The palladium-catalyzed cross-coupling reactions of 3-chloro-4-halogeno-1,2,5-thiadiazoles

Article abstract of DOI:10.3987/COM-02-9550

3,4-Dichloro- and 3-chloro-4-halogeno-1,2,5-thiadiazoles (halogeno-: bromo- and iodo-) are involved in Pd-catalyzed cross-coupling reactions under Stille and Suzuki conditions. As a result, by using the commercially available 3,4-dichloro-1,2,5-thiadiazole as substrate, several 3-alkyl-, 3-alkenyl-, 3-alkynyl-and 3-aryl-4-chloro-1,2,5-thiadiazoles can easily be prepared. However, these reactions through direct desymmetrization of the 3,4-dichloro-1,2,5-thiadiazole always occur with side-reactions resulting from the concurrent decomposition of the heterocyclic ring of the starting material. These problems are resolved by involving, in these Pd-catalyzed cross-coupling reactions, the more reactive and selective 3-bromo-4-chloro- and 3-chloro-4-iodo-1,2,5-thiadiazole. These new dihalogeno-1,2,5-thiadiazoles can easily be prepared, via diazotization reaction followed by halogen substitution, from the 3-amino-4-chloro-1,2,5-thiadiazole.

Full text of DOI:10.3987/COM-02-9550

HETEROCYCLES, Vol. 60, No. 1, 2003
29
HETEROCYCLES, Vol. 60, No. 1, 2003, pp. 29 - 45
Received, 26th June, 2002, Accepted, 18th November, 2002, Published online, 25th November, 2002
THE PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF
3-CHLORO-4-HALOGENO-1,2,5-THIADIAZOLES
Alain Merschaert* and Hugo J. Gorissen
Lilly Research Laboratories, Chemical Process R & D, Lilly Development Centre
S.A., B-1348 Mont-Saint-Guibert, Belgium; e-mail : merschaert_alain@lilly.com
Abstract – 3,4-Dichloro- and 3-chloro-4-halogeno-1,2,5-thiadiazoles (halogeno-:
bromo- and iodo-) are involved in Pd-catalyzed cross-coupling reactions under
Stille and Suzuki conditions. As a result, by using the commercially available
3,4-dichloro-1,2,5-thiadiazole as substrate, several 3-alkyl-, 3-alkenyl-, 3-alkynyl-
and 3-aryl-4-chloro-1,2,5-thiadiazoles can easily be prepared. However, these
reactions through direct desymmetrization of the 3,4-dichloro-1,2,5-thiadiazole
always occur with side-reactions resulting from the concurrent decomposition of
the heterocyclic ring of the starting material. These problems are resolved by
involving, in these Pd-catalyzed cross-coupling reactions, the more reactive and
selective 3-bromo-4-chloro- and 3-chloro-4-iodo-1,2,5-thiadiazole. These new
dihalogeno-1,2,5-thiadiazoles can easily be prepared, via diazotization reaction
followed by halogen substitution, from the 3-amino-4-chloro-1,2,5-thiadiazole.
INTRODUCTION
Although highlighting the relevance of 1,2,5-thiadiazole derivatives in several areas such as polymer
chemistry and material science, it is obvious that this typical heterocyclic moiety can be incorporated into
the structure of compounds that display a wide range of biological activities.1 In most cases, the active
compounds correspond to unsymmetrical 3,4-disubtituted 1,2,5-thiadiazoles. In order to get access to all
these derivatives the involvement of different synthetic approaches is required.2 In addition, it is well-
known that many of these synthetic methods use hazardous, corrosive and highly toxic reagents.1,2
Recently, an innovative method for the synthesis of 3-alkyl-4-aryl- and unsymmetrical
3,4-diaryl-1,2,5-thiadiazoles, involving the Stille reaction, has been reported (Scheme 1a).3 This type of
Pd-catalyzed cross-coupling reaction, involving as substrates 3-alkyl- and 3-aryl-4-halogeno- (halogeno-:
chloro- and bromo-) 1,2,5-thiadiazoles, and their corresponding 4-triflate analogues, has not so far been

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HETEROCYCLES, Vol. 60, No. 1, 2003
applied on the more versatile substrates, i.e. the symmetrical and unsymmetrical
3,4-dihalogeno-1,2,5-thiadiazoles (Scheme 1b).4
Scheme 1
X = X' = Cl
X = Cl, Br, OTf
X = Cl & X' = Br, I
R = Alkyl, Alkenyl, Alkynyl, Aryl
R = Alkyl, Aryl
Ar
R
X
X'
X
R
X
R
cross-coupling
cross-coupling
(a)
(b)
N
N
N
N
N
N
N
N
S
S
S
S
In this paper, we report the use of 3,4-dichloro-1,2,5-thiadiazole as substrate in both Stille and Suzuki
reactions.5,6 These methods make it possible to quickly prepare 3-alkyl-, 3-alkenyl-, 3-alkynyl- and
3-aryl-4-chloro-1,2,5-thiadiazole key intermediates. Additionally, in order to circumvent the problems
resulting from the occurrence of a competitive degradation of the 3,4-dichloro-1,2,5-thiadiazole starting
material, a more productive alternative using the new 3-chloro-4-halogeno-1,2,5-thiadiazoles (halogeno-:
bromo- and iodo-) is proposed.7
The readily commercially available 3,4-dichloro-1,2,5-thiadiazole has been tentatively used as starting
material in many nucleophilic substitution reactions. However, the intrinsic reactivity of this dichloro-
substituted heterocycle (isoelectronic to the pyrazine heterocyclic nucleus) is suffering from major
selectivity issues: susceptibility of the endocyclic sulfur atom to a nucleophilic attack and lack of control
over the reactivity of the second chlorine atom. For example, under reaction of lithium and sodium amides
or of lithium 2-(trimethylsilyl)acetylide, the only product still bearing the heterocyclic nucleus,
corresponds to the symmetrical disubstituted 1,2,5-thiadiazole in very low yield (about 4%).8 In these two
reported cases, the authors claim that the main side-reaction, occurring by nucleophilic attack on the
heterocyclic sulfur atom, leads by ring opening, essentially to degradation products. In contrast, a unique
but very productive case is reported for the preparation of 3-chloro-4-(N-morpholino)-1,2,5-thiadiazole.9
This key intermediate for the synthesis of the potent β-adrenergic blocking agent timolol, is prepared by
reaction of morpholine on the 3,4-dichloro-1,2,5-thiadiazole with an almost quantitative yield (97%).
These conflicting results might be explained by selectivity differences related to the multi-center
reactivity of the 3,4-dichloro-1,2,5-thiadiazole heterocycle.

