On the reaction of thiazole-2,4-diamines with isothiocyanates - Preparation and transformation of 2,4-diaminothiazole-5-carbothioamides

Article abstract of DOI:10.1002/hlca.200390154

In the reaction of thiazole-2,4-diamines 8 with isothiocyanates 1, 2,4-diaminothiazole-5-carbothioamides 9, 10, 18, and 19 as well as thiazolo[4,5-d]pyrimidine-7(6H)-thiones 21 were formed. The carbothioamides 9, 10, and 18 were transformed by reaction with different types of monofunctional and bifunctional electrophiles into hitherto unknown acceptor-substituted 4,4′-([2,5′-bithiazole]-2′,4′-diyl)bis[morpholines] 24 and 29, the 2′,4′-bis(dialkylamino)[2,5′-bithiazol]-4-(5H)-ones 30, and the 4-substituted 2′,4′-bis(dialkylamino)-2,5′-bithiazoles 31. From 30 and 31 new 4-mono- or 4,5-disubstituted 2′,4′-bis(dialkylamino)-2,5′-bithiazoles 34, 35, 38, and 39 as well as 5-substituted 2′,4′- bis(dialkylamino)[2,5′-bithiazol]-4(5H)-ones 33, 36, and 37 were prepared.

Full text of DOI:10.1002/hlca.200390154

Helvetica Chimica Acta Vol. 86 (2003)
1949
On the Reaction of Thiazole-2,4-diamines with Isothiocyanates
Preparation and Transformation of 2,4-Diaminothiazole-5-carbothioamides
by Cornelia Hahnemann and Horst Hartmann*
Fachbereich Chemie und Umweltingenieurwesen, Fachhochschule Merseburg, Geusaer Strasse,
D-06217Merseburg
In the reaction of thiazole-2,4-diamines 8 with isothiocyanates 1, 2,4-diaminothiazole-5-carbothioamides 9,
10, 18, and 19 as well as thiazolo[4,5-d]pyrimidine-7(6H)-thiones 21 were formed. The carbothioamides 9, 10,
and 18 were transformed by reaction with different types of monofunctional and bifunctional electrophiles into
hitherto unknown acceptor-substituted 4,4'-([2,5'-bithiazole]-2',4'-diyl)bis[morpholines] 24 and 29, the 2',4'-
bis(dialkylamino)[2,5'-bithiazol]-4-(5H)-ones 30, and the 4-substituted 2',4'-bis(dialkylamino)-2,5'-bithiazoles
31. From 30 and 31 new 4-mono- or 4,5-disubstituted 2',4'-bis(dialkylamino)-2,5'-bithiazoles 34, 35, 38, and 39 as
well as 5-substituted 2',4'-bis(dialkylamino)[2,5'-bithiazol]-4(5H)-ones 33, 36, and 37 were prepared.
Introduction. Isothiocyanates 1 are, similar to other heterocumulenes, electro-
philic compounds able to react with different types of nucleophiles [1]. For example,
they can react with a series of electron-rich olefinic compounds 2, such as enamines [2]
or ketene N,S-acetals [3]. Independently of the substitution degree at the amino group,
they usually react with the nucleophilic C-atom of compounds 2 to yield 3-amino-
substituted thioacrylamides 3 [4] (Scheme 1). In contrast, with simple aromatic amines,
isothiocyanates 1 react at their nucleophilic N-atom, as long as the amino moiety is not
disubstituted, yielding corresponding thiourea derivatives 4 [5]. With N,N-disubsti-
tuted anilines, however, the reaction usually fails. The same is also observed for the
reaction with N,N-disubstituted heteroaromatic amines such as thiazol-2-amines,
whereas, e.g., N-unsubstituted or N-monosubstituted thiazol-2-amines are able to react
at the amino group with isothiocyanates giving rise to the formation of the
corresponding thiourea derivatives [6].
Scheme 1

1950
Helvetica Chimica Acta Vol. 86 (2003)
The situation is significantly different in the case of thiazole-2,4-diamines 8. As
documented in the literature for one example so far, these compounds are able to react
with aryl isothiocyanates 1 (R ˆ Aryl) at C(5) of the heterocyclic system to yield 2,4-
diaminothiazole-5-carbothioamides 9 [7]. Because this reaction was not generalized
hitherto and the product obtained was not used for other reactions, we studied the
reaction thiazole-2,4-diamines 8 with a series of different isothiocyanates 1 in more
detail.
Results and Discussion. The required substituted thiazole-2,4-diamines 8 were
easily prepared starting from N,N-disubstituted thioureas 5 and chloroacetonitrile (6)
[8] (Scheme 2). In a first step, 2-aminothiazol-4(5H)-iminium chlorides 7 were formed.
These salts could be transformed, subsequently, by reaction with primary or secondary
amines into the N2,N2,N4,N4-tetrasubstituted thiazole-2,4-diamines 8 [9].
Scheme 2
Advantageously, the highly reactive heteroaromatic diamines 8 had to be stored as
their mineral-acid adducts 8 ¥ HX and generated from those by addition of a base before
their use in the reaction with the isothiocyanates 1. This reaction was performed, in
general, by heating the mixture of 1 and 8 in MeOH, from which the products of the
general structure 9 separated on cooling (Scheme 3). The yields of the thus prepared
2,4-diaminothiazol-5-carbothioamides 9a v ranged from 25 to 93% (see Table 1 in the
Exper. Part). Their structures were elucidated from elemental analyses and spectro-
scopic data. Whereas there is no doubt about the structure of the products 9 obtained
from N2,N2,N4,N4-tetrasubstituted thiazole-2,4-diamines 8, some doubt is legitimated
regarding the structure of the products 10 obtained from the reaction of isothiocyanates
1 with thiazole-2,4-diamines which bear a monosubstituted or unsubstituted amino
group at C(4) and were generated in situ from their iminium salts 7; alternatively to the
formation of 2,4-diaminothiazole-5-carbothioamides 10 with a primary amino group at
C(4), thiourea derivatives 11 might have been generated by the attack of isothiocya-
1
nates 1 at the 4-amino group of 7. However, the H-decoupled 13C-NMR spectra
unambiguously established the general structure 10 for the products obtained from 1
and 7 (see also data in Tables 1 and 2 in the Exper. Part). It is worth mentioning that the
formation of compounds 10 was not accompanied by the simultaneous or exclusive
formation of N2,N2,N2',N2'-tetraalkyl[4,5'-bithiazole]-2,2',4'-triamines, the self-conden-
sation products of the free thiazole-2,4-diamines primarily formed from their 2-
aminothiazol-4(5H)-iminium precursors 7 [10].

