyH), 12.18 (br. s, 2 H, 2 ϫ CSNH) ppm. 13C{1H} NMR H]ϩ. APCI-MS (neg., MeCN): m/z ϭ 214 [M Ϫ H]Ϫ. TLC (SiO2,
(125 MHz, CDCl3): δ ϭ 122.99 (4 ϫ PhCH), 124.95 (2 ϫ 3-PyC),
126.24 (2 ϫ 5-PyC), 136.84 (2 ϫ PhCq), 137.72 (2 ϫ 4-PyC), 146.72
(2 ϫ 6-PyC), 151.58 (2 ϫ 2-PyC), 187.60 (2 ϫ CSNH) ppm. IR
(KBr): ν˜ ϭ 3122, 1583, 1545, 1510, 1453, 1434, 1417, 1391, 1362,
1315, 1280, 1195, 1089, 1040, 992, 839, 779, 740, 718, 617, 523
cmϪ1. APCI-MS (pos., MeCN): m/z ϭ 351 [M ϩ H]ϩ. APCI-MS
(neg., MeCN): m/z ϭ 349 [M Ϫ H]Ϫ. TLC (SiO2, EtOAc): Rf ϭ
0.66.
EtOAc): Rf ϭ 0.28.
N-(4-Methylphenyl)pyridine-2-thiocarboxamide (6): A mixture of 4-
methylaniline (10.7 g, 0.10 mol), sulfur (9.62 g, 0.30 mol) and so-
dium sulfide nonahydrate (0.48 g, 2 mol %) in 2-methylpyridine
(60 mL) was refluxed for 48 h. After cooling and removal of all
volatiles in vacuo, the dark solid residue was taken up in dichloro-
methane (200 mL), and the mixture was filtered through a column
of silica gel. The filtrate was evaporated under reduced pressure,
and the resulting solid was dried in vacuo. Recrystallisation from
N-(4-Aminophenyl)pyridine-2-thiocarboxamide (4): A mixture of
1,4-phenylenediamine (2.70 g, 25.0 mmol), sulfur (1.92 g, ethanol gave 18.1 g (79%) of analytically pure N-(4-methylphe-
60.0 mmol), 2-methylpyridine (4.66 g, 50.0 mmol) and sodium sulf- nyl)pyridine-2-thiocarboxamide (6) as a yellow crystalline solid.
ide nonahydrate (0.30 g, 5 mol %) was heated at 150 °C for 18 h. M.p. 99Ϫ101 °C. C13H12N2S (228.31): calcd. C 68.39, H 5.30, N
1
After cooling, 2  aqueous sodium hydroxide (50 mL) was added,
and the mixture was filtered. The filtrate was acidified to pH 5 by
dropwise addition of concd. hydrochloric acid, and the resulting
yellow precipitate was filtered off and washed thoroughly with
water. Drying in vacuo gave 3.35 g (58%) of essentially pure N-(4-
aminophenyl)pyridine-2-thiocarboxamide (4) as a yellow powder.
An analytically pure sample was obtained as orange-brown blocks
by recrystallisation from acetonitrile. M.p. 145Ϫ147 °C. C12H11N3S
(229.31): calcd. C 62.86, H 4.84, N 18.32, S 13.98; found C 62.69,
12.27, S 14.04; found C 68.10, H 5.58, N 12.40, S 13.88. H NMR
(500 MHz, CDCl3): δ ϭ 2.38 (s, 3 H, PhCH3), 7.26 (d, 3J ϭ 8.4 Hz,
2 H, 3- and 5-PhH), 7.46 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5
1.2 Hz, 1 H, 5-PyH), 7.87 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz,
3
3
4
ϭ
3
3
4
3
1 H, 4-PyH), 7.93 (d, J ϭ 8.4 Hz, 2 H, 2- and 6-PhH), 8.54 (ddd,
3J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 1 H, 6-PyH), 8.80 (ddd,
4
5
3J3,4 ϭ 7.7, J3,5 ϭ 1.2, 5J3,6 ϭ 0.9 Hz, 1 H, 3-PyH), 11.99 (br. s, 1
4
H, CSNH) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ 21.29
(PhCH3), 122.87 (2- and 6-PhC), 124.93 (3-PyC), 126.05 (5-PyC),
129.54 (3- and 5-PhC), 136.35 (1-PhC), 136.63 (4-PhC), 137.54 (4-
1
H 4.97, N 18.53, S 13.72. H NMR (500 MHz, CDCl3): δ ϭ 3.79
(br. s, 2 H, PhNH2), 6.75 (d, 3J ϭ 8.5 Hz, 2 H, 3- and 5-PhH), 7.44 PyC), 146.64 (6-PyC), 151.60 (2-PyC), 187.66 (CSNH) ppm. IR
Eur. J. Org. Chem. 2004, 3422Ϫ3434
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3429

M. H. Klingele, S. Brooker
FULL PAPER
(KBr): ν˜ ϭ 3197, 1586, 1535, 1512, 1458, 1435, 1380, 1197, 1147, The resulting dark oily residue solidified with difficulty. It was
1093, 1038, 993, 829, 808, 792, 757, 736, 666, 618, 507 cmϪ1. APCI-
MS (pos., MeCN): m/z ϭ 229 [M ϩ H]ϩ. APCI-MS (neg., MeCN):
m/z ϭ 227 [M Ϫ H]Ϫ. TLC (SiO2, EtOAc): Rf ϭ 0.69.
taken up in dichloromethane (200 mL), and the solution was
washed with 2  hydrochloric acid (50 mL) and water (50 mL), and
dried with anhydrous sodium sulfate. The solution was then filtered
through a column of silica gel. The filtrate was evaporated under
reduced pressure, and the resulting orange solid was dried in vacuo.
Recrystallisation from ethanol gave 10.2 g (44%) of analytically
pure N-benzylpyridine-2-thiocarboxamide (9) as a yellow crystal-
line solid. M.p. 75Ϫ77 °C. C13H12N2S (228.31): calcd. C 68.39, H
5.30, N 12.27, S 14.04; found C 68.64, H 5.21, N 12.45, S 13.90. 1H
NMR (500 MHz, CDCl3): δ ϭ 5.07 (d, 3J ϭ 5.5 Hz, 2 H, PhCH2),
N-(2,4,6-Trimethylphenyl)pyridine-2-thiocarboxamide (7): The reac-
tion of 2,4,6-trimethylaniline (13.5 g, 0.10 mol), sulfur (9.62 g, 0.30
mol), sodium sulfide nonahydrate (0.48 g, 2 mol %) and 2-methyl-
pyridine (60 mL), following the procedure described above for the
preparation of N-(4-methylphenyl)-2-pyrdinethiocarboxamide (6),
gave 19.1 g (74%) of analytically pure N-(2,4,6-trimethylphe-
nyl)pyridine-2-thiocarboxamide (7) as yellow-brown lustrous flakes.