HETEROCYCLES, Vol. 60, No. 1, 2003
31
RESULTS AND DISCUSSION
Despite these apparent contradictory results, we anticipate in the context of the Pd-catalyzed cross-
coupling using as substrate the strong electron-deficient heterocycle 3,4-dichloro-1,2,5-thiadiazole, that
the presence of two chlorine atoms will, via their synergistic electron withdrawing effects, enhance the
reactivity of the first chlorine involved in the reaction. After this step, the reactivity of the second chlorine
still present on the resulting product (2) is reduced to such a level that the consecutive cross-coupling
reaction could be avoided (Scheme 2). In addition, involvement of highly selective reagents such as
stannane or boronic acid derivatives should favor selectivity for the first chlorine and also decrease the
probability of nucleophilic attack on the heterocyclic sulfur atom.
Scheme 2
Cl
Cl
PhSn(n-Bu)3
Cl
Pd/Ligand
N
N
N
N
N
N
S
S
S
1
2
3
Preliminary trials have been performed by reaction of 3,4-dichloro-1,2,5-thiadiazole (1) with
tributylphenyl stannane (I) in the presence of several Pd-catalysts and in various solvents.10 Generally, the
use of tetrakis(triphenylphosphine)palladium(0) as catalyst provides the best results (Table 1). When the
reaction proceeds, its advancement is limited by some side-reactions, with formation of benzonitrile and
triphenylphosphine sulfide as by-products (Scheme 3).
These data show that the 3,4-dichloro-1,2,5-thiadiazole (1) can be used as substrate in the Pd-catalyzed
cross-coupling reaction with tributylphenyl stannane (I), by yielding the 3-chloro-4-phenyl-
1,2,5-thiadiazole11 (2) without occurrence of the consecutive reaction leading to 3,4-diphenyl-
1,2,3-thiadiazole12 (3). Involvement of Pd-catalysts lacking phosphinic ligands (Runs 10, 11) does not
allow the cross-coupling reaction to proceed. Involvement of Pd-catalysts bearing bidentate phospinic
ligands (Runs 7, 8, 9) and use of aprotic polar solvents (Run 4) are ineffective. When using the readily
available tetrakis(triphenylphosphine)palladium(0), it is possible, by portionwise addition of the catalyst,
to get yields close to 50% (Runs 5, 6). Under these conditions, the unwanted 3,4-diphenyl-
1,2,3-thiadiazole (3) could not be detected (< 1-2%). This is in accordance with the important difference

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HETEROCYCLES, Vol. 60, No. 1, 2003
in reactivity between the 3-chloro- and 3-bromo-4-phenyl-1,2,5-thiadiazole used in the synthesis of the
3-(4-chlorophenyl)-4-phenyl-1,2,5-thiadiazole (7% and 89% yields respectively), as reported by
Hanasaki.3
Table 1.
Trials using Stille approach in the cross-coupling on substrate (1) with reagent (I).
Run
1
Catalyst
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(dppe)Cl2
Pd(dppf)Cl2
Pd(dppf)
mol % Solvent(a)
2(b)
25
35
28
14
45
48
0
PhCN(b)
Ph3PS(b)
5
10
5
Toluene
Toluene
Dioxane
DMF
nd
nd
2
nd
nd
3
nd
nd
4
5
nd
nd
5
8(c)
Dioxane
nd
nd
6
7.5(d) Toluene
37.5
nd
17.5
n/a
n/a
n/a
n/a
n/a
7
10
10(e)
6.5(f)
10
Dioxane
Toluene
Toluene
Dioxane
8
19
11
0
17
9
21
10
11
Pd(CH3CN)2Cl2
Pd2(dba)3
0
2.5(g) Toluene
0
3.5
(a) reflux under N2 (b) HPLC assay (mol %) (c) 4% + 4% at 24 h (d) 5% + 2.7% at 8 h.
(e) 5% + 5% at 6 h (f) Pd(dppf)Cl2 + BuLi (–78°C) (g) corresponds to 5% Pd.
nd: not determined, n/a: non-applicable.
However, our method is hampered by the desulfurization side-reactions of the 1,2,5-thiadiazole nucleus.
This degradation might, in theory, affect either the starting material (1) (Scheme 3a) or its resultant
product (2) (Scheme 3b).13 Depending upon which mechanism or pathway is involved, either two or one
equiv of cyanogen chloride is formed. However, since cyanogen chloride is then able to react in the next
step (Scheme 2c) with tributylphenyl stannane (I), the overall balance of the reaction corresponds to two
equiv. of benzonitrile for one equiv. of triphenylphosphine sulfide (Run 6). In theory, it cannot be
excluded that the first or second degradation pathway alone or both degradation pathways together can be
involved. These side-reactions affect not only the stoichiometry of reactants and products, but by
consuming both phosphine and palladium also block the catalytic cycle. It is therefore not surprising that
the best results have been obtained by portionwise addition of the catalyst (Runs 5, 6).

HETEROCYCLES, Vol. 60, No. 1, 2003
33
Scheme 3
Cl
Cl
Cl
Cl
N
Cl
N
PPh3
PPh3
Pd
2
(a)
P
S
P
S
(b)
+
+
+
N
N
N
N
Pd
S
S
N
1
2
Cl
N
PhSn(n-Bu)3
(c)
Cl
Sn
+
N
In this context some control experiments have been done. On one hand, the stability of the 3,4-dichloro-
1,2,5-thiadiazole (1) was assessed, in the presence of either palladium or triphenylphosphine alone or in
the presence of both catalytic components. On the other hand, the stability of the 3-chloro-4-phenyl-
1,2,5-thiadiazole (2) was assessed in the presence of tetrakis(triphenylphosphine)palladium(0). These
stability data show that the 3-chloro-4-phenyl-1,2,5-thiadiazole (2) is much more stable than the
3,4-dichloro analogue (1). The 3,4-dichloro-1,2,5-thiadiazole (1) displays a relative instability against
each catalytic component alone, but is far more unstable in the presence of both catalytic ingredients
(Ph3P < Pd <<< Pd/Ph3P). As the decomposition pathway occurs competitively the overall yield in
expected product reach about the 50%. The mass balance accounts in this case for 102-103%, when taking
into account unreacted 3,4-dichloro-1,2,5-thiadiazole (1), 3-chloro-4-phenyl-1,2,5-thiadiazole (2) and
either benzonitrile or triphenylphosphine sulfide taken either as 2 or 1 equiv. respectively (see
Experimental : 3-chloro-4-phenyl-1,2,5-thiadiazole: 1st example).
This method was then generalized by using a series of commercially available stannane reagents
[RSn(n-Bu)3] permitting access to a family of 3-chloro-4-substituted 1,2,5-thiadiazoles as illustrated in
Scheme 4. This family of 3-chloro-4-substituted 1,2,5-thiadiazoles14 includes phenyl (2), pyrid-3-yl
(4),15,16 furan-2-yl (5), thiophen-2-yl (6), vinyl (7), 1-ethoxyvinyl (8), phenylethynyl (9) and allyl (10)
4-substituted derivatives (Scheme 4).
As shown in Table 2, the in situ yields vary from 35 to 60%. Here also, as in the example related to
compound (2) (Scheme 3), similar side-reactions have been observed. In each case, occurrence of the
corresponding nitrile (R-CN) has been demonstrated (by comparison with an authentic reference) or
evaluated (unstable or volatile) on the basis of the degree of conversion. Accordingly, both the
triphenylphosphine sulfide and the nitrile (1 equiv. Ph3PS vs. 2 equiv. R-CN) were formed as expected.