Helvetica Chimica Acta Vol. 86 (2003)
Scheme 3a)
1951
The 2,4-diaminothiazole-5-carbothioamides 9 and 10 are yellow or orange solids
that are highly reactive towards alkylating reagents. As exemplified with 9p and MeI,
alkylation at the thiocarbonyl group occurred, and the N-[(diaminothiazolyl)-
(methylthio)methylene]benzenaminium iodide 12 was formed (Scheme 4). Its struc-
ture was unambiguously elucidated from analytic and spectroscopic data.
With halomethyl carbonyl compounds 13, which are also strong electrophilic
reagents and, moreover, versatile synthons for preparing thiazoles via a Hantzsch
reaction [11], the 2,4-diaminothiazole-5-carbothioamides 9 also reacted. However, the
products could be isolated only under special conditions and in the case of specially
substituted starting materials, e.g., from chloro- or nitro-substituted phenacylmethyl
halides 13e and 13f. Thus, by heating an equimolar mixture of 2,4-diaminothiazole-5-
carbothioamides 9l or 9g, 2-bromo-2-(4-nitrophenyl)ethanone (13f), and Mg(ClO4)2 in
Ac2O, the corresponding 2',4'-bis(dialkylamino)-3,4-diaryl[2,5'-bithiazol]-3-ium per-
chlorates 15j and 15f were isolated (Scheme 4). These compounds result, obviously, via
the primarily formed 14 by a ring-closure reaction between the carbonyl and iminium
groups.
However, a mixture of 9 and 13e or 13f in AcOH at reflux temperature reacted to
give products 16 having lost the amino group of the starting compound 9 (Scheme 4).
The alternative formation of 17 was excluded by the fact that 9r containing a piperidin-
1-yl group at C(2) and a morpholin-4-yl group at C(4) yielded 16a containing only a
1
morpholin-4-yl group, as established by its characteristic H-NMR signals. Thus, the
piperidin-1-yl moiety at C(2) of the putative intermediate 15i was selectively
hydrolyzed to give 16a. The 2',4'-bis(dialkylamino)-3,4-diaryl[2,5'-bithiazol]-3-ium

1952
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 4
perchlorates 15 and the 5-[3-aryl-4-aryl'-thiazol-2(3H)-ylidene]-4-(dialkylamino)thia-
zol-2(5H)-ones 16 are deep red compounds which absorb in CH2Cl2 at ca. 470 and
420 nm, respectively.
The reaction of thiazole-2,4-diamines 8 with isothiocyanates can also be extended to
acyl isothiocyanates, as exemplified with pivaloyl isothiocyanate (1w). In this case, new
N5-pivaloyl-substituted 2,4-diaminothiazole-5-carbothioamides 18 were obtained
(Scheme 5). When N4-unsubstituted thiazole-2,4-diamines, generated in situ from the
corresponding hydrochlorides 7, were used for this reaction, fused thiazolo[4,5-
d]pyrimidine-7(6H)-thiones 21 were obtained instead of the corresponding N5-
pivaloyl-substituted 2,4-diaminothiazole-5-carbothioamides 20. Obviously, these com-
pounds result from the primarily formed 20 by a condensation reaction between
the pivaloyl group and the free amino group at C(4). In contrast to compounds 18,

Helvetica Chimica Acta Vol. 86 (2003)
1953
Scheme 5
which are deep yellow, the fused thiones 21 are nearly colorless. Their structures were
determined from elemental analysis, NMR, and MS data.
Similarly to other N-acylthioureas [12], the N5-pivaloyl-substituted 2,4-diamino-
thiazole-5-carbothioamides 18 formally vinylogous N-acylthioureas, react with accept-
or-substituted halomethyl compounds 13 or 22 (Scheme 6). The reaction was
performed with 18a and some halomethyl compounds in analogy to the previously
mentioned alkylations of the N5-alkyl- or N5-aryl-substituted 2,4-diaminothiazole-5-
carbothioamides 9 (see Scheme 4) by heating the components in MeCN and subsequent
addition of Et3N to the hot mixture. In contrast to the reaction with chloroacetone
(13a) and 4-nitrobenzyl bromide (22a), from which the expected acetyl-(tert-butyl)-
and (tert-butyl)-(4-nitrophenyl)-substituted 4,4'-([2,5'-bithiazole]-2',4'-diyl)bis[mor-
pholines] 24a and 24e, respectively, were obtained, unexpected products could be
isolated with other halomethyl compounds, such as from chloroacetonitrile (22d) or
phenacyl bromide (13d). In these cases, 2,4-di(morpholin-4-yl)thiazole-5-carbonitrile
(26) was obtained as the sole product. This compound was unambiguously identified by
an IR absorption band at 2200 cmÀ1 and was obviously formed by base-initiated
splitting of a pivaloyl and a phenacylthio or mercaptoacetonitrile (Acc ˆ CN) moiety
from the intermediate 25 similar to other compounds of comparable structures recently
described [13].
The N5-pivaloyl-substituted 2,4-diaminothiazole-5-carbothioamides 18 decom-
posed, analogously to other N-acylthioamides and thioureas [14], into the N5-
unsubstituted 5-carbothioamides 19 in the presence of strong mineral acid at room
temperature. With the unsubstituted carbothioamide moiety, compounds 19 are
interesting starting materials for preparing the unknown acceptor-substituted 4,4'-
([2,5'-bithiazole]-2',4'-diyl)bis[morpholines] 29 (Scheme 7). For example, 19a was
transformed by reaction with triethyl orthoformate and morpholine according to a
recently published procedure [15] into 2,4-di(morpholin-4-yl)-N5-[(morpholin-4-yl)-
methylene]thiazole-5-carbothioamide (27), from which the 5-acceptor-substituted 4,4'-