M.p. 117Ϫ119 °C. C15H16N2S (256.37): calcd. C 70.28, H 6.29, N
3
3
7.32Ϫ7.44 (m, 6 H, 5-PyH and 5 ϫ PhH), 7.84 (dt, J3,4 ϭ J4,5
ϭ
7.7, 4J4,6 ϭ 1.8 Hz, 1 H, 4-PyH), 8.45 (ddd, 3J5,6 ϭ 4.8, 4J4,6 ϭ 1.8,
1
10.93, S 12.51; found C 70.21, H 6.41, N 11.22, S 12.27. H NMR
3
4
5J3,6 ϭ 0.9 Hz, 1 H, 6-PyH), 8.73 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2,
5J3,6 ϭ 0.9 Hz, 1 H, 3-PyH), 10.38 (br. s, 1 H, CSNH) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ ϭ 50.03 (PhCH2), 125.09 (3-
PyC), 126.20 (5-PyC), 128.09 (4-PhC), 128.41 (2- and 6-PhC),
129.03 (3- and 5-PhC), 136.52 (1-PhC), 137.38 (4-PyC), 147.06 (6-
PyC), 151.11 (2-PyC), 191.02 (CSNH) ppm. IR (KBr): ν˜ ϭ 3237,
1514, 1453, 1435, 1377, 1337, 1326, 1278, 1242, 1197, 1073, 996,
944, 794, 751, 734, 698, 497 cmϪ1. APCI-MS (pos., MeCN): m/z ϭ
229 [M ϩ H]ϩ. APCI-MS (neg., MeCN): m/z ϭ 227 [M Ϫ H]Ϫ.
TLC (SiO2, EtOAc): Rf ϭ 0.71.
(500 MHz, CDCl3): δ ϭ 2.22 (s, 6 H, 2- and 6-PhCH3), 2.33 (s, 3
3
H, 4-PhCH3), 6.99 (s, 2 H, 3- and 5-PhH), 7.50 (ddd, J4,5 ϭ 7.7,
4
3
3
3J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 1 H, 5-PyH), 7.89 (dt, J3,4 ϭ J4,5
ϭ
7.7, 4J4,6 ϭ 1.8 Hz, 1 H, 4-PyH), 8.58 (ddd, 3J5,6 ϭ 4.8, 4J4,6 ϭ 1.8,
3
4
5J3,6 ϭ 0.9 Hz, 1 H, 6-PyH), 8.80 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2,
5J3,6 ϭ 0.9 Hz, 1 H, 3-PyH), 11.29 (br. s, 1 H, CSNH) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ ϭ 18.19 (2- and 6-PhCH3),
21.23 (4-PhCH3), 125.02 (3-PyC), 126.27 (5-PyC), 129.19 (3- and
5-PhC), 133.84 (1-PhC), 135.10 (2- and 6-PhC), 137.43 (4-PyC),
137.98 (4-PhC), 147.09 (6-PyC), 151.14 (2-PyC), 191.27 (CSNH)
ppm. IR (KBr): ν˜ ϭ 3268, 2975, 2947, 2908, 2852, 1585, 1565,
1499, 1460, 1431, 1422, 1366, 1259, 1212, 1139, 1093, 1044, 1006,
992, 853, 805, 790, 757, 743, 701, 661, 648, 617, 601, 574, 505, 407
cmϪ1. APCI-MS (pos., MeCN): m/z ϭ 257 [M ϩ H]ϩ. APCI-MS
(neg., MeCN): m/z ϭ 255 [M Ϫ H]Ϫ. TLC (SiO2, EtOAc): Rf ϭ
0.72.
N-Isobutylpyridine-2-thiocarboxamide (10): A mixture of pyridine-
2-thiocarboxamide (11) (9.67 g, 70.0 mmol) and isobutylamine
(35 mL) was refluxed for 2 h. All volatiles were then evaporated
under reduced pressure, and the residue was dissolved in dichloro-
methane (100 mL). The solution was washed with water (50 mL)
and sat. aqueous sodium chloride (50 mL), and dried with anhy-
drous sodium sulfate. Evaporation of the solvent under reduced
pressure, and distillation of the residue in vacuo gave 11.1 g (81%)
of analytically pure N-isobutylpyridine-2-thiocarboxamide (10) as
a golden liquid. C10H14N2S (194.29): calcd. C 61.82, H 7.26, N
N-Methylpyridine-2-thiocarboxamide (8): A mixture of methyl-
amine hydrochloride (13.5 g, 0.20 mol), sulfur (19.2 g, 0.60 mol)
and sodium sulfide nonahydrate (0.96 g, 2 mol %) in 2-methylpyri-
dine (80 mL) was refluxed for 24 h. After cooling, all volatiles were
removed in vacuo. The dark residue was taken up in 6  hydro-
chloric acid (200 mL), and the mixture was filtered. Solid sodium
hydroxide (48.0 g, 1.20 mol) was added to the filtrate in portions
at 0 °C, followed by 2  aqueous sodium hydroxide until the aque-
ous phase was neutral. The resulting heterogeneous mixture was
extracted with dichloromethane (5 ϫ 100 mL). The combined or-
ganic layers were dried with anhydrous sodium sulfate and filtered
through a column of silica gel. The filtrate was evaporated under
reduced pressure, and the brown crystalline solid thus obtained was
dried in vacuo. Recrystallisation from cyclohexane/ethyl acetate
(5:1) gave 21.1 g (69%) of analytically pure N-methylpyridine-2-
thiocarboxamide (8) as yellow prisms. M.p. 75Ϫ77 °C. C7H8N2S
(152.21): calcd. C 55.24, H 5.30, N 18.40, S 21.06; found C 55.29,
1
14.42, S 16.50; found C 62.10, H 7.47, N 14.23, S 16.33. H NMR
(500 MHz, CDCl3): δ ϭ 1.05 [d, 3J ϭ 6.8 Hz, 6 H, CH2CH(CH3)2],
3
3
2.16 [non, J ϭ 6.8 Hz, 1 H, CH2CH(CH3)2], 3.70 [dd, JC,H,CH
ϭ
3
3
6.8, JC,H,NH ϭ 5.8 Hz, 2 H, CH2CH(CH3)2], 7.41 (ddd, J4,5
ϭ
7.7, 3J5,6 ϭ 4.8, 4J3,5 ϭ 1.2 Hz, 1 H, 5-PyH), 7.82 (dt, 3J3,4 ϭ 3J4,5 ϭ
7.7, 4J4,6 ϭ 1.8 Hz, 1 H, 4-PyH), 8.48 (ddd, 3J5,6 ϭ 4.8, 4J4,6 ϭ 1.8,
5J3,6 ϭ 0.9 Hz, 1 H, 6-PyH), 8.70 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2,
5J3,6 ϭ 0.9 Hz, 1 H, 3-PyH), 10.26 (br. s, 1 H, CSNH) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ ϭ 20.60 [CH2CH(CH3)2],
27.78 [CH2CH(CH3)2], 53.24 [CH2CH(CH3)2], 124.93 (3-PyC),
126.05 (5-PyC), 137.33 (4-PyC), 147.00 (6-PyC), 151.23 (2-PyC),
190.80 (CSNH) ppm. IR (neat): ν˜ ϭ 3290, 2957, 1586, 1519, 1461,
1434, 1332, 1282, 1257, 1214, 1097, 1067, 1043, 999, 970, 795, 742
cmϪ1. APCI-MS (pos., MeCN): m/z ϭ 195 [M ϩ H]ϩ. APCI-MS
(neg., MeCN): m/z ϭ 193 [M Ϫ H]Ϫ. TLC (SiO2, EtOAc): Rf ϭ
0.72.