34
HETEROCYCLES, Vol. 60, No. 1, 2003
However, in some cases significant amounts of stannane homo-coupling (R-R) by-products have also
been observed. For example 3,3’-bipyridine and 1,4-diphenylbutadiyne homo-coupling by-products have
been found in the synthesis of compounds (4) and (9). Generally, as in the case of (2) (Scheme 2), no
detectable amounts of the symmetrical 3,4-disubstituted 1,2,5-thiadiazole by-product could be observed.
In this context, as an alternative to the Stille approach, the Suzuki cross-coupling using 3,4-dichloro-
1,2,5-thiadiazole was tested for the synthesis of 3-chloro-4-phenyl-1,2,5-thiadiazole (2) and
3-chloro-4-(pyrid-3-yl)-1,2,5-thiadiazole (4). For this purpose, phenylboronic acid (II) and
diethyl(3-pyridyl)borane (III) or 3-pyridylboronic acid17 (IV) were involved as reagents under different
catalyst, base and solvent conditions.18
Scheme 4
Cl
R-CN
PPh3S
R-R
Cl
Cl
Cl
R
RSn(n-Bu)3
Cl
N
N
N
+
N
N
N
N
S
Cl
Pd(PPh3)4
S
S
N
N
2
S
N
N
10
S
4
3-Chloro-4-substituted 1,2,5-thiadiazoles
Run Compd Catalyst(a) Assay(b) Yield(c)
Cl
Cl
mol %
mol %
%
Cl
O
1
2
3
4
5
6
7
8
2
4
5
6
7
8
9
10
5+2.5
7.5+4.5
5+1.6
5+1.6
5+2.2
5+2.5
5+2.5 +2.5
5+2.5+2.5
48
38
60
54
35
55
38
60
-
-
Cl
N
N
(51)
(47)
(31)
(42)
(28.5)
(31)
N
N
S
S
1
N
N
5
S
9
O
Cl
S
Cl
(a) 2 or 3 successive additions (b) HPLC (c) isolated
Cl
N
N
N
N
S
S
N
N
6
8
S
7
As shown in Table 3, the best conditions for the synthesis of 3-chloro-4-phenyl-1,2,5-thiadiazole (2)
require the use of tetrakis(triphenylphosphine)palladium(0) as catalyst and potassium fluoride as base in a
biphasic toluene-water mixture (Run 3). The traditional Suzuki conditions using potassium carbonate as
base were found to be less productive (Runs 1, 2). Other conditions using cesium fluoride as base do not
bring any improvement (Runs 4, 5). Interestingly, the isolated 56% yield of compound (2) (Run 3) is even
higher than that measured in situ under the best conditions in the Stille approach (Table 1, Run 6). In
contrast, similar conditions applied for the synthesis of 3-chloro-4-(pyrid-3-yl)-1,2,5-thiadiazole (4) with
involvement of two different Suzuki reagents were found to be rather unproductive (Runs 6, 7, 8). Finally,
in addition to the lack of general conditions applicable with this cross-coupling method, side-reactions

HETEROCYCLES, Vol. 60, No. 1, 2003
35
similar to these observed in the previous approach (Scheme 3) could not be avoided in this alternative.
Table 3.
Trials using the Suzuki cross-coupling on substrate (1) with reagents (II, III and IV).
Run Compd Suzuki
Catalyst
(mol %)
Base
Solvent
(v/v)
Yield(b)
reagent(a)
(equiv)
1
2
3
4
5
6
7
8
2
2
2
2
2
4
4
4
II
II
Pd(PPh3)4 (5)
K2CO3 (2) Toluene/EtOH/H2O (4/2/1) (26)
Pd(dppb)Cl2 (10) K2CO3 (2) Toluene/EtOH/H2O (4/2/1) (31)
II
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
KF (3)
CsF (3)
CsF (3)
K2CO3 (2)
KF (3)
Toluene/H2O (1/1)
Dioxane/H2O (4/1)
Dioxane
(56)
30
II
II
25
III
III
IV
Toluene/H2O (2/1)
Toluene/H2O (1/1)
Toluene/H2O (2/1)
(18)
(13)
5
KF (3)
(a) II = phenylboronic acid; III = diethyl(3-pyridyl)borane; IV = 3-pyridylboronic acid.
(b) By HPLC assay (mol %) or isolated (%) between brackets.
At this stage, it is obvious that the readily available 3,4-dichloro-1,2,5-thiadiazole can be involved as
substrate in Pd-catalyzed cross-coupling reactions, using either Stille or Suzuki conditions. While this
straightforward method does not achieve consistent yields in all cases, it makes it possible to quickly
access a broad family of useful key intermediates. However, due to the competitive desulfurization
side-reaction affecting the starting material, this approach cannot be considered as optimal.
Scheme 5
Cl
Cl
Br
CuBr2
N
N
N
+
S
Cl
NH2
Cl
N2
t-BuONO
12
I
N
N
N
N
S
S
11
N
CuI
S
13
In order to avoid this major issue, the involvement of unsymmetrical 3,4-dihalogeno-1,2,5-thiadiazoles,
such as the 3-bromo-4-chloro- and the 3-chloro-4-iodo-analogues has been proposed. These new