1954
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 6
([2,5'-bithiazole]-2',4'-diyl)bis[morpholines] 29 were available via the reaction with 13.
Alternatively, 29 could be prepared also by the reaction of 19a with 22 to yield the
intermediate carbothioamide hydrohalide 28 (not isolated), from which the products
29 were obtained, subsequently, by reaction with a formylating agent, e.g., with the
Vilsmeier reagent prepared from DMF and POCl3 [16].
Furthermore, the 2,4-diaminothiazole-5-carbothioamides 19 were transformed into
2',4'-diamino[2,5'-bithiazol]-4(5H)-ones 30 by reaction with methyl bromoacetate
(13c) or into 4-substituted 2',4'-diamino-2,5'-bithiazoles 31 by reaction with halomethyl
ketones 13a, 13b, or 13d. Satisfactory yields of products were obtained by heating the
appropriate components in EtOH solution (see Scheme 8).
To study the reactivity of 30 and 31 towards electrophiles, they were allowed to
react with arenediazonium salts and with the Vilsmeier reagent. As reported earlier
[17][18], such reagents are able to react with 2-amino-substituted thiazol-4(5H)-ones
or thiazole-2-amines unsubstituted at C(5). Thus, the reaction of 30a with 4-
nitrobenzenediazonium salt gave the 2',4'-di(morpholin-4-yl)[2,5'-bithiazole]-4,5-dione
5-[4-nitrophenyl)hydrazone] (33a), which, by subsequent reaction with H3BO3 and
Ac2O, was converted to the fused thiazolo[5,4-e]-1,3,4,2-oxadiazaborine derivative 32,
in analogy to the reaction of other 1,2-dione monohydrazones [19]. With the Vilsmeier
reagent, 30a yielded, depending on the reaction conditions, the chloro-substituted 4,4'-
([2,5'-bithiazol]-2',4'-diyl)bis[morpholine] 34a or 2',4'-di(morpholin-4-yl)[2,5'-bithia-
zole]-5-carboxaldehyde 35a. Obviously, 34a is the precursor of 35a.

Helvetica Chimica Acta Vol. 86 (2003)
1955
Scheme 7
Owing to their thiazol-4(5H)-one structure, compounds 30 undergo also base-
catalyzed reactions with less-reactive electrophiles, e.g., with 4-(dimethylamino)benz-
aldehyde or CS2. Whereas, in the former case, deeply colored 5-[(4-dimethylamino)-
benzylidene][2,5'-bithiazol]-4(5H)-ones 36 were formed, in the latter case, unstable
4,5-dihydro-4-oxo[2,5'-bithiazole]carbodithioic acids were generated. These com-
pounds could be transformed into stable 5-(1,3-dithiolan-2-ylidene)[2,5'-bithiazol]-
4(5H)-ones 37 by reaction with 1,2-dibromoethane.
In contrast to 30, the 2,5'-bithiazole derivatives 31 were unable to react with less-
reactive electrophilic reagents such as arenediazonium salts. With the Vilsmeier reagent
at elevated temperatures, however, they were transformed into 4-substituted [2,5'-
bithiazole]-5-carboxaldehydes 38. These compounds can be subsequently transformed,
e.g., by treatment with malononitrile in the presence of catalytic amounts of Et3N, into
deeply colored 2-[([2,5'-bithiazol]-5-yl)methylene]propanedinitriles 39.
Because thiazole-2-amines are frequently biologically active, e.g., as active
compounds for treatment of allergies [20], hypertension [21], inflammation [22],
tumors [23], schizophrenia [24], HIV infection [25], as antibiotics [26], or as inhibitors
for cyclin-dependent kinases [27], several of the compounds described in this paper,
especially carbothioamide derivatives 9 and 10, were tested for some of these activities.
Other compounds, such as the 2-methylenepropanedinitriles 39 or the [2,5'-bithiazole]-
5-carboxaldehydes 35a and 38, were tested accordingly to their nonlinear optical
properties [28] or used as precursors for preparing compounds with such properties