3
4
1
H 5.26, N 18.29, S 20.86. H NMR (500 MHz, CDCl3): δ ϭ 3.39
3
3
(d, 3J ϭ 5.1 Hz, 3 H, CH3), 7.41 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8,
4J3,5 ϭ 1.2 Hz, 1 H, 5-PyH), 7.81 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6
1.8 Hz, 1 H, 4-PyH), 8.47 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6
0.9 Hz, 1 H, 6-PyH), 8.69 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6
ϭ
ϭ
ϭ
3
3
4
3
4
5
Pyridine-2-thiocarboxamide (11): A solution of pyridine-2-car-
bonitrile (15.6 g, 0.15 mol) in dry ethanol (150 mL) was saturated
with gaseous ammonia, and a slow stream of hydrogen sulfide was
then passed through the solution for 1 h. The resulting yellow sus-
pension was stirred at room temperature for 2 h and was then eva-
porated to dryness under reduced pressure. The residue was dis-
solved in dichloromethane (500 mL), and the solution was washed
with water (100 mL) and sat. aqueous sodium chloride (100 mL),
and dried with anhydrous sodium sulfate. Evaporation of the sol-
vent under reduced pressure, and drying of the residue in vacuo
gave 18.0 g (86%) of essentially pure pyridine-2-thiocarboxamide
(11) as yellow prisms. This material could be used for subsequent
reactions without further purification. An analytically pure sample
3
4
5
0.9 Hz, 1 H, 3-PyH), 10.21 (br. s, 1 H, CSNH) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ ϭ 32.72 (CH3), 124.69 (3-PyC), 126.09 (5-
PyC), 137.34 (4-PyC), 147.00 (6-PyC), 151.15 (2-PyC), 191.85
(CSNH) ppm. IR (KBr): ν˜ ϭ 3272, 1585, 1533, 1438, 1351, 1271,
1224, 1163, 1100, 1045, 993, 956, 796, 743, 702, 604 cmϪ1. APCI-
MS (pos., MeCN): m/z ϭ 153 [M ϩ H]ϩ. APCI-MS (neg., MeCN):
m/z ϭ 151 [M Ϫ H]Ϫ. TLC (SiO2, EtOAc): Rf ϭ 0.68.
N-Benzylpyridine-2-thiocarboxamide (9): A mixture of benzylamine
(10.7 g, 0.10 mol), sulfur (9.62 g, 0.30 mol) and sodium sulfide
nonahydrate (0.48 g, 2 mol %) in 2-methylpyridine (60 mL) was re-
fluxed for 48 h. After cooling, all volatiles were removed in vacuo.
3430
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3422Ϫ3434

From N-Substituted Thioamides to Symmetrical and Unsymmetrical 3,4,5-Trisubstituted 4H-1,2,4-Triazoles
FULL PAPER
was obtained as large yellow needles by recrystallisation from
cyclohexane/ethyl acetate (5:1). M.p. 138Ϫ140 °C. C6H6N2S
(138.19): calcd. C 52.15, H 4.38, N 20.27, S 23.20; found C 51.97,
was added to a solution of sodium ethoxide, prepared by dissolving
sodium (1.15 g, 50.0 mmol) in dry ethanol (200 mL), and the reac-
tion mixture was stirred at room temperature for 30 minutes.
Bromoethane (5.45 g, 50.0 mmol) was then added to the resulting
orange-brown solution, and the reaction mixture was heated at 50
1
H 4.25, N 20.26, S 23.02. H NMR (500 MHz, CDCl3): δ ϭ 7.45
(ddd, 3J4,5 ϭ 7.7, 3J5,6 ϭ 4.8, 4J3,5 ϭ 1.2 Hz, 1 H, 5-PyH), 7.83 (dt,
3
4
3J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 1 H, 4-PyH), 7.90 (br. s, 1 H, °C for 6 h during which time some sodium bromide precipitated.
cis-CSNH), 8.51 (ddd, 3J5,6 ϭ 4.8, 4J4,6 ϭ 1.8, 5J3,6 ϭ 0.9 Hz, 1 H, After allowing the suspension to cool to room temperature, it was
3
4
5
6-PyH), 8.69 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 1 H, 3-
PyH), 9.54 (br. s, 1 H, trans-CSNH) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ ϭ 125.20 (3-PyC), 126.51 (5-PyC), 137.27 (4-
filtered, and the filtrate was evaporated under reduced pressure.
The residue was taken up in dichloromethane (150 mL), and the
mixture was washed with water (3 ϫ 50 mL), sat. aqueous sodium
PyC), 147.33 (6-PyC), 150.61 (2-PyC), 195.98 (CSNH2) ppm. IR carbonate (50 mL) and sat. aqueous sodium chloride (50 mL), and
(KBr): ν˜ ϭ 3346, 3235, 3147, 1600, 1582, 1565, 1441, 1397, 1305,
dried with anhydrous sodium sulfate. Evaporation of the solvent
1275, 1256, 1046, 994, 901, 795, 725, 671, 526, 438 cmϪ1. APCI- under reduced pressure, and drying of the residue in vacuo gave
MS (pos., MeCN): m/z ϭ 139 [M ϩ H]ϩ. APCI-MS (neg., MeCN): 12.6 g (98%) of crude ethyl N-(4-methylphenyl)pyridine-2-carbox-
m/z ϭ 137 [M Ϫ H]Ϫ. TLC (SiO2, EtOAc): Rf ϭ 0.68.
imidothioate (14) as an orange oil. This material could be used
in subsequent reactions without further purification. C15H16N2S
3-Phenyl-5-(2-pyridyl)-4-(4-pyridyl)-4H-1,2,4-triazole (pyppt, 12): A
mixture of N-(4-pyridyl)pyridine-2-thiocarboxamide (5) (4.30 g,
20.0 mmol) and benzohydrazide (1) (3.27 g, 24.0 mmol) in 1-buta-
nol (80 mL) was refluxed for 24 h. On cooling, the product crystal-
lised from the orange reaction mixture. It was filtered off, washed
with ethanol and dried in vacuo to give 4.71 g (78%) of analytically
pure pyppt (12) as fine colourless needles. M.p. 251Ϫ253 °C.
C18H13N5 (299.33): calcd. C 72.23, H 4.38, N 23.40; found C 72.25,
3
(256.37). 1H NMR (500 MHz, CDCl3): δ ϭ 1.05 (t, J ϭ 7.4 Hz, 3
H, SCH2CH3), 2.31 (s, 3 H, PhCH3), 2.70 (q, 3J ϭ 7.4 Hz, 2 H,
SCH2CH3), 6.60 (d, 3J ϭ 8.4 Hz, 2- and 6-PhH), 6.92 (d, 3J ϭ
3
3
4
8.4 Hz, 3- and 5-PhH), 7.17 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5
ϭ
ϭ
3
4
5
1.2 Hz, 1 H, 5-PyH), 7.45 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6
0.9 Hz, 1 H, 3-PyH), 7.81 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz,
3
3
4
3
4
5
1 H, 4-PyH), 8.65 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 1
H, 6-PyH) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ 15.03
(SCH2CH3), 21.00 (PhCH3), 27.22 (SCH2CH3), 121.67 (2- and 6-
PhC), 123.16 (3-PyC), 124.39 (5-PyC), 129.51 (3- and 5-PhC),
137.06 (4-PyC), 149.60 (6-PyC), 156.13 (2-PyC), 164.29 (CNS)
ppm. ESI-MS (pos., MeCN): m/z ϭ 257 [M ϩ H]ϩ.