36
HETEROCYCLES, Vol. 60, No. 1, 2003
1,2,5-thiadiazole key intermediates (12) and (13) have been prepared from 3-amino-4-chloro-
1,2,5-thiadiazole19 (11) via a Sandmeyer-like reaction involving successively tert-butyl nitrite and either
copper dibromide or copper iodide (Scheme 5) in anhydrous acetonitrile according to standard
experimental conditions reported for the conversion of arylamines into their corresponding aryl bromide
and iodide derivatives.20,21
Table 4.
Comparative trials on substrates (1, 12 and 13) using Stille (V)(a) and Suzuki (II)(b) reagents.
Run
1
Substrate
Reagent
Product
Catalyst
Pd2(dba)3
Yield(c)
0
1
1
V
V
V
V
II
II
II
4
4
4
4
2
2
2
2
Pd(2-furyl3P)4
Pd(2-furyl3P)4
Pd2(dba)3
(25)
51
3
12
13
1
4
76
5
Pd(Ph3P)4
(56)
(95)
(87)
6
Pd(Ph3P)4
12
7
Pd(Ph3P)4
13
(a) V = tributyl-(3-pyridyl)stannane and 5 mol % catalyst in toluene.
(b) II = phenylboronic acid and 5 mol % catalyst + 3 equiv. KF in toluene-water.
(c) By HPLC assay (mol %) or isolated (%) between brackets.
The data in Table 4 show that the cross-coupling reaction is in all cases significantly improved by using as
substrate, the 3-bromo-4-chloro- (12) or 3-chloro-4-iodo-1,2,5-thiadiazole (13), instead of the
corresponding 3,4-dichloro analogue (1). In accordance with this increased productivity, no substantial
levels of the by-products resulting from degradation of the heterocycle have been detected. Furthermore,
involvement of the bromo and iodo analogues makes it possible to promote the reaction by catalysts that
were found to be poorly active or inactive with 3,4-dichloro-1,2,5-thiadiazole. For example, under the
Stille conditions the cross-coupling reaction works by using Pd-catalysts lacking phosphinic ligands such
as tris(dibenzylideneacetone)dipalladium(0) (Run 4 vs. Run 1). Finally, the involvement of
3-bromo-4-chloro- (12) and/or 3-chloro-4-iodo-1,2,5-thiadiazoles (13) are compatible with both Stille and
Suzuki cross-coupling approaches.
CONCLUSIONS
The desymmetrization of 3,4-dichloro-1,2,5-thiadiazole via either the Stille or the Suzuki cross-coupling
reaction is achievable. The reaction proceeds with formation of the 4-substituted 3-chloro-

HETEROCYCLES, Vol. 60, No. 1, 2003
37
1,2,5-thiadiazole without occurrence of the next consecutive reaction leading to the symmetrical
3,4-disubstituted analogue. This method using the commercially available 3,4-dichloro-1,2,5-thiadiazole
makes it possible to prepare many different 4-substituted 3-chloro-1,2,5-thiadiazoles. Such a method
might be appropriate by parallel syntheses to prepare series of key intermediates highly useful in
medicinal
chemistry.
However,
this
cross-coupling
reaction
using
as
substrate
3,4-dichloro-1,2,5-thiadiazole suffers from a major selectivity issue due to a competitive side-reaction by
degradation of the heterocyclic nucleus. Due to the intrinsic reactivity of the strong electron-deficient
heterocycle 3,4-dichloro-1,2,5-thiadiazole, this unwanted desulfurization side-reaction by the Pd-catalyst
cannot be avoided. Therefore, the productivity of this reaction remains limited and varies dramatically
depending on the nature of the reagents and catalysts typically used in the Stille or Suzuki approaches.
Utilization of the unsymmetrical 3-bromo-4-chloro- and 3-chloro-4-iodo-1,2,5-thiadiazoles makes it
possible to by-pass the major issue associated with 3,4-dichloro-1,2,5-thiadiazole. When using the new
bromo-chloro- and chloro-iodo- unsymmetrical dihalogeno-substrates, the cross-coupling reaction occurs
in all cases with much better yields. In accordance to that, involvement of these new substrates makes it
possible to avoid the major competitive side-reaction(s) leading to degradation of the heterocyclic starting
material. This improvement can easily been rationalized by the higher susceptibility of aryl bromides and
iodides, relative to the corresponding chlorides, to be involved in the initial Pd-insertion rate-determining
step of the overall cross-coupling reaction. In addition, the replacement of one chlorine of the
3,4-dichloro-1,2,5-thiadiazole, by a less electronegative halogen such as the bromine or iodine, should
reduce the susceptibility of the endocyclic sulfur atom for a nucleophilic attack leading to degradation of
the heterocycle. In this perspective, the use of these new unsymmetrical 3,4-dihalogeno-1,2,5-thiadiazoles
opens the opportunity to develop and scale-up reactions that avoid the hazardous, corrosive and highly
toxic reagents that are generally required in this type of chemistry. In this scope, the Suzuki approach
involving boronic acid derivatives should be considered as the method of choice. In addition, our work is
complementary to that developed earlier3, by providing direct access to series of intermediates enabling
the preparation of the 3-alkyl-4-aryl- and 3,4-diaryl-1,2,5-thiadiazoles (Scheme 1).
EXPERIMENTAL
Melting points were recorded on an Electrothermal Melting Point apparatus (according to Totolli) and are
uncorrected. MS were recorded on a Nermag R3010 mass spectrometer. High-resolution MS were
recorded on a VG AutoSpec (Fisons Intruments) mass spectrometer or a Q-TOF Ultima (Micromass).
NMR spectra were performed on a Brücker 400 MHz spectrometer. Reactions are monitored by TLC
(silica gel plates, Merck 60 F254) and by HPLC in an isocratic mode using Zorbax-CN column with eluant