[29]. The results of these studies will be reported elsewhere.
The authors thank ChemTec, Leuna, for generous financial support. They also thank Mrs. C. Kˆnig and Mrs.
A. Schrˆder for recording the NMR and UV/VIS spectra.

1956
Helvetica Chimica Acta Vol. 86 (2003)
Scheme 8
‡
i) 13c Et3N. ii) 13a,b,d Et3N. iii) 4-NO2C6H4N2 . iv) H3BO3, Ac2O. v) DMF, POCl3. vi) 4-Me2NC6H4CHO.
vii) 1. CS2, NaOH: 2. (CH2Br)2. viii) CH2(CN)2, Et3N.

Helvetica Chimica Acta Vol. 86 (2003)
1957
Experimental Part
General. M.p.: Boetius heating-table microscope; uncorrected. IR Spectra: KBr pellets; Philips FTIR-PU-
9624 spectrometer; in cmÀ1. UV/VIS Spectra: Zeiss MC-400 spectrometer; lmax (log e) in nm. NMR Spectra:
Varian Gemini-300 300 MHz spectrometer; d in ppm. Elemental analyses: Leco CHNS-932 analyzer.
2-(Dialkylamino)thiazol-4(5H)-iminium Chlorides 7 and N2,2,N4,N4-Tetraalkyl-Substituted Thiazole-2,4-
diamines 8. These starting materials were prepared according to [8][9].
2,4-Bis(dialkylamino)thiazole-5-carbothioamides 9: General Procedure. A mixture of a thiazole-2,4-
diamine 8 (0.01 mol), prepared from the corresponding mineral-acid adduct 8 ¥ HX [8] by treatment with aq.
NaOH soln., and an isothiocyanate 1 (0.01 mol) in MeOH (50 ml) was heated to reflux for 15 min. The
precipitated product was filtered off after cooling to r.t. and then washed with EtOH and Et2O: 9a v, see
Tables 1 and 2.
4-Amino-2-(dialkylamino)thiazole-5-carbothioamides 10: General Procedure. To a suspension of a 2-
(dialkylamino)thiazol-5(5H)-iminium chloride 7 (0.02 mol) in toluene (100 ml), Et3N (28 ml, 0.02 mol) and
isothiocyanate 1 (0.02 mol) were added. After refluxing the mixture for 1 h, the precipitated Et3N ¥ HCl was
filtered off and washed with hot toluene. After cooling, the product crystallized from the filtrate. The crystals
were washed with Et2O: 10a f, see Tables 1 and 2.
Table 1. Characteristic Data of Compounds 9 and 10
R1R2Na) R3R4Na)
R
Yield [%] M.p. [8] Formula calc.
(Mr) found
C
H
N
S
9a mor
mor
pip
Me
Me
Me
Me
34
84
80
25
172 173 C13H20N4O2S2
(328.46)
191 193 C15H24N4S2
(324.51)
193 195 C13H20N4S2
(296.46)
127 129 C 14H22N4OS2
(326.48)
128 130 C15H22N4O2S2
(354.49)
84 85 C16H24N4OS2
(358.52)
171 173 C19H24N4O2S2
(404.55)
170 172 C21H28N4S2
(400.61)
47.54 6.14 17.06 19.53
47.87 6.17 16.99 19.48
55.52 7.45 17.27 19.76
55.53 7.47 17.19 19.44
52.676.80 18.90 21.63
52.51 6.88 18.85 21.43
51.50 6.79 17.16 19.64
52.08 6.45 17.19 19.66
50.82 6.26 15.80 18.09
50.49 6.18 15.93 18.05
54.51 6.86 15.89 18.19
54.08 6.99 16.00 18.61
56.41 5.98 13.85 15.85
56.32 5.94 13.86 15.83
62.96 7.04 13.00 16.01
63.376.80 13.82 16.06
58.73 6.23 14.42 16.51
59.28 6.33 14.69 16.77
59.676.51 13.92 15.93
59.90 6.36 14.00 15.77
55.36 5.68 14.35 16.42
55.73 5.32 14.23 16.31
62.14 6.78 14.49 16.59
62.01 6.83 14.80 16.45
60.30 6.18 15.63 17.89
60.52 6.34 15.58 17.65
57.72 5.92 14.96 17.12
58.01 5.83 14.80 17.45
58.73 6.23 14.42 16.51
59.19 6.15 14.72 16.68
54.26 5.75 13.32 15.25
54.65 5.84 13.38 15.26
60.54 6.77 13.45 15.39
60.85 6.75 13.51 15.36
b
c
pip
pyr
pip
pyr
d
e
f
mor
mor
mor
mor
pip
mor
pip
CH2ˆCHCH2 69
CH2ˆCHCH2 71
g
h
i
mor
pip
PhCH2
PhCH2
PhCH2
PhCH2
Ph
83
88
mor
pip
pyr
69
117 119 C 19H24N4OS2
(388.55)
j
mor
mor
pip
87191 192
C
20H26N4OS2
(402.58)
k
l
mor
pip
73
74
72
70
211
C18H22N4O2S2
(390.53)
Ph
168 170 C20H26N4S2
(386.56)
m
n
o
p
q
pyr
mor
pip
pyr
Ph
164
C18H22N4S2
(358.53)
pyr
Ph
160 162 C18H22N4OS2
(374.53)
mor
mor
pip
Ph
2180720C7
19H24N4OS2
(388.55)
mor
pip
4-MeOC6H4
4-MeOC6H4
86
74
172
C19H24N4O3S2
(420.55)
178 180 C21H28N4OS2
(416.61)