1
H 4.44, N 23.67. H NMR (500 MHz, CDCl3): δ ϭ 7.15Ϫ7.17 (m,
3
3
4
2 H, 3Ј- and 5Ј-PyH), 7.25 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5
ϭ
1.2 Hz, 1 H, 5-PyH), 7.30Ϫ7.34 (m, 2 H, 3- and 5-PhH), 7.38Ϫ7.42
3
4
(m, 3 H, 2-, 4- and 6-PhH), 7.81 (dt, J3,4
ϭ
3J4,5 ϭ 7.7, J4,6
ϭ
ϭ
ϭ
3
4
5
1.8 Hz, 1 H, 4-PyH), 8.26 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6
0.9 Hz, 1 H, 3-PyH), 8.28 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6
3
4
5
4-(4-Methylphenyl)-3-phenyl-5-(2-pyridyl)-4H-1,2,4-triazole (pmppt,
15): A mixture of crude ethyl N-(4-methylphenyl)pyridine-2-carb-
oximidothioate (14) (5.13 g, 20.0 mmol) and benzohydrazide (1)
(3.27 g, 24.0 mmol) in 1-butanol (50 mL) was refluxed for 24 h. On
cooling, the product crystallised from the orange reaction mixture.
It was filtered off and washed with ethanol. Drying in vacuo gave
3.28 g (52%) of analytically pure pmppt (15) as very fine colourless
needles. Evaporation of the filtrate and recrystallisation of the solid
residue from 2-propanol gave another 0.87 g (13%) of analytically
pure material. M.p. 241Ϫ243 °C. C20H16N4 (312.37): calcd. C
0.9 Hz, 1 H, 6-PyH), 8.65Ϫ8.67 (m, 2 H, 2Ј- and 6Ј-PyH) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ ϭ 123.03 (3Ј- and 5Ј-PyC),
124.30 (3-PyC), 124.38 (5-PyC), 126.31 (1-PhC), 128.80 (3- and 5-
PhC), 129.12 (2- and 6-PhC), 130.31 (4-PhC), 137.04 (4-PyC),
144.05 (4Ј-PyC), 146.62 (2-PyC), 148.89 (6-PyC), 151.12 (2Ј- and
6Ј-PyC), 153.21 (5-TzC), 155.43 (3-TzC) ppm. IR (KBr): ν˜ ϭ 3055,
3035, 1591, 1569, 1508, 1469, 1451, 1419, 1217, 1165, 1087, 1074,
989, 846, 789, 771, 739, 712, 693, 631, 608, 500 cmϪ1. ESI-MS
(pos., MeCN): m/z ϭ 300 [M ϩ H]ϩ, 322 [M ϩ Na]ϩ, 338 [M ϩ
K]ϩ. TLC (SiO2, EtOAc): Rf ϭ 0.12.
1
76.90, H 5.16, N 17.94; found C 76.62, H 5.20, N 17.85. H NMR
3
(500 MHz, CDCl3): δ ϭ 2.39 (s, 3 H, CH3), 7.08 (d, J ϭ 8.4 Hz,
3,5-Di(2-pyridyl)-4-(4-pyridyl)-4H-1,2,4-triazole (pydpt, 13): The re-
action of N-(4-pyridyl)pyridine-2-thiocarboxamide (5) (4.30 g,
20.0 mmol) and pyridine-2-carbohydrazide (2) (3.29 g, 24.0 mmol)
in 1-butanol (80 mL), following the procedure described above for
the preparation of pyppt (12), gave 4.20 g (69%) of analytically pure
pydpt (13) as fine colourless needles. M.p. 264Ϫ266 °C. C17H12N6
(300.32): calcd. C 67.99, H 4.03, N 27.98; found C 67.92, H 3.86,
N 28.14. 1H NMR (500 MHz, CDCl3): δ ϭ 7.20Ϫ7.22 (m, 2 H, 3Ј-
2 H, 2- and 6-PhMeH), 7.16 (d, 3J ϭ 8.4 Hz, 2 H, 3- and 5-PhMeH),
3
3
4
7.22 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 1 H, 5-PyH),
7.27Ϫ7.31 (m, 2 H, 3- and 5-PhH), 7.33Ϫ7.37 (m, 1 H, 4-PhH),
3
7.44Ϫ7.47 (m, 2 H, 2- and 6-PhH), 7.74 (dt, J3,4
ϭ
3J4,5 ϭ 7.7,
4J4,6 ϭ 1.8 Hz, 1 H, 4-PyH), 8.05 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2,
3
4
5J3,6 ϭ 0.9 Hz, 1 H, 3-PyH), 8.37 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8,
5J3,6 ϭ 0.9 Hz, 1 H, 6-PyH) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ ϭ 21.42 (CH3), 123.93 (5-PyC), 124.55 (3-PyC), 127.15
(1-PhC), 127.82 (2- and 6-PhMeC), 128.49 (3- and 5-PhC), 129.01
(2- and 6-PhC), 129.75 (4-PhC), 129.91 (3- and 5-PhMeC), 133.31
(1-PhMeC), 136.65 (4-PyC), 139.19 (4-PhMeC), 147.34 (2-PyC),
149.14 (6-PyC), 154.04 (5-TzC), 155.75 (3-TzC) ppm. IR (KBr):
ν˜ ϭ 1583, 1566, 1537, 1513, 1469, 1451, 1433, 1407, 1275, 1165,
1050, 999, 975, 849, 823, 796, 774, 743, 718, 709, 693, 622, 603
cmϪ1. ESI-MS (pos., MeCN): m/z ϭ 313 [M ϩ H]ϩ, 335 [M ϩ
Na]ϩ, 351 [M ϩ K]ϩ. TLC (SiO2, EtOAc): Rf ϭ 0.21.
3
4
3
3
4
and 5Ј-PyH), 7.24 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 2
3
3
4
H, 2 ϫ 5-PyH), 7.79 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 2 H,
3
4
5
2 ϫ 4-PyH), 8.21 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 2
3
4
5
H, 2 ϫ 3-PyH), 8.28 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz,
2 H, 2 ϫ 6-PyH), 8.62Ϫ8.64 (m, 2 H, 2Ј- and 6Ј-PyH) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ ϭ 123.28 (3Ј- and 5Ј-PyC),
124.39 (2 ϫ 5-PyC), 124.49 (2 ϫ 3-PyC), 136.94 (2 ϫ 4-PyC),
144.90 (4Ј-PyC), 146.53 (2 ϫ 2-PyC), 148.99 (2 ϫ 6-PyC), 150.41
(2Ј- and 6Ј-PyC), 153.99 (3- and 5-TzC) ppm. IR (KBr): ν˜ ϭ 3060,
3037, 1595, 1586, 1573, 1509, 1464, 1445, 1431, 1421, 1174, 1148,
1087, 844, 791, 744, 714, 686, 637, 606 cmϪ1. ESI-MS (pos.,
MeCN): m/z ϭ 301 [M ϩ H]ϩ, 323 [M ϩ Na]ϩ, 339 [M ϩ K]ϩ.