38
HETEROCYCLES, Vol. 60, No. 1, 2003
acetonitrile–water–trifluoroacetic acid mixture (5/95/0.1, v/v). Quantitative analyses are performed by
HPLC using C18 Merck 60RP Select B column (25 cm × 4.6 mm) with eluant acetonitrile–water–
trifluoroacetic acid (5/95/0.1 → 95/5/0.1, v/v) in a gradient mode for 25 min and at the end in isocratic
mode for 10 min, injection 10 µL, concentration 20 mg/50 mL, detection 220 and 235 nm. Reference
materials have been prepared, whether independently (2, 3) or by extensive purification of an aliquot
withdrawn from the reaction pool (4 to 10). 3,4-Dichloro-1,2,5-thiadiazole has been redistilled
(155°C/760 mm Hg) before use. All solvents have been used after degassing under nitrogen or argon
atmosphere. Purification by flash chromatography is performed using silica gel 60, 63-100 µm (Merck).
3-Chloro-4-phenyl-1,2,5-thiadiazole (2)
1st Example (Table 1, Run 6 or Table 2, Run 1)
Tributylphenyl stannane (1.9 g, 5.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29 g,
0.25 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (0.775 g, 5 mmol) in toluene
(10 mL). This mixture is heated to reflux under nitrogen for 8 h. An additional amount of tetrakis
(triphenylphosphine)palladium(0) (0.145 g, 0.125 mmol) is then added to the reaction mixture. At 24 h,
the reaction medium is analyzed by quantitative HPLC: 472 mg (48%) in situ of 2. In process monitoring
against authentic reference samples shows also 280 mg (36%) of unreacted 3,4-dichloro-1,2,5-thiadiazole
(1) starting material together with 193 mg (37.5%) of benzonitrile and 257 mg (17.5%) of
triphenylphosphine sulfide degradation products.
2nd Example (Table 3, Run 3)
Potassium fluoride (0.35 g, 6 mmol), phenylboronic acid (0.245 g, 2 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (0.115 g, 0.1 mmol) are added to a solution of 3,4-dichloro-
1,2,5-thiadiazole (0.31 g, 2 mmol) in a biphasic mixture of toluene (5 mL) and water (5 mL). The reaction
mixture is heated under vigorous stirring under nitrogen for 48 h. The organic layer is decanted off and
the aqueous layer is re-extracted with ether. The combined organic phases are dried on magnesium
sulfate, filtered and evaporated to dryness. The crude oily residue is purified by chromatography on a
silica gel column eluted successively with cyclohexane and a mixture of cyclohexane – ether (98/2, v/v).
The pooled fractions containing 2 are evaporated to dryness to give a colorless oil, which crystallizes on
standing: 220 mg (56%) (mp 33°C, lit.,2b 31-33°C).
13
1H-NMR (CDCl3) δ 7.50 (3H, m), 7.92 (2H, dd); C-NMR (CDCl3) δ 128.6 (4C), 130.2, 130.7, 143.4,
157.9.
3rd Example (Table 4, Run 6)
Tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.05 mmol) and 1M potassium fluoride aqueous
solution (3 mL, 3 mmol) are added to a mixture of 3-bromo-4-chloro-1,2,5-thiadiazole (0.2 g, 1 mmol)

HETEROCYCLES, Vol. 60, No. 1, 2003
39
and phenylboronic acid (0.135 g, 1.1 mmol) in toluene (5 mL). The biphasic reaction mixture is heated
under vigorous stirring under nitrogen for 26 h. The organic layer is decanted off and the aqueous layer is
re-extracted twice with toluene (2 ×10 mL). The combined organic phases are dried on magnesium sulfate,
filtered and evaporated to dryness. The crude oily residue is purified by chromatography on a silica gel
column eluted successively with a mixture of n-hexane – ethyl acetate (99/1, v/v). The pooled fractions
containing 2 are evaporated to dryness to give a colorless oil which crystallizes on standing: 180 mg
(95%) (mp 33°C).
3-Chloro-4-(pyrid-3-yl)-1,2,5-thiadiazole (4)
1st Example (Table 2, Run 2)
Tributyl(3-pyridyl)stannane (0.4 g, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.086 g,
0.0745 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (0.16 g, 1 mmol) in toluene
(2 mL). This mixture is heated to reflux under argon for 2 h. An additional amount of tetrakis
(triphenylphosphine)palladium(0) (0.052 g, 0.045 mmol) is then added to the reaction mixture. At 24 h,
the reaction medium is analyzed by quantitative HPLC (all the stannane is consumed): 75.2 mg (38%) in
situ of 4.
2nd Example: (Table 3, Run 6)
Diethyl(3-pyridyl)borane (0.147 g, 1 mmol), 1M potassium carbonate aqueous solution (2 mL, 2 mmol)
and tetrakis(triphenylphosphine)palladium(0) (0.057 g, 0.05 mmol) are added to a solution of
3,4-dichloro-1,2,5-thiadiazole (0.155 g, 1 mmol) in toluene (4 mL). The reaction mixture is heated under
stirring under nitrogen for 24 h. The organic phase is decanted and the aqueous phase is re-extracted with
ether. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to
dryness. The crude oily residue is purified by chromatography on a silica gel column eluted successively
with a mixture of cyclohexane – ethyl acetate (80/20, v/v). The pooled fractions containing 4 are
evaporated to dryness give a colorless oil which slowly crystallizes on standing: 35 mg (18%) (mp 45°C,
lit.,16 48-49°C).
1H-NMR (CDCl3) δ 7.46 (1H, m), 8.29 (1H, m), 8.74 (1H, dd, J = 5 Hz and 2 Hz); 13C-NMR (CDCl3) δ
123.3, 126.8, 135.6, 143.4, 149.3, 150.9, 155.0.
3rd Example: (Table 4, Run 4)
Tributyl(3-pyridyl)stannane (0.092 g, 0.25 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.086 g,
0.0745 mmol) are added to a solution of 3-chloro-4-iodo-1,2,5-thiadiazole (0.062 g, 0.25 mmol) in toluene
(1 mL). This mixture is heated to reflux under nitrogen for 2 h. The reaction medium is then analyzed by
quantitative HPLC (no by-product detected): 38 mg (76%) in situ of 4.