1958
Helvetica Chimica Acta Vol. 86 (2003)
Table 1 (cont.)
r
pip
mor
mor
pip
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
88
74
184 185
216 218
C20H26N4O2S2
(418.58)
C18H21ClN4O2S2
(424.97)
20H25ClN4S2
(421.02)
C18H21ClN4OS2
(408.97)
C19H23ClN4OS2
(423.00)
C14H16N4OS2
(320.44)
C15H18N4S2
(318.46)
C14H16N4S2
(304.44)
57.39
57.18
50.874.98
51.31
57.05
57.26
52.86
52.93
53.95
54.19
52.48
52.24
56.57
56.25
55.23
55.08
57.45
57.71
47.38
47.29
51.41
51.14
6.26
6.44
13.39
13.69
15.32
15.58
15.09
s
mor
pip
13.18
5.04
5.99
6.08
5.18
5.12
5.48
5.86
5.03
4.82
5.70
5.65
5.30
4.85
6.63
6.74
4.26
3.80
5.18
4.62
13.17
13.31
13.31
13.70
14.15
13.25
15.06
15.23
15.30
15.68
15.99
15.16
t
67183 185
C
u
v
10a
b
c
mor
pip
pyr
61
93
75
72
65
63
79
81
169 171
mor
180 182
205 207
190 193
185 186
138 139
204 206
217 218
13.6715.50
mor
pip
17.48
17.01
17.59
17.11
18.40
18.59
16.75
16.39
15.79
16.10
15.99
16.02
20.01
19.79
20.14
19.98
21.07
20.86
19.17
18.78
18.07
17.76
18.30
18.23
Ph
pyr
Ph
d
e
f
Pr2N
mor
mor
Ph
C16H22N4S2
(334.50)
C14H15ClN4OS2
(354.88)
C 15H18N4O2S2
(350.46)
4-ClC6H4
4-MeOC6H4
a) morˆ morpholin-4-yl, pip ˆ piperidin-1-yl, pyrˆ pyrrolidin-1-yl.
N-{[2,4-Di(morpholin-4-yl)thiazol-5-yl](methylthio)methylene}-4-methoxybenzenaminium Iodide (12). To
a soln. of N5-(4-methoxyphenyl)-2,4-di(morpholin-4-yl)thiazole-5-carbothioamide (9p; 4.2 g, 10 mmol) in
CH2Cl2 (50 ml), Mel (1.4 g, 10 mmol) was added. After keeping the mixture overnight, the precipitate was
filtered off: 4.3 g (77%) of 12. Yellow crystals. M.p. 207 210 8. 1H-NMR (CDCl3): 1.57( s, MeS); 2.24 (s, MeN);
3.68 (m, 8 H, CH2N); 3.78 (m, 8 H, CH2O); 6.83 (d, 2 arom. H); 7.50 (d, 2 arom. H); 11.29 (s, NH). Anal. calc.
for C20H27IN4O3S2 (562.49): C 42.71, H 4.84, N 9.96, S 11.40; found: C 42.57, H 4.99, N 10.04, S 11.25.
2',4'-Bis(dialkylamino)-3,4-diaryl[2,5'-bithiazol]-3-ium Perchlorates 15: General Procedure. A mixture of
2,4-bis(dialkylamino)thiazole-5-carbothioamide 9l or 9q (0.01 mol), phenacyl bromide 13f (0.01 mol),
Mg(ClO4)2 (1.15 g, 5 mmol), and Ac2O (15 ml) was refluxed for 25 min. After cooling, the mixture was diluted
with aq. EtOH soln. (50 ml). The precipitated product was filtered off and recrystallized from AcOH: 15a' or
15f, resp.
4-(4-Nitrophenyl)-3-phenyl-2',4'-dipiperidin-1-yl)[2,5'-bithiazol]-3-ium Perchlorate (15j) from N5-phenyl-
2,4-di(piperidin-1-yl) thiazole-5-carbothioamide (9o) and 4-nitrophenacyl bromide (13f). Yield 19%. M.p.
303 3058. UV/VIS (CH2Cl2): 467(4.38). 1H-NMR ((D6)DMSO): 1.54 (m, 6 H, CH2); 1.68 (m, 6 H, CH2); 3.32
(t, 4 H, CH2N); 3.46 (t, 4 H, CH2N); 7.7 5 (m, 5 arom. H); 8.10 (d, 2 arom. H); 8.40 (d, 2 arom. H); 10.82
(s, 1 heteroarom. H). Anal. calc. for C28H30ClN5O6S2 (632.15): C 53.20, H 4.78, N 11.08, S 10.15; found: C 53.41,
H 4.91, N 10.88, S 9.99.
3-(4-Methoxyphenyl)-4-(4-nitrophenyl)-2',4'-di(piperidin-1-yl)[2,5'-bithiazol]-3-ium Perchlorate (15f).
From N5-(4-methoxyphenyl)-2,4-di(piperidin-1-yl)thiazole-5-carbothioamide (9q) and 4-nitrophenacyl bro-
mide (13f). Yield 23%. M.p. 268 2698. UV/VIS: 470 (4.43). 1H-NMR ((D6)DMSO): 1.57( m, 6 H, CH2); 1.69
(m, 6 H, CH2); 3.28 (t, 4 H, CH2N); 3.47( t, 4 H, CH2N); 3.89 (s, MeO); 7.24 (d, 2 arom. H); 7.65 (d, 2 arom. H);
8.09 (d, 2 arom. H); 8.41 (d, 2 arom. H); 10.69 (s, 1 heteroarom. H). Anal. calc. for C29H32ClN5O7S2 (662.14):
C 52.60, H 4.87, N 10.58, S 9.69; found: C 52.32, H 5.01, N 10.38, S 9.97.
5-[3-Aryl-4-aryl'-thiazol-2(3H)-ylidene]-4-(dialkylamino)-thiazol-2(5H)-ones 16: General Procedure. A
mixture of a 2,4-bis(dialkylamino)thiazole-5-carbothioamide 9 (0.01 mol) and a phenacyl bromide 13f or 13e
(0.01 mol) in AcOH (15 ml) was refluxed for 20 min. The products precipitated during heating were isolated by
filtration after cooling to r.t.: 16a h.