TLC (SiO2, EtOAc): Rf ϭ 0.06.
4-(4-Methylphenyl)-3,5-di(2-pyridyl)-4H-1,2,4-triazole (pmdpt, 16):
The reaction of crude ethyl N-(4-methylphenyl)pyridine-2-carbox-
imidothioate (14) (5.13 g, 20.0 mmol) and pyridine-2-carbohydra-
zide (2) (3.29 g, 24.0 mmol) in 1-butanol (50 mL), following the
procedure described above for the preparation of pmppt (15), gave
3.18 g (50%) of analytically pure pmdpt (16) as very fine colourless
Ethyl N-(4-Methylphenyl)pyridine-2-carboximidothioate (14): N-(4-
Methylphenyl)pyridine-2-thiocarboxamide (6) (11.4 g, 50.0 mmol)
Eur. J. Org. Chem. 2004, 3422Ϫ3434
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3431

M. H. Klingele, S. Brooker
FULL PAPER
needles. Evaporation of the filtrate, and recrystallisation of the
solid residue from 2-propanol gave another 1.35 g (21%) of analyti-
24.0 mmol) in 1-butanol (50 mL), following the procedure de-
scribed above for the preparation of meppt (18), gave 2.49 g (52%)
cally pure material. M.p. 204Ϫ206 °C. C19H15N5 (313.36): calcd. C of analytically pure medpt (19) as colourless flakes. M.p. 175Ϫ177
1
72.84, H 4.80, N 22.47; found C 72.82, H 4.76, N 22.56. H NMR °C. C13H11N5 (237.26): calcd. C 65.81, H 4.67, N 29.52; found C
1
(500 MHz, CDCl3): δ ϭ 2.37 (s, 3 H, CH3), 7.09Ϫ7.14 (m, 4 H, 2-
65.81, H 4.64, N 29.58. H NMR (500 MHz, CDCl3): δ ϭ 4.43 (s,
3
3
4
3
3
4
, 3-, 5- and 6-PhMeH), 7.22 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5
ϭ
3 H, CH3), 7.33 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 2 H,
2 ϫ 5-PyH), 7.82 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 2 H, 2 ϫ
4-PyH), 8.28 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 2 H, 2
ϫ 3-PyH), 8.67 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 2 H,
3
4
3
3
4
1.2 Hz, 2 H, 2 ϫ 5-PyH), 7.73 (dt, J3,4
ϭ
3J4,5 ϭ 7.7, J4,6
ϭ
1.8 Hz, 2 H, 2 ϫ 4-PyH), 7.98 (ddd, 3J3,4 ϭ 7.7, 4J3,5 ϭ 1.2, 5J3,6 ϭ
0.9 Hz, 2 H, 2 ϫ 3-PyH), 8.40 (ddd, 3J5,6 ϭ 4.8, 4J4,6 ϭ 1.8, 5J3,6 ϭ
3
4
5
3
4
5
0.9 Hz, 2 H, 2 ϫ 6-PyH) ppm. 13C{1H} NMR (125 MHz, CDCl3): 2 ϫ 6-PyH) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ 34.97
δ ϭ 21.40 (CH3), 124.00 (2 ϫ 5-PyC), 124.71 (2 ϫ 3-PyC), 127.76 (CH3), 124.03 (2 ϫ 5-PyC), 124.48 (2 ϫ 3-PyC), 137.00 (2 ϫ 4-
(2- and 6-PhMeC), 129.31 (3- and 5-PhMeC), 133.67 (1-PhMeC),
PyC), 148.22 (2 ϫ 2-PyC), 148.89 (2 ϫ 6-PyC), 154.22 (3- and 5-
136.59 (2 ϫ 4-PyC), 138.60 (4-PhMeC), 147.20 (2 ϫ 2-PyC), 149.29 TzC) ppm. IR (KBr): ν˜ ϭ 3041, 1586, 1571, 1512, 1485, 1458, 1431,
(2 ϫ 6-PyC), 154.63 (3- and 5-TzC) ppm. IR (KBr): ν˜ ϭ 1582, 1283, 1251, 1146, 1094, 992, 889, 793, 735, 724, 706, 674, 620, 567,
1568, 1541, 1514, 1460, 1444, 1428, 1244, 1173, 1093, 1045, 995,
490 cmϪ1. ESI-MS (pos., MeCN): m/z ϭ 238 [M ϩ H]ϩ, 260 [M
844, 821, 799, 787, 742, 642, 625, 602 cmϪ1. ESI-MS (pos., MeCN): ϩ Na]ϩ, 276 [M ϩ K]ϩ. TLC (SiO2, EtOAc): Rf ϭ 0.12.
m/z ϭ 314 [M ϩ H]ϩ, 336 [M ϩ Na]ϩ, 352 [M ϩ K]ϩ. TLC (SiO2,
Ethyl N-Isobutylpyridine-2-carboximidothioate (20): The reaction of
N-(isobutyl)pyridine-2-thiocarboxamide (11) (9.72 g, 50.0 mmol)
and bromoethane (5.45 g, 50.0 mmol) in the presence of sodium
ethoxide, prepared by dissolving sodium (1.15 g, 50.0 mmol) in dry
ethanol (200 mL), following the procedure described above for the
preparation of ethyl N-(4-methylphenyl)pyridine-2-carboximido-
thioate (14) gave 10.0 g (89%) of crude ethyl N-(isobutyl)pyridine-
2-carboximidothioate (20) as an orange oil. This material could be
used in subsequent reactions without further purification.
C12H18N2S (222.35). 1H NMR (500 MHz, CDCl3): δ ϭ 0.99 [d,
3J ϭ 6.8 Hz, 6 H, NCH2CH(CH3)2], 1.07 (t, 3J ϭ 7.4 Hz, 3 H,
SCH2CH3), 2.08 [non, 3J ϭ 6.8 Hz, 1 H, NCH2CH(CH3)2], 2.75
(q, 3J ϭ 7.4 Hz, 2 H, SCH2CH3), 3.42 [d, 3J ϭ 6.8 Hz, 2 H,
NCH2CH(CH3)2], 7.27 (ddd, 3J4,5 ϭ 7.7, 3J5,6 ϭ 4.8, 4J3,5 ϭ 1.2 Hz,
EtOAc): Rf ϭ 0.13.