40
HETEROCYCLES, Vol. 60, No. 1, 2003
3-Chloro-4-(furan-2-yl)-1,2,5-thiadiazole (5) (Table 2, Run 3)
2-(Tributylstannyl)furan (0.85 g, 2.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g,
0.1 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (0.33 g, 2.13 mmol) in toluene (4 mL)
and heated to reflux under nitrogen. After 3 and 6 h respectively, two supplementary amounts of
tetrakis(triphenylphosphine)palladium(0) (2 × 0.04 g, 2 × 0.035 mmol) are added. After 24 h of reflux,
quantitative HPLC shows that 60% of product is formed (all the stannane is consumed). The reaction
medium is diluted with ethyl acetate (5 mL) and vigorously stirred with 1M aqueous solution of potassium
fluoride (10 mL) for 2 h. After filtration through celite, the aqueous phase is re-extracted with ethyl
acetate, the combined organic phases are dried over magnesium sulfate, filtered and concentrated. The
resulting 0.86 g of a black oily material is triturated in a n-hexane – ethyl acetate mixture (97/3, v/v). The
precipitate which consists primarily of triphenylphosphine sulfide is eliminated and the supernatant is
purified by chromatography on silica gel (eluant: n-hexane – ethyl acetate, 99/1, v/v) to produce 0.2 g of a
crude solid material. After crystallization in n-pentane, 0.14 g of 5 is isolated (36%) (mp 46°C).
1H-NMR (CDCl3) δ 6.59 (1H, dd, 2J = 1.85 Hz, 3.58 Hz), 7.35 (1H, dd, 2J = 3.58 Hz, 3J = 0.62 Hz), 7.65
2
3
13
(1H, dd, J = 1.85 Hz, J = 0.62 Hz); C-NMR (CDCl3) δ 111.6, 112.5, 141.2, 144.9, 145.7, 148.5;
HR-MS (DEI) m/z: Found: 185.964892 (M+.), Calcd for C6H3N2OClS: 185.965462.
Anal. Calcd for C6H3N2OClS : C, 38.62; H, 1.62; N, 15.01. Found: C, 37.42; H, 1.53; N, 15.03.
3-Chloro-4-(thiophen-2-yl)-1,2,5-thiadiazole (6) (Table 2, Run 4)
2-(Tributylstannyl)thiophene (0.92 g, 2.46 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g,
0.1 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (0.33 g, 2.13 mmol) in toluene (4 mL)
and heated to reflux under nitrogen. After 3 and 6 h respectively, two supplementary amounts of
tetrakis(triphenylphosphine)palladium(0) (2 × 0.04 g, 2 × 0.035 mmol) are added. After 24 h of reflux,
quantitative HPLC shows that 54% of product is formed (all the stannane is consumed). The reaction
medium is diluted with ethyl acetate (5 ml) and vigorously stirred with 1M aqueous solution of potassium
fluoride (10 mL) for 2 h. After filtration through celite, the aqueous phase is re-extracted with ethyl
acetate, the combined organic phases are dried over magnesium sulfate, filtered and concentrated. The
resulting 0.77 g of a black oily material is triturated in a n-hexane – ethyl acetate mixture (97/3, v/v). The
precipitate which consists primarily of triphenylphosphine sulfide is eliminated and the supernatant is
purified by chromatography on silica gel (eluant: n-hexane) to produce 0.3 g of a crude solid material.
After crystallization in n-pentane, 0.2 g of 6 is isolated (47%) (mp range 45-47°C). An analytical sample
is prepared by further crystallization from methanol (mp 54-55°C).
1H-NMR (CDCl3) δ 7.175 (1H, dd, 2J = 5.09 Hz, 3.58 Hz), 7.35 (1H, dd, 2J = 5.09 Hz, 3J = 1.23 Hz), 8.00
(1H, dd, 2J = 3.85 Hz, 3J = 1.23 Hz); 13C-NMR (CDCl3) δ 127.8, 128.5, 129.4, 133.1, 141.5, 152.1;

HETEROCYCLES, Vol. 60, No. 1, 2003
41
HR-MS (DEI) m/z: Found: 201.942459 (M+.), Calcd for C6H3N2ClS2: 201.942619.
Anal. Calcd for C6H3N2ClS2 : C, 35.56; H, 1.49; N, 13.82; Cl, 17.49; S, 31.64. Found: C, 35.90; H, 1.62,
N, 13.24; Cl, 17.64; S, 31.70.
3-Chloro-4-vinyl-1,2,5-thiadiazole (7) (Table 2, Run 5)
2-Tributyl(vinyl)stannane (3.17 g, 10 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.56 g,
0.5 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (1.55 g, 10 mmol) in toluene (10 mL)
and heated to reflux under nitrogen. After 8 h,
a
supplementary amount of
tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.25 mmol) is added. After 24 h of reflux, quantitative
HPLC shows that 35% of product was formed. The reaction medium is diluted with ethyl acetate (10 mL)
and vigorously stirred with 1M aqueous solution of potassium fluoride (15 mL) for 2 h. After filtration
through celite, the aqueous phase is re-extracted with ethyl acetate, the combined organic phases are dried
over magnesium sulfate, filtered and concentrated. The resulting black oily material is triturated in a
n-hexane – ethyl acetate mixture (97/3, v/v). The precipitate which consists primarily of
triphenylphosphine sulfide is eliminated and the supernatant is purified by chromatography on silica gel
(eluant: n-pentane) to produce 7 in the form of a colorless oil: 0.45 g (31%).
1H-NMR (CDCl3) δ 5.71 (1H, dd, Jgem = 1.30 Hz, Jcis 11.1 Hz), 6.38 (1H, dd, Jgem = 1.30 Hz, Jtrans = 17.14
13
Hz), 6.91 (1H, dd, Jcis = 11.1 Hz, Jtrans = 17.4 Hz); C-NMR (CDCl3) δ 122.9, 123.7, 142.9, 154.6;
HR-MS (+ESI) m/z: Found: 146.9785 (M+H)+, Calcd for C4H4N2ClS: 146.9784.
3-Chloro-4-(1-ethoxyvinyl)-1,2,5-thiadiazole (8) (Table 2, Run 6)
1-(Ethoxyvinyl)tributylstannane (1.805 g, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.26 g,
0.225 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (0.775 g, 5 mmol) in toluene (6 mL)
and heated to reflux under nitrogen. After 8 h,
a
supplementary amount of
tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.25 mmol) is added. After 24 h of reflux, quantitative
HPLC shows that 55% of product was formed. The reaction medium is diluted with ethyl acetate (10 mL)
and vigorously stirred with 1M aqueous solution of potassium fluoride (15 mL) for 1 h. After filtration
through celite, the aqueous phase is re-extracted with ethyl acetate, the combined organic phases are dried
over magnesium sulfate, filtered and concentrated. The resulting black oily material is triturated in a
n-hexane – ethyl acetate mixture (97/3, v/v). The precipitate which consists primarily of
triphenylphosphine sulfide is eliminated and the supernatant is purified by chromatography on silica gel
(eluant: n-pentane – diethyl ether, 99/1, v/v) to produce 8 in the form of a colorless oil: 0.45 g (42%).
1H-NMR (CDCl3) δ 1.40 (3H, t, J = 7.0 Hz), 3.93 (2H, q, J = 7.0 Hz), 4.60 (1H, d, Jgem = 3.2 Hz), 5.04
(1H, d, Jgem = 3.2 Hz); 13C-NMR (CDCl3) δ 13.9, 63.8, 90.1, 143.4, 152.0, 154.1; HR-MS (+ESI) m/z:

42
HETEROCYCLES, Vol. 60, No. 1, 2003
Found: 191.0043 (M+H) +, Calcd for C6H8N2OClS : 191.0046.
3-Chloro-4-phenylethynyl-1,2,5-thiadiazole (9) (Table 2, Run 7)
Tributyl(phenylethynyl)stanne (2 g, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.23 g,
0.2 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (0.62 g, 4 mmol) in toluene (8 mL)
and heated to reflux under nitrogen. After 4 and 24 h respectively, two supplementary amounts of
tetrakis(triphenylphosphine)palladium(0) (2 × 0.115 g, 2 × 0.1 mmol) are added. After 30 h of reflux,
quantitative HPLC shows that 38% of product is formed. The reaction medium is diluted with ethyl
acetate (10 mL) and vigorously stirred with 1M aqueous solution of potassium fluoride (15 mL) for 2 h.
After filtration through celite, the aqueous phase is re-extracted with ethyl acetate, the combined organic
phases are dried over magnesium sulfate, filtered and concentrated. The resulting 2.83 g of a black oily
material is triturated in a n-hexane – ethyl acetate mixture (97/3, v/v). The precipitate which consists
primarily of triphenylphosphine sulfide is eliminated and the supernatant is purified by chromatography
on silica gel (eluant: n-hexane) to produce 0.34 g of a crude oily material which crystallizes slowly. After
crystallization in n-hexane, 9 is isolated as a white solid: 0.25 g (28.5%) (mp 57°C).
13
1H-NMR (CDCl3) δ 7.42 (3H, m), 7.62 (2H, dd); C-NMR (CDCl3) δ 79.5, 96.8, 121.2, 129.0 (2C),
130.5, 132.7 (2C); HR-MS (DEI) m/z: Found: 219.985638 (M+.), Calcd for C10H5N2ClS: 219.986198.
Anal. Calcd for C10H5N2ClS : C, 54.43; H, 2.28; N, 12.69; Cl, 16.07; S, 14.53. Found: C, 54.05; H, 2.43;
N, 12.52; Cl, 16.05; S, 14.39.
3-Allyl-4-chloro-1,2,5-thiadiazole (10) (Table 2, Run 8)
Tributyl(phenylethynyl)stannane (1.75 g, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.23 g,
0.2 mmol) are added to a solution of 3,4-dichloro-1,2,5-thiadiazole (0.62 g, 4 mmol) in toluene (8 mL)
and heated to reflux under nitrogen. After 4 and 24 h respectively, two supplementary amounts of
tetrakis(triphenylphosphine)palladium(0) (2 × 0.115 g, 2 × 0.1 mmol) are added. After 30 h of reflux,
quantitative HPLC shows that 60% of product was formed. The reaction medium is diluted with ethyl
acetate (10 mL) and vigorously stirred with 1M aqueous solution of potassium fluoride (15 mL) for 2 h.
After filtration through celite, the aqueous phase is re-extracted with ethyl acetate, the combined organic
phases are dried over magnesium sulfate, filtered and concentrated. The resulting 1.6 g of a black oily
material is triturated in a n-hexane – ethyl acetate mixture (97/3, v/v). The precipitate which consists
primarily of triphenylphosphine sulfide is eliminated and the supernatant is purified by chromatography
on silica gel (eluant: n-hexane) to produce 10 as an oil: 0.2 g (31%).
13
1H-NMR (CDCl3) δ 3.68 (2H, dd), 5.18 (1H, dd), 5.24 (1H), 6.01 (1H, m); C-NMR (CDCl3) δ 34.1,
118.8, 132.1, 144.9, 159.3; HR-MS (DEI) m/z: Found: 159.9860 (M+.), Calcd for C5H5N2ClS: 159.9861.

HETEROCYCLES, Vol. 60, No. 1, 2003
43
3-Bromo-4-chloro-1,2,5-thiadiazole (12)
To a solution of copper(II) bromide (53 g, 0.2385 mol) in anhydrous acetonitrile (500 mL) under nitrogen
is added tert-butyl nitrite (34 g, 0.3 mmol). The resulting mixture is heated to 60-70°C and a solution of
4-amino-3-chloro-1,2,5-thiadiazole (27 g, 0.2 mmol) in anhydrous acetonitrile (300 mL) is added
dropwise. Heating is maintained for 30 min after the end of addition. After cooling to rt, water (400 mL)
is added and acetonitrile is distilled off under reduced pressure. The resulting oily material is extracted
with cyclohexane (2 × 400 mL). The combined organic layers are dried over magnesium sulfate, filtered
and concentrated to a mass of 30 g. Distillation under reduced pressure (bp 58°C/5 mbar) affords 27.6 g of
12 (70%).
13C-NMR (CDCl3) δ 133.1, 147.2; GC-MS (EI) m/z: 198 (M+.); Anal. Calcd for C2N2BrClS : C, 12.04;
N, 14.04; Br, 40.06; Cl, 17.77; S, 16.08. Found: C, 12.33; N, 13.92; Br, 39.80; Cl, 17.49; S, 15.79.
3-Chloro-4-iodo-1,2,5-thiadiazole (13)
To a solution of copper(I) iodide (22.83 g, 0.12 mol) in anhydrous acetonitrile (200 mL) under nitrogen is
added tert-butyl nitrite (15 g, 0.146 mmol). The resulting mixture is heated to 60°C and a solution of
4-amino-3-chloro-1,2,5-thiadiazole (13.45 g, 0.1 mmol) in anhydrous acetonitrile (200 mL) is added
dropwise whitin 30 min. Heating is maintained for 30 min after the end of addition. After cooling to rt,
water (1 L) is added and acetonitrile is distilled off under reduced pressure. The resulting oily material is
extracted with cyclohexane (2 × 500 mL). The combined organic layers are washed with water
(2 × 200 mL), dried over magnesium sulfate, filtered and concentrated to a mass of 15 g. Distillation
under reduced pressure (bp 50-51°C/0.2 mbar) affords 15 g of 13 (41%).
13C-NMR (CDCl3) δ 107.8, 152.7; GC-MS (EI) m/z: 246 (M+.); Anal. Calcd for C2N2ClIS : C, 9.75;
N, 11.37; Cl, 14.39; I, 51.49; S, 13.01. Found: C, 10.34; N, 11.21; Cl, 14.33; I, 51.47; S, 13.17.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Prof. J. Reisse, Dr. V. Libert and Dr. M. Martinelli for helpful
discussions and reviewing of the present paper. Mrs. A. Mockel (NMR), Dr. P. Delbeke (NMR), Dr. I.
Hoes (MS), Mr. E.Marlot (MS) and Mr. B. Bonnier (HPLC) are also acknowledged for their analytical
support.
REFERENCES AND NOTES