Helvetica Chimica Acta Vol. 86 (2003)
1959
Table 2. 1H-NMR Data of Compounds 9 and 10. In CDCl3
9a 3.03 (t, 4 H, CH2N); 3.24 (t, 4 H, CH2N); 3.48 (t, 4 H, CH2O); 3.76 (m, 7H, CH 2O, Me); 9.99 (s, NH)
b
c
d
1.61 (m, 12 H, CH2); 2.95 (t, 4 H, CH2N); 3.23 (d, 3 H, Me); 3.45 (t, 4 H, CH2N); 10.70 (s, NH)
1.87( m, 4 H, CH2); 1.98 (m, 4 H, CH2); 3.26 (t, 7H, CH 2N, Me); 3.40 (t, 4 H, CH2N); 8.75 (s, NH)
1.63 (m, 6 H, CH2); 3.05 (t, 4 H, CH2N); 3.24 (d, 3 H, Me); 3.46 (t, 4 H, CH2N); 3.82 (t, 4 H, CH2N); 9.88
(s, NH)
e
f
3.02 (t, 4 H, CH2N); 3.48 (t, 4 H, CH2N); 3.75 (m, 8 H, CH2O); 4.35 (t, 2 H, CH2); 5.24 5.35
(m, 2 H, CH2); 5.96 (m, CH); 10.09 (s, NH)
1.62 (m, 6 H, CH2); 3.01 (t, 4 H, CH2N); 3.46 (t, 4 H, CH2N); 3.73 (t, 4 H, CH2O); 4.37( t, 2 H, CH2);
5.22 5.35 (m, 2 H, CH2); 5.98 (m, CH); 9.99 (s, NH)
g
h
i
2.88 (t, 4 H, CH2N); 3.30 (t, 4 H, CH2N); 3.48 (t, 4 H, CH2O); 3.75 (t, 4 H, CH2O); 4.84 (d, 2 H, CH2); 7.34
(m, 5 arom. H); 10.26 (s, NH)
1.62 (m, 12 H, CH2); 2.85 (t, 4 H, CH2N); 3.46 (t, 4 H, CH2N); 4.87( d, 2 H, CH2); 7.36 (m, 5 arom. H);
10.45 (s, NH)
1.64 (m, 4 H, CH2); 1.98 (t, 4 H, CH2N); 3.11 (t, 4 H, CH2N); 3.41 (t, 4 H, CH2O); 4.91 (d, 2 H, CH2); 7.33
(m, 5 arom. H); 9.35 (s, NH)
j
1.62 (m, 6 H, CH2); 2.89 (t, 4 H, CH2N); 3.29 (t, 4 H, CH2N); 3.47( t, 4 H, CH2O); 4.85 (d, 2 H, CH2); 7.35
(m, 5 arom. H); 10.16 (s, NH)
k
l
3.12 (t, 4 H, CH2N); 3.53 (t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 3.82 (t, H, CH2O); 7.19 (m, 1 arom. H);
7.38 (m, 2 arom. H); 7.81 (d, 2 arom. H); 12.11 (s, NH)
1.64 (m, 12 H, CH2); 3.05 (t, 4 H, CH2N); 3.50 (t, 4 H, CH2N); 7.15 (m, 1 arom. H); 7.36 (m, 2 arom. H);
7.81 (d, 2 arom. H); 12.28 (s, NH)
m
n
o
p
r
1.90 (m, 4 H, CH2); 2.01 (m, 4 H, CH2); 3.34 (t, 4 H, CH2N); 3.44 (t, 4 H, CH2N); 7.12 (m, 1 arom. H); 7.30
(m, 2 arom. H); 7.67 (d, 2 arom. H); 10.64 (s, NH)
1.90 (t, 4 H, CH2); 2.02 (t, 4 H, CH2N); 3.34 (t, 4 H, CH2N); 3.45 (t, 4 H, CH2O); 7.13 (m, 1 arom. H); 7.33
(m, 2 arom. H); 7.67 (d, 2 arom. H); 10.64 (s, NH)
1.65 (m, 6 H, CH2); 3.13 (t, 4 H, CH2N); 3.51 (t, 4 H, CH2N); 3.83 (t, 4 H, CH2O); 7.19 (m, 1 arom. H);
7.34 (m, 2 arom. H); 7.80 (d, 2 arom. H); 12.00 (s, NH)
3.11 (t, 4 H, CH2N); 3.52 (t, 4 H, CH2N); 3.80 (m, 11 H, CH2O, MeO); 6.90 (d, 2 arom. H); 7.66
(d, 2 arom. H); 11.96 (s, NH)
1.65 (m, 6 H, CH2); 3.12 (t, 4 H, CH2N); 3.50 (t, 4 H, CH2N); 3.80 (m, 7H, CH 2O, MeO); 6.90
(d, 2 arom. H); 7.65 (d, 2 arom. H); 11.85 (s, 1 H, NH)
q
s
1.64 (m, 12 H, CH2); 3.04 (t, 4 H, CH2N); 3.50 (t, 4 H, CH2N); 3.80 (s, 3 H, MeO); 6.90 (d, 2 arom. H);
7.66 (d, 2 arom. H); 12.11 (s, NH)
3.11 (t, 4 H, CH2N); 3.53 (t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 3.83 (t, 4 H, CH2O); 7.32 (d, 2 arom. H);
7.76 (d, 2 arom. H); 12.11 (s, 1 H, NH)
t
1.64 (m, 12 H, CH2); 3.04 (t, 4 H, CH2N); 3.51 (t, 4 H, CH2N); 7.30 (d, 2 arom. H); 7.76 (d, 2 arom. H);
12.29 (s, NH)
u
v
1.92 (m, 4 H, CH2); 2.02 (m, 4 H, CH2N); 3.33 (t, H, CH2N); 3.44 (t, 4 H, CH2O); 7.26 (d, 2 arom. H);
7.63 (d, 2 arom. H); 10.61 (s, 1 H, NH)
1.65 (m, 6 H, CH2); 3.12 (t, 4 H, CH2N); 3.51 (t, 4 H, CH2N); 3.82 (t, 4 H, CH2O); 7.31 (d, 2 arom. H); 7.76
(d, 2 arom. H); 12.00 (s, NH)
10a 3.51 (t, 4 H, CH2N); 3.75 (t, 4 H, CH2O); 7.36 (m, 5 arom. H); 7.40 8.24 (br., 3 H, NH)
b
1.65 (m, 6 H, CH2); 3.45 (t, 4 H, CH2N); 7.18 (m, 1 arom. H); 7.35 (m, 4 arom. H); 7.50 8.20
(br., 3 H, NH)
c
d
2.03 (m, 4 H, CH2); 3.44 (t, 4 H, CH2N); 7.17 7.40 (m, 5 arom. H); 7.50 8.10 (br., 3 H, NH)
0.91 (t, 6 H, Me); 1.64 (m, 4 H, CH2); 3.33 (t, 4 H, CH2N); 7.14 (m, 1 arom. H); 7.29 7.40
(m, 4 arom. H); 7.50 8.00 (br., 3 H, NH)
e
f
3.53 (t, 4 H, CH2N); 3.76 (t, 4 H, CH2O); 7.22 (d, 2 arom. H); 7.29 (d, 2 arom. H); 7.40 8.20
(br., 3 H, NH)
3.50 (t, 4 H, CH2N); 3.76 (m, 7H, CH 2O, MeO); 6.86 (d, 2 arom. H); 7.26 (d, 2 arom. H); 7.50 8.10
(br., 3 H, NH)