Ethyl N-Methylpyridine-2-carboximidothioate (17): The reaction of
N-methylpyridine-2-thiocarboxamide (9) (7.91 g, 50.0 mmol) and
bromoethane (5.45 g, 50.0 mmol) in the presence of sodium ethox-
ide, prepared by dissolving sodium (1.15 g, 50.0 mmol) in dry etha-
nol (200 mL), following the procedure described above for the prep-
aration of ethyl N-(4-methylphenyl)pyridine-2-carboximidothioate
(14) gave 8.39 g (93%) of crude ethyl N-methylpyridine-2-carboxim-
idothioate (17) as an orange oil. This material could be used in
subsequent reactions without further purification. C9H12N2S
(180.27). 1H NMR (500 MHz, CDCl3): δ ϭ 1.07 (t, 3J ϭ 7.4 Hz, 3
H, SCH2CH3), 2.77 (q, 3J ϭ 7.4 Hz, 2 H, SCH2CH3), 3.43 (s, 3 H,
3
3
4
NCH3), 7.27 (ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 1 H, 5-
3
4
5
PyH), 7.55 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 1 H, 3-
3
4
5
1 H, 5-PyH), 7.59 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 1
3
4
PyH), 7.72 (dt, J3,4
ϭ
3J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 1 H, 4-PyH),
3
4
H, 3-PyH), 7.73 (dt, J3,4
ϭ
3J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 1 H, 4-
3
4
5
8.60 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 1 H, 6-PyH)
ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ 15.51 (SCH2CH3),
26.80 (SCH2CH3), 41.27 (NCH3), 122.91 (3-PyC), 123.95 (5-PyC),
136.99 (4-PyC), 148.77 (6-PyC), 156.21 (2-PyC), 165.32 (CNS)
ppm. ESI-MS (pos., MeCN): m/z ϭ 181 [M ϩ H]ϩ.
3
4
5
PyH), 8.61 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 1 H, 6-
PyH) ppm. 13C{1H} NMR (125 MHz, CDCl3):
δ ϭ 15.51
(SCH2CH3), 21.58 [NCH2CH(CH3)2], 26.91 (SCH2CH3), 29.82
[NCH2CH(CH3)2], 62.08 [NCH2CH(CH3)2], 123.08 (3-PyC),
123.87 (5-PyC), 137.01 (4-PyC), 148.68 (6-PyC), 156.35 (2-PyC),
163.06 (CNS) ppm. ESI-MS (pos., MeCN): m/z ϭ 223 [M ϩ H]ϩ.
4-Methyl-3-phenyl-5-(2-pyridyl)-4H-1,2,4-triazole (meppt, 18):
A
mixture of crude ethyl N-methylpyridine-2-carboximidothioate (17)
(3.61 g, 20.0 mmol) and benzohydrazide (1) (3.27 g, 24.0 mmol) in
1-butanol (50 mL) was refluxed for 24 h. Evaporation of the reac-
tion mixture, and recrystallisation of the solid residue from ethyl
acetate gave 2.81 g (59%) of analytically pure meppt (18) as colour-
less needles. M.p. 147Ϫ149 °C. C14H12N4 (236.28): calcd. C 71.17,
H 5.12, N 23.71; found C 71.03, H 5.07, N 23.67. 1H NMR
4-Isobutyl-3-phenyl-5-(2-pyridyl)-4H-1,2,4-triazole (ibppt, 21):
A
mixture of crude ethyl N-(isobutyl)pyridine-2-carboximidothioate
(20) (8.89 g, 40.0 mmol) and benzohydrazide (1) (6.13 g,
45.0 mmol) in 1-butanol (100 mL) was refluxed for 24 h. The sol-
vent was evaporated under reduced pressure, and the residue was
dissolved in dichloromethane (100 mL). The solution was washed
with 2  aqueous sodium hydroxide (3 ϫ 50 mL), water (50 mL)
and sat. aqueous sodium chloride (50 mL), and dried with anhy-
drous sodium sulfate. Column chromatography on silica gel eluting
with ethyl acetate/cyclohexane (2:1) gave 7.56 g (67%) of analyti-
cally pure ibppt (21) as a colourless crystalline solid. M.p. 131Ϫ133
°C. C17H18N4 (278.36): calcd. C 73.35, H 6.52, N 20.13; found C
3
(500 MHz, CDCl3): δ ϭ 4.05 (s, 3 H, CH3), 7.34 (ddd, J4,5 ϭ 7.7,
3J5,6 ϭ 4.8, 4J3,5 ϭ 1.2 Hz, 1 H, 5-PyH), 7.48Ϫ7.53 (m, 3 H, 3-, 4-
3
and 5-PhH), 7.66Ϫ7.71 (m, 2 H, 2- and 6-PhH), 7.83 (dt, J3,4
ϭ
3J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 1 H, 4-PyH), 8.33 (ddd, J3,4 ϭ 7.7,
4
3
4J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 1 H, 3-PyH), 8.66 (ddd, J5,6 ϭ 4.8,
5
3
4J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 1 H, 6-PyH) ppm. 13C{1H} NMR
5
1
73.21, H 6.31, N 20.23. H NMR (500 MHz, CDCl3): δ ϭ 0.59 [d,
(125 MHz, CDCl3): δ ϭ 34.34 (CH3), 124.05 (5-PyC), 124.10 (3-
PyC), 127.24 (1-PhC), 128.97 (3- and 5-PhC), 129.31 (2- and 6-
PhC), 130.21 (4-PhC), 137.12 (4-PyC), 148.22 (2-PyC), 148.87 (6-
PyC), 153.46 (5-TzC), 157.00 (3-TzC) ppm. IR (KBr): ν˜ ϭ 3047,
1588, 1569, 1517, 1485, 1470, 1443, 1430, 1278, 1150, 1096, 1076,
991, 927, 889, 789, 779, 773, 737, 722, 706, 699, 668, 623, 578, 485
cmϪ1. ESI-MS (pos., MeCN): m/z ϭ 237 [M ϩ H]ϩ, 259 [M ϩ
Na]ϩ, 275 [M ϩ K]ϩ. TLC (SiO2, EtOAc): Rf ϭ 0.15.
3J ϭ 6.8 Hz, 6 H, CH2CH(CH3)2], 1.71 [non, 3J ϭ 6.8 Hz, 1 H,
CH2CH(CH3)2], 4.51 [d, 3J ϭ 6.8 Hz, 2 H, CH2CH(CH3)2], 7.34
3
3
4
(ddd, J4,5 ϭ 7.7, J5,6 ϭ 4.8, J3,5 ϭ 1.2 Hz, 1 H, 5-PyH),
7.49Ϫ7.54 (m, 3 H, 3-, 4- and 5-PhH), 7.61Ϫ7.65 (m, 2 H, 2- and
3
3
4
6-PhH), 7.84 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 1 H, 4-PyH),
8.33 (ddd, J3,4 ϭ 7.7, J3,5 ϭ 1.2, J3,6 ϭ 0.9 Hz, 1 H, 3-PyH),
3
4
5
3
4
5
8.65 (ddd, J5,6 ϭ 4.8, J4,6 ϭ 1.8, J3,6 ϭ 0.9 Hz, 1 H, 6-PyH)
ppm. 13C{1H} NMR (125 MHz, CDCl3):
δ
ϭ
19.59
4-Methyl-3,5-di(2-pyridyl)-4H-1,2,4-triazole (medpt, 19): The reac-
tion of crude ethyl N-methylpyridine-2-carboximidothioate (17)
[CH2CH(CH3)2], 29.74 [CH2CH(CH3)2], 52.46 [CH2CH(CH3)2],
124.06 (5-PyC), 124.12 (3-PyC), 128.06 (1-PhC), 128.97 (3- and 5-
(3.61 g, 20.0 mmol) and pyridine-2-carbohydrazide (2) (3.29 g, PhC), 129.59 (2- and 6-PhC), 130.06 (4-PhC), 137.15 (4-PyC),
3432  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 3422Ϫ3434

From N-Substituted Thioamides to Symmetrical and Unsymmetrical 3,4,5-Trisubstituted 4H-1,2,4-Triazoles
FULL PAPER
[3]
U. Beckmann, S. Brooker, Coord. Chem. Rev. 2003, 245,
17Ϫ29.