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HETEROCYCLES, Vol. 60, No. 1, 2003
1. Y. Hanasaki, H. Watanabe, K. Katsuura, H. Takayama, S. Shirakawa, K. Yamaguchi, S. Sakai,
K. Ijichi, M. Fujiwara, K. Konno, T. Yokota, S. Shigeta, and M. Baba, J. Med. Chem., 1995, 38, 2038.
See also references cited in this paper.
2. For the [4+1] approach (N-C-C-N/S): see (a) L. M. Weinstock, P. Davis, B. Handelsman, and R.
J. Tull, J. Org. Chem., 1967, 32, 2823. For the [3+2] approach (C-C-N/N-S): see (b) S. C. Yoon, J.
Cho, and K. Kim, J. Chem. Soc., Perkin Trans. I, 1998, 109. For the [2+3] approach (C-C/N-S-N): see
(c) L. M. Weinstock and I. Shinkai, “1,2,5-Thiadiazoles and Their Benzo Derivatives” in
“Comprehensive Heterocyclic Chemistry”, ed. by A. R. Katritzky, C. W. Rees and K. T. Potts,
Pergamon Press, Oxford, 1984, Vol. 6, p. 513.
3. Y. Hanasaki, Heterocycles, 1996, 43, 2435.
4. A. Merschaert and R. L. Robey, Eli Lilly & Co., “Palladium-catalyzed cross-coupling chemistry on
3-chloro-4-halogeno-1,2,5-thiadiazole”, US Application 09/370957, 1998.
5. J.K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508.
6. A. Suzuki, Pure & Appl. Chem., 1994, 66, 213.
7. Both 3-bromo-4-chloro- and 3-chloro-4-iodo-1,2,5-thiadiazole are not reported in the current literature
yet. Only the 3-chloro-4-fluoro-1,2,5-thiadiazole is reported as occurring into a mixture (mono- and
difluorinated 1,2,5-thiadiazoles) resulting from the reaction of potassium fluoride on the 3,4-dichloro-
1,2,5-thiadiazole in sulfolane: see M. Geisel and R. Mews, Chem. Ber., 1982, 115, 2135.
8. Formation of 3,4-diamino-1,2,5-thiadiazole: see (a) A.P. Komin and M. Carmack, J. Heterocycl.
Chem., 1976, 13, 13. Formation of 3,4-bis(2-(trimethylsilyl)ethynyl)-1,2,5-thiadiazole: see (b)
J. Kouvetakis, D. Grotjahn, P. Becker, S. Moore, and R. Dupon, Chem. Mater., 1994, 6, 636.
9. L. M. Weinstock, D. M. Mulvey, and R. Tull, J. Org. Chem., 1976, 41, 3121.
10. A. Merschaert, “Réactivité des 3,4-dihalogéno-1,2,5-thiadiazoles. Application au 3,4-dichloro-
1,2,5-thiadiazole de la réaction de couplage croisé catalysée par les métaux de transition”,
Dissertation, Free University of Brussels, 1998.
11. A sample of 3-chloro-4-phenyl-1,2,5-thiadiazole was prepared by cyclization reaction of α-amino-
α-phenylacetonitrile with sulfur monochloride: see reference 2a.
12. The 3,4-diphenyl-1,2,5-thiadiazole was prepared by Pd-catalyzed cross-coupling reaction of 3-chloro-
4-phenyl-1,2,5-thiadiazole with tributylphenyl stannane under the Stille conditions reported in
reference 3.
13. Occurrence of minor degradations via pathway 2b is also suggested in reference 3.
14. According to the nomenclature the 3- and 4-position are ranked by alphabetic order. For example:
3-chloro-4-vinyl- vs. 3-allyl-4-chloro-1,2,5-thiadiazole.

HETEROCYCLES, Vol. 60, No. 1, 2003
45
15. In this case the cross-coupling reaction, involving 3,4-dichloro-1,2,5-thiadiazole as substrate and
tributyl(3-pyridyl)stannane as Stille reagent, was screened with several other catalysts than Pd(Ph3P)4,
i.e. Pd(2-furyl3P)4, Pd[(C6F5)3P]4, Pd(o-tolyl3P)4, Pd(c-hex3P)4, Pd(Ph3As)4, Pd(Ph3Sb)4, Pd(dppe)Cl2,
Pd(dppp), Pd(dppp)2, Pd(dppb), Pd(dppf)2, Pd2(dba)3 and Pd(CH3CN)2Cl2. No any of these catalysts,
except Pd(2-furyl3P)4 was found to be effective: see reference 10.
16. Synthesis of 3-chloro-4-(pyrid-3-yl)-1,2,5-thiadiazole is reported by cyclization of the Strecker adduct
of pyridine-3-carboxaldehyde with sulfur monochloride: see P. Sauerberg, P. H. Olesen, S. Nielsen,
S. Treppendahl, M. J. Sheardown, T. Honoré, C. H. Mitch, J. S. Ward, A. J. Pike, F. B. Bymaster, B.
D. Sawyer, and U. H. E. Shannon, J. Med. Chem., 1992, 35, 2274.
17. 3-Pyridylboronic acid was prepared by reaction of 3-pyridylmagnesium bromide on a trialkylborate:
see F. C. Fischer and E. Havinga, Rec. Trav. Chim. Pays-Bas, 1965, 84, 439; ibid., 1974, 93, 21.
18. Screening trials involving other catalyst, base and solvent conditions were found to be ineffective: see
reference 10.
19. Preparation of 3-amino-4-chloro-1,2,5-thiadiazole: see reference 2a. See also the next patent
applications: K. Menzl, Lentia GmbH, “Verfahren zur Herstellung von 1,2,5-Thiadiazolderivaten”,
DE 1175683, 1962 (Chem. Abstr., 1964, 61, 69177); Oesterreichische Stickstoffwerke AG, “Nouvelle
sulfonamide et procédé pour sa préparation”, BE 629551, 1963 (Chem. Abstr., 1963, 60, 90900).
20. M. P. Doyle, B. Siegfried, and J. F. Dellaria, Jr., J. Org. Chem., 1977, 42, 2426.
21. C. A. Alt, L. Merritt, G. A. Rhodes, R. L. Robey, E. E. Van Meter, J. S. Ward, and C. H. Mitch, Eli
Lilly & Co., “Preparation of 1,2,5-thiadiazoles as CNS agents”, Eur. Pat. Appl., 0709381, 1996
(Chem. Abstr., 1996, 125, 86647).