1960
Helvetica Chimica Acta Vol. 86 (2003)
5-[3-(4-Methoxyphenyl)-4-(4-nitrophenyl)thiazol-2(3 H)-ylidene]-4-(morpholin-4-yl)thiazol-2-(5H)-one
(16a). From N5-(4-methoxyphenyl)-2,4-dimorpholin-4-yl)thiazole-5-carbothioamide (9p) or N5-(4-methoxy-
phenyl)4-(morpholin-4-yl)-2-(piperidin-1-yl)thiazole-5-carbothioamide (9r) and 4-nitrophenacyl bromide
(13f). Yield 79 and 56%, resp. M.p. 303 3058. UV/VIS: 431 (4.24). 1H-NMR ((D6)DMSO): 3.35 (t, 4 H,
CH2N); 3.61 (t, 4 H, CH2O); 6.97( d, 2 arom. H); 7.19 (d, 2 arom. H); 7.98 (d, 2 arom. H); 8.22 (d, 2 arom. H);
10.02 (s, 1 heteroarom. H). Anal. calc. for C23H20N4O5S2 (496.56): C 55.63, H 4.06, N 11.28, S 12.92; found:
C 55.79, H 4.28, N 11.29, S 13.11.
5-[3-(4-Chlorophenyl)-4-(4-nitrophenyl)thiazol-2(3H)-ylidene]-4-(morpholin-4-yl)thiazol-2(5H)-one
(16b). From N5-(4-chlorophenyl)-4-(morpholin-4-yl)-2-(piperidin-1-yl)thiazole-5-carbothioamide (9v) and 4-
nitrophenacyl bromide (13f). Yield 80%. M.p. 248 2508. UV/VIS: 422 (4.29). 1H-NMR ((D6)DMSO): 3.20
(t, 4 H, CH2N); 3.63 (t, 4 H, CH2O); 7.22 (d, 2 arom. H); 7.41 (d, 2 arom. H); 8.01 (d, 2 arom. H); 8.22
(d, 2 arom. H); 10.06 (s, 1 heteroarom. H). Anal. calc. for C22H17ClN4O4S2 (500.98): C 52.74, H 3.42, N 11.18,
S 12.80; found: C 52.36, H 3.96, N 11.08, S 12.65.
5-[3,4-Bis(4-chlorophenyl)thiazol-2(3H)-ylidene]-4-(morpholin-4-yl)thiazol-2(5H)-one (16c). From N5-
(4-chlorophenyl)-2,4-di(morpholin-4-yl)thiazole-5-carbothioamide (9s) and 4-chlorophenacyl bromide (13e).
Yield 62%. M.p. 285 2878. UV/VIS: 409 (4.32). 1H-NMR ((D6)DMSO): 3.43 (t, 4 H, CH2N); 3.66 (t, 4 H,
CH2O); 7.19 (d, 2 arom. H); 7.41 (d, 2 arom. H); 7.47 (d, 2 arom. H); 7.87 (d, 2 arom. H); 10.11 (s, 1 heteroarom.
H). Anal. calc. for C22H17Cl2N3O2S2 (489.01): C 53.88, H 3.49, N 8.57, S 13.08; found: C 53.81, H 3.71, N 8.96,
S 13.42.
5-[4-(4-Chlorophenyl-3-(4-methoxyphenyl)thiazol-2(3H)-ylidene]-4-(morpholin-4-yl)thiazol-2(5H)-one
(16d). From N5-(4-methoxyphenyl)-2,4-di(morpholin-4-yl)thiazole-5-carbothioamide (9p) and 4-chloro-
phenacyl bromide (13e). Yield 65%. M.p. 280 2828. UV/VIS: 415 (4.35). 1H-NMR ((D6)DMSO): 3.40
(t, 4 H, CH2N); 3.65 (t, 4 H, CH2O); 3.75 (s, MeO); 6.96 (d, 2 arom. H); 7.18 (d, 2 arom. H); 7.45 (d, 2 arom. H);
7.85 (d, 2 arom. H); 9.88 (s, 1 heteroarom. H). Anal. calc. for C23H20ClN3O3S2 (485.06): C 56.84, H 4.15, N 8.65,
S 13.20; found: C 57.04, H 4.47, N 8.40, S 13.36.
5-[3-(4-Chlorophenyl)-4-(4-nitrophenyl)thiazol-2(3H )-ylidene]-4-(piperidin-1-yl)thiazol-2(5H)-one
(16e). From N5-(4-chlorophenyl)-2,4-di(piperidin-1-yl)thiazole-5-carbothioamide (9t) and 4-nitrophenacyl
bromide (13f). Yield 76%. M.p. 293 2948. UV/VIS: 417(4.32). 1H-NMR ((D6)DMSO): 1.51 (m, 6 H, CH2);
3.35 (t, 4 H, CH2N); 7.20 (d, 2 arom. H); 7.41 (d, 2 arom. H); 7.97 (d, 2 arom. H); 8.22 (d, 2 arom. H); 10.17
(s, 1 heteroarom. H). Anal. calc. for C23H19ClN4O3S2 (498.06): C 55.36, H 3.84, N 11.23, S 12.85; found: C 55.54,
H 4.13, N 11.18, S 12.98.
5-[3-(4-Methoxyphenyl)-4-(4-nitrophenyl)thiazol-2(3H)-ylidene]-4-(piperidin-1-yl)thiazol-2(5H)-one
(16f). From N5-(4-methoxyphenyl)-2,4-di(piperidin-1-yl)-5-carbothioamide (9q) and 4-nitrophenacyl bromide
(13f). Yield 71%. M.p. 290 2918. UV/VIS: 427(4.37). 1H-NMR ((D6)DMSO): 1.50 (m, 6 H, CH2); 3.33 (t, 4 H,
CH2N); 3.76 (s, MeO); 6.97( d, 2 arom. H); 7.18 (d, 2 arom. H); 7.95 (d, 2 arom. H); 8.21 (d, 2 arom. H); 9.96
(s, 1 heteroarom. H). Anal. calc. for C24H22N4O4S2 (494.59): C 58.28, H 4.48, N 11.33, S 12.97; found: C 58.18,
H 4.79, N 11.07, S 13.00.
5-[4-(4-Chlorophenyl)-3-phenyl-thiazol-2(3H)-ylidene]-4-(piperidin-1-yl)thiazol-2(5H)-one (16g). From
N5-(4-chlorophenyl)-2,4-di(piperidin-1-yl)thiazole-5-carbothioamide (9l) and 4-chlorophenacyl bromide
(13e). Yield 54%. M.p. 218 2208. UV/VIS: 409 (4.28). 1H-NMR ((D6)DMSO): 1.56 (m, 6 H, CH2); 3.40
(t, 4 H, CH2N); 7.07 (t, 1 arom. H); 7 .20 (d, 2 arom. H); 7 .36 (t, 2 arom. H); 7 .44 (d, 2 arom. H); 7 .84
(d, 2 arom. H); 10.00 (s, 1 heteroarom. H). Anal. calc. for C23H20ClN3OS2 (453.07): C 60.85, H 4.44, N 9.26,
S 14.13; found: C 60.51, H 4.60, N 9.48, S 13.98.
5-[3,4-Bis(4-chlorophenyl)thiazol-2(3H)-ylidene]-4-(piperidin-1-yl)thiazol-2(5H)-one (16h). From N5-(4-
chlorophenyl)-2,4-di(piperidin-1-yl)thiazole-5-carbothioamide (9t) and 4-chlorophenacyl bromide (13e). Yield
59%. M.p. 284 2858. UV/VIS: 409 (4.33). 1H-NMR ((D6)DMSO): 1.60 (m, 6 H, CH2); 3.44 (t, 4 H, CH2N); 7.19
(d, 2 arom. H); 7.41 (d, 2 arom. H); 7.46 (d, 2 arom. H); 7.87 (d, 2 arom. H); 9.90 (s, 1 heteroarom. H). Anal.
calc. for C23H19Cl2N3OS2 (487.03): C 56.56, H 3.92, N 8.60, S 13.13; found: C 56.35, H 4.35, N 8.24, S 13.11.
N-[(2,4-Diaminothiazol-5-yl)thioxomethyl]-2,2-dimethylpropanamides 18: General Procedure. To a soln. of
pivaloyl isothiocyanate (ˆ2,2-dimethylpropanoyl isothiocyanate; 1w), prepared from KSCN (63.6 g, 0.6 mol)
and pivaloyl chloride (66.4 ml, 0.54 mol) in MeCN (300 ml), a thiazole-2,4-diamine 8 (0.5 mol) was added, and
the mixture was refluxed for 30 min. After concentration to half of the volume, the precipitated product was
filtered off: 18a or 18d.
N-{[2,4-Di(morpholin-4-yl)thiazol-5-yl]thioxomethyl}-2,2-dimethylpropanamide (18a). From 4,4'-(thiazol-
2,4-diyl)bis[morpholine] (8a) and 1w. Yield 73%. Red-brown crystals. M.p. 163 1648 (BuOH). 1H-NMR

Helvetica Chimica Acta Vol. 86 (2003)
1961
(CDCl3): 1.26 (s, Me3C); 3.59 (m, 8 H, CH2N); 3.72 (m, 8 H, CH2O); 8.82 (s, NH). Anal. calc. for C17H26N4O3S2
(398.55): C 51.23, H 6.58, N 14.06, S 16.09; found: C 51.34, H 5.98, N 13.92, S 16.08.
Similarly, 18b and 18c were obtained and used as raw materials.
N-{[4-(Morpholin-4-yl)-2-(pyrrolidin-1-yl)thiazol-5-yl]thioxomethyl}-2,2-dimethylpropanamide (18d).
From 4-[2-(pyrrolidin-1-yl)thiazol-4-yl]morpholine (8e) and 1w. Yield 65%. Red-brown crystals. M.p. 156
1578 (EtOH). 1H-NMR (CDCl3): 1.21 (s, Me3C); 1.95 (m, 4 H, CH2); 3.24 (t, 4 H, CH2N); 3.51 (t, 4 H, CH2N);
3.67( t, 4 H, CH2O); 8.37( s, NH). Anal. calc. for C17H26N4O2S2 (382.55): C 53.37, H 6.85, N 14.65, S 16.76;
found: C 53.44, H 7.28, N 14.46, S 16.94.
Thiazolo[4,5-d]pyrimidine-7(6H)-thiones 21: General Procedure. To a soln. of 1w, prepared from KSCN
(11.7g, 0.12 mol) and pivaloyl chloride (13.3 ml, 0.11 mol) in MeCN (60 ml), 2-(dialkylamino)thiazol-4(5 H)-
iminium chloride 7 (0.1 mol) and Et3N (14 ml, 0.1 mol) were added successively, and the resulting mixture was
refluxed for 30 min. After cooling to r.t., the mixture was diluted with H2O (100 ml). The precipitated product
was filtered off, washed with H2O, and recrystallized from BuOH: 21a c.
5-(tert-Butyl)-2-(morpholin-4-yl)thiazolo[4,5-d]pyrimidine-7(6H)-thione (21a). From 2-(morpholin-4-yl)-
thiazol-4(5H)-iminium chloride (7a) and 1w. Yield 71%. Brown crystals. M.p. 175 1768. 1H-NMR (CDCl3):
1.42 (s, Me3C); 3.72 (t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 10.00 (s, NH). Anal. calc. for C13H18N4OS2 (310.44):
C 50.30, H 5.84, N 18.05, S 20.66; found: C 50.62, H 6.44, N 17.65, S 20.58.
5-(tert-Butyl)-2-(piperidin-1-yl)thiazolo[4,5-d]pyrimidine-7(6H)-thione (21b). From 2-(piperidin-1-yl)-
1
thiazol-4(5H)-iminium chloride (7b) and 1w. Yield 69%. Orange crystals. M.p. 250 2528. H-NMR (CDCl3):
1.41 (s, Me3C); 1.69 (m, 6 H, CH2); 3.69 (t, 4 H, CH2N); 9.94 (s, NH). Anal. calc. for C14H20N4S2 (308.47):
C 54.51, H 6.54, N 18.16, S 20.79; found: C 54.71, H 6.56, N 17.97, S 21.03.
5-(tert-Butyl)-2-(pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidine-7(6H)-thione (21c). From 2-(pyrrolidin-1-
yl)thiazol-4(5H)-iminium chloride (7c) and 1w. Yield 62%. Light green crystals. M.p. 295 2978. 1H-NMR
(CDCl3): 1.42 (s, Me3C); 2.09 (m, 4 H, CH2); 3.41 (m, CH2N); 3.81 (m, CH2N); 9.91 (s, NH). Anal. calc. for
C13H18N4S2 (294.44): C 53.03, H 6.16, N 19.03, S 21.78; found: C 53.34, H 6.45, N 18.94, S 21.81.
2,4-Bis(dialkylamino)thiazole-5-carbothioamides 19: General Procedure. A suspension of propanamide 18
(0.5 mol) in conc. HCl soln. (300 ml) was stirred at r.t. for 24 h while it separated into two phases. The aq. soln.
was neutralized with aq. NH3 soln. The precipitated product was filtered off and washed with H2O: 19a d.
2,4-Di(morpholin-4-yl)thiazole-5-carbothioamide (19a). From 18a. Yield 81%. Brown crystals. M.p. 194
1968 (BuOH). 1H-NMR (CDCl3): 3.09 (t, 4 H, CH2N); 3.52 (t, 4 H, CH2N); 3.76 (m, 8 H, CH2O); 8.90 (br.
s, NH2). Anal. calc. for C12H18N4O2S2 (314.43): C 45.84, H 5.77, N 17.82, S 20.40; found: C 46.02, H 5.78, N 18.01,
S 20.33.
2,4-Di(piperidin-1-yl)thiazole-5-carbothioamide (19b). From 1,1'-(thiazol-2,4-diyl)bis[piperidine] (8b) via
N-{[2,4-di(piperidin-1-yl)thiazol-5-yl]thioxomethyl}-2,2-dimethylpropanamide (18b). Yield 74%. Brown crys-
tals. M.p. 171 1738 (EtOH). 1H-NMR (CDCl3): 1.62 (m, 12 H, CH2); 3.02 (t, 4 H, CH2N); 3.48 (t, 4 H, CH2N);
8.80 (br. s, NH2). Anal. calc. for C14H22N4S2 (310.48): C 54.16, H 7.14, N 18.05, S 20.66; found: C 54.60, H 7.04,
N 17.80, S 21.05.
2,4-Di(pyrrolidin-1-yl)thiazole-5-carbothioamide (19c). From N-{[2,4-di(pyrrolidin-1-yl)thiazol-5-yl]thiox-
omethyl}-2,2-dimethylpropanamide (18c). Yield 83%. Brown crystals. M.p. 181 1838 (EtOH). 1H-NMR
(CDCl3): 1.85 (m, 4 H, CH2); 1.97( m, 4 H, CH2); 3.37( m, 8 H, CH2N); 6.98 (s, NH2). Anal. calc. for C12H18N4S2
(282.43): C 51.03, H 6.42, N 19.84, S 22.71; found: C 51.21, H 6.07, N 19.64, S 22.35.
4-(Morpholin-4-yl)-2-(pyrrolidin-1-yl)thiazole-5-carbothioamide (19d). From 18d. Yield 85%. Brown
crystals. M.p. 193 1958 (EtOH). 1H-NMR (CDCl3): 2.00 (m, 4 H, CH2N); 3.10 (t, 4 H, CH2N); 3.41 (t, 4 H,
CH2N); 3.75 (t, 4 H, CH2O); 8.70 (br. s, NH2). Anal. calc. for C12H18N4OS2 (298.43): C 48.30, H 6.08, N 18.77,
S 21.49; found: C 48.12, H 6.23, N 18.61, S 21.65.
Acceptor-Substituted 4,4'-([2,5'-Bithiazole]-2',4'-diyl)bis[morpholines] 24: General Procedure. A mixture
18a (0.01 mol) and a a-halomethyl compound 13 or 22 (0.01 mol) was heated in MeCN (50 ml) for 3 h. Then
Et3N (1.4 ml, 0.01 mol) was added at r.t., and the soln. was refluxed for 1 h. After cooling to r.t., H2O (20 ml) was
added, and the precipitated product was filtered off: 24a and 24e.
1-[4-(tert-Butyl)-2',4'-di(morpholin-4-yl)[2,5'-bithiazol]-5-yl]ethanone (24a). From 18a and 1-chloropro-
pan-2-one (13b). Yield 63%. Yellow crystals. M.p. 149 1508 (EtOH). UV/VIS: 413 (4.30). 1H-NMR (CDCl3):
1.40 (s, Me3C); 2.53 (s, Me); 3.17( t, 4 H, CH2N); 3.53 (t, 4 H, CH2N); 3.79 (t, 4 H, CH2O); 3.88 (t, 4 H, CH2O).
Anal. calc. for C20H28N4O3S2 (436.59): C 55.02, H 6.46, N 12.83, S 14.69; found: C 55.08, H 6.87, N 12.57, S 14.59.
4,4'-[4-(tert-Butyl)-5-(4-nitrophenyl)-[2,5'-bithiazole]-2',4'-diyl]bis[morpholine] (24e). From 18a and 4-
nitrobenzyl bromide (22a). Yield 75%. Yellow crystals. M.