O. Kahn, E. Codjovi, Phil. Trans. R. Soc., Lond. A 1996, 354,
359Ϫ379.
J. G. Haasnoot, in Magnetism: A Supramolecular Function
(Ed.: O. Kahn), Kluwer, Dordrecht, 1996, pp. 299Ϫ321.
L. G. Lavrenova, S. V. Larionov, Koord. Khim. 1998, 24,
403Ϫ420; Russ. J. Coord. Chem. 1998, 24, 379Ϫ395.
O. Kahn, C. J. Martinez, Science 1998, 279, 44Ϫ48.
M. H. Klingele, S. Brooker, Inorg. Chim. Acta 2004, 357,
1598Ϫ1602.
M. H. Klingele, S. Brooker, Inorg. Chim. Acta 2004, 357, in
press (DOI: 10.1016/j.ica.2004.03.044).
M. H. Klingele, PhD Thesis, University of Otago (New Zea-
land), 2004.
K. T. Potts, Chem. Rev. 1961, 61, 87Ϫ127.
J. H. Boyer, in Heterocyclic Compounds (Ed.: R. C. Elderfield),
Wiley, New York, 1961, vol. 7 pp. 384Ϫ461.
C. Temple Jr., Chem. Heterocycl. Compd. 1981, 37, 1Ϫ739.
J. B. Polya, in Comprehensive Heterocyclic Chemistry (Eds.: A.
R. Katritzky, C. W. Rees, K. T. Potts), Pergamon, Oxford,
1984, vol. 5, pp. 733Ϫ790.
P. J. Garratt, in Comprehensive Heterocyclic Chemistry II (Eds.:
A. R. Katritzky, C. W. Rees, E. F. V. Scriven, R. C. Storr),
Pergamon, Oxford, 1996, vol. 4, pp. 127Ϫ163.
R. Wegler, E. Kühle, W. Schäfer, Angew. Chem. 1958, 70,
351Ϫ367.
R. N. Hurd, G. DeLaMater, Chem. Rev. 1961, 61, 45Ϫ86.
W. Walter, K.-D. Bode, Angew. Chem. 1966, 78, 517Ϫ532; An-
gew. Chem. Int. Ed. Engl. 1966, 5, 447Ϫ461.
148.63 (2-PyC), 148.88 (6-PyC), 153.15 (5-TzC), 157.25 (3-TzC)
ppm. IR (KBr): ν˜ ϭ 2968, 2950, 2868, 1587, 1568, 1511, 1473,
1457, 1446, 1389, 1280, 1249, 1149, 1102, 991, 975, 923, 792, 772,
741, 729, 722, 698, 575 cmϪ1. ESI-MS (pos., MeCN): m/z ϭ 279
[M ϩ H]ϩ, 301 [M ϩ Na]ϩ, 317 [M ϩ K]ϩ. TLC (SiO2, EtOAc):
Rf ϭ 0.30.
[4]
[5]
[6]
4-Isobutyl-3,5-di(2-pyridyl)-4H-1,2,4-triazole (ibdpt, 22): The reac-
tion of crude ethyl N-(isobutyl)pyridine-2-carboximidothioate (20)
(8.89 g, 40.0 mmol) and pyridine-2-carbohydrazide (2) (6.17 g,
45.0 mmol) in 1-butanol (100 mL), following the procedure de-
scribed above for the preparation of ibppt (21), gave 8.17 g (73%)
of analytically pure ibdpt (22) as a colourless crystalline solid. M.p.
91Ϫ93 °C. C16H17N5 (279.34): calcd. C 68.80, H 6.13, N 25.07;
found C 68.91, H 6.18, N 25.30. 1H NMR (500 MHz, CDCl3): δ ϭ
[7]
[8]
[9]
[10]
[11]
[12]
3
0.69 [d, 3J ϭ 6.8 Hz, 6 H, CH2CH(CH3)2], 1.90 [non, J ϭ 6.8 Hz,
3
1 H, CH2CH(CH3)2], 5.20 [d, J ϭ 6.8 Hz, 2 H, CH2CH(CH3)2],
[13]
[14]
7.34 (ddd, 3J4,5 ϭ 7.7, 3J5,6 ϭ 4.8, 4J3,5 ϭ 1.2 Hz, 2 H, 2 ϫ 5-PyH),
3
3
4
7.84 (dt, J3,4 ϭ J4,5 ϭ 7.7, J4,6 ϭ 1.8 Hz, 2 H, 2 ϫ 4-PyH), 8.31
(ddd, 3J3,4 ϭ 7.7, 4J3,5 ϭ 1.2, 5J3,6 ϭ 0.9 Hz, 2 H, 2 ϫ 3-PyH), 8.68
(ddd, 3J5,6 ϭ 4.8, 4J4,6 ϭ 1.8, 5J3,6 ϭ 0.9 Hz, 2 H, 2 ϫ 6-PyH) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ ϭ 19.63 [CH2CH(CH3)2],
30.25 [CH2CH(CH3)2], 52.18 [CH2CH(CH3)2], 124.04 (2 ϫ 5-PyC),
124.61 (2 ϫ 3-PyC), 137.05 (2 ϫ 4-PyC), 148.74 (2 ϫ 2-PyC),
148.88 (2 ϫ 6-PyC), 154.15 (3- and 5-TzC) ppm. IR (KBr): ν˜ ϭ
2962, 2868, 1586, 1571, 1514, 1477, 1451, 1429, 1386, 1364, 1279,
1250, 1153, 1109, 1096, 996, 893, 809, 793, 742, 726, 713, 625, 620,
574 cmϪ1. ESI-MS (pos., MeCN): m/z ϭ 280 [M ϩ H]ϩ, 302 [M
ϩ Na]ϩ, 318 [M ϩ K]ϩ. TLC (SiO2, EtOAc): Rf ϭ 0.26.
[15]
[16]
[17]
[18]
[19]
[20]
W. Walter, J. Voss, in The Chemistry of Amides (Ed.: J. Za-
bicky), Interscience, London, 1970, pp. 383Ϫ475.
E. Schaumann, in Comprehensive Organic Synthesis (Eds.: B.
M. Trost, I. Fleming, E. Winterfeldt), Pergamon, Oxford, 1991,
vol. 6, pp. 419Ϫ434.
Crystal Data for ibdpt (22): C16H17N5, M ϭ 279.35 g molϪ1
colourless block, 0.35 ϫ 0.32 ϫ 0.26 mm, monoclinic, space group
,
˚
˚
˚
P21, a ϭ 8.1813(16) A, b ϭ 10.571(2) A, c ϭ 8.7214(17) A, β ϭ
[21]
[22]
[23]
H. Takahata, T. Yamazaki, Heterocycles 1988, 27, 1953Ϫ1973.
98.41(3)°, V ϭ 746.2(3) A , Z ϭ 2, ρcalcd. ϭ 1.243 g cmϪ3, T ϭ
3
˚
´
T. S. Jagodzinski, Chem. Rev. 2003, 103, 197Ϫ227.
293(2) K, µ ϭ 0.078 mmϪ1, F(000) ϭ 296, 4918 reflections collected
[2.36° Ͻ Θ Ͻ 26.23°], 2509 independent reflections [R(int) ϭ
0.0180], R1 ϭ 0.0288 [I Ͼ 2σ(I)], wR2 ϭ 0.0724 (all data), GOF ϭ
1.005, absolute structure factor Ϫ1(2), max./min. residual electron
H. Paulsen, D. Stoye, in The Chemistry of Amides (Ed.: J. Za-
bicky), Interscience, London, 1970, pp. 515Ϫ600.
M. Santus, Liebigs Ann. Chem. 1988, 179Ϫ182.
L. A. Reiter, G. E. Berg, Heterocycles 1992, 34, 771Ϫ780.
M. H. Klingele, P. D. W. Boyd, B. Moubaraki, K. S. Murray,
S. Brooker, manuscript in preparation.
M. R. Atkinson, J. B. Polya, J. Chem. Soc. 1954, 141Ϫ145.
J. F. Geldard, F. Lions, J. Org. Chem. 1965, 30, 318Ϫ319.
S. Kubota, M. Uda, T. Nakagawa, J. Heterocycl. Chem. 1975,
12, 855Ϫ860.
M. Uda, Y. Hisazumi, K. Sato, S. Kubota, Chem. Pharm. Bull.
1976, 24, 3103Ϫ3108.
H. Takalo, V.-M. Mukkala, L. Meriö, J. C. Rodrıguez-Ubis, R.
Sedano, O. Juanes, E. Brunet, Helv. Chim. Acta 1997, 80,
372Ϫ387.
M. Carmack, M. A. Spielman, Org. React. 1946, 3, 83Ϫ107.
E. V. Brown, Synthesis 1975, 358Ϫ375.
B. Emmert, M. Groll, Chem. Ber. 1953, 86, 208Ϫ213.
H. D. Porter, J. Am. Chem. Soc. 1954, 76, 127Ϫ128.
W. S c h äfer, R. Wegler (Farbenfabriken Bayer AG), DE Patent
1149356, 1963; Chem. Abstr. 1963, 59, 11441c.
S. I. Burmistrov, L. G. Romanovskaya, A. P. Ranskii, T. Ya.
Mashchenko (Dnepropetrovsk Chemical-Technological Insti-
tute), SU Patent 1121261, 1984; Chem. Abstr. 1985, 102,
203963p.
A. Spassov, E. Golowinsky, Compt. Rend. Acad. Bulg. Sci.
1962, 15, 171Ϫ174.
T. Hisano, M. Ichikawa, Chem. Pharm. Bull. 1976, 24,
1451Ϫ1458.
[24]
[25]
[26]
density 0.088/Ϫ0.080 e·AϪ3. CCDC-233197 contains the supple-
˚
mentary crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: ϩ44-
1223-336-033; E-mail: deposit@ccdc.cam.ac.uk].
[27]
[28]
[29]
[30]
[31]
´
Acknowledgments
This work was supported by a number of grants from the Univer-
sity of Otago, including a University of Otago Postgraduate Schol-
arship to MHK and a Bridging Grant. The authors are grateful to
Prof. A. K. Powell and Dr. C. E. Anson (University of Karlsruhe)
for granting free access to their X-ray facilities and for collecting
the X-ray data. Technical assistance by Dr. M. Thomas and Mr. I.
Stewart (University of Otago) in recording some of the NMR and
mass spectra is also gratefully acknowledged. Prof. G. B. Jameson
(Massey University), Ms. J. Hausmann and Dr. C. D. Brandt (Uni-
versity of Otago) are thanked for helpful discussions, and Mr. T.
Fritz (University of Zürich) is thanked for translating the Russian
literature cited in this paper.
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
K. V. Martin, J. Am. Chem. Soc. 1958, 80, 233Ϫ236.
[1]
ˇ ˇ
L. Kramberger, P. Lorencak, S. Polanc, B. Vercek, B. Stanov-
J. G. Haasnoot, Coord. Chem. Rev. 2000, 200Ϫ202, 131Ϫ185.
M. H. Klingele, S. Brooker, Coord. Chem. Rev. 2003, 241,
[2]
ˇ
ˇ
nik, M. Tisler, F. Povazanec, J. Heterocycl. Chem. 1975, 12,
119Ϫ132.
337Ϫ342.
Eur. J. Org. Chem. 2004, 3422Ϫ3434
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3433

M. H. Klingele, S. Brooker
FULL PAPER
[42]
[50]
[51]
[52]
[53]
[54]
[55]
F. Lions, K. V. Martin, J. Am. Chem. Soc. 1958, 80,
S.-C. Shao, D.-R. Zhu, X.-H. Zhu, X.-Z. You, S. S. S. Raj, H.-
K. Fun, Acta Crystallogr., Sect. C 1999, 55, 1412Ϫ1413.
S. C. Shao, D. R. Zhu, T. W. Wang, Y. Zhang, S. S. S. Raj, H.
K. Fun, Chin. Chem. Lett. 2000, 11, 93Ϫ94.
D.-R. Zhu, Y. Song, Y. Xu, Y. Zhang, S. S. S. Raj, H.-K. Fun,
X.-Z. You, Polyhedron 2000, 19, 2019Ϫ2025.
D. Zhu, Y. Xu, Z. Yu, Z. Guo, H. Sang, T. Liu, X. You, Chem.
Mater. 2002, 14, 838Ϫ843.
A. R. Katritzky, T.-B. Huang, M. V. Voronkov, M. Wang, H.
Kolb, J. Org. Chem. 2000, 65, 8819Ϫ8821.
H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997,
62, 7512Ϫ7515.
1591Ϫ1592.
[43]
H. Saikachi, T. Hisano, Chem. Pharm. Bull. 1959, 7, 349Ϫ356.
A. V. Golounin, A. P. Kiunova, A. I. Kholkin, V. I. KuzЈmin
[44]
(Krasnoyarsk State University, Institute of Chemistry and
Chemical Technology), SU Patent 1214665, 1986; Chem. Abstr.
1986, 105, 190956y.
[45]
W. S c h äfer, R. Wegler (Farbenfabriken Bayer AG), DE Patent
964142, 1957; Chem. Abstr. 1959, 53, 13178a.
T. Taguchi, K. Yoshihira, Chem. Pharm. Bull. 1963, 11,
430Ϫ435.
R. W. Kluiber, Inorg. Chem. 1965, 4, 829Ϫ833.
E. G. Rukhadze, Yu. E. IlЈichev, V. M. Potapov, Zh. Obshch.
[46]
[47]
[56]
[57]
[58]
G. M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467Ϫ473.
G. M. Sheldrick, Methods Enzymol. 1997, 276, 628Ϫ641.
G. M. Sheldrick, T. R. Schneider, Methods Enzymol. 1997,
277, 319Ϫ343.
[48]
Khim. 1974, 44, 669Ϫ671; J. Gen. Chem. USSR 1974, 44,
638Ϫ640.
[49]
P. Karrer, J. Schukri, Helv. Chim. Acta 1945, 28, 820Ϫ824.
Received March 21, 2004
3434
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3422Ϫ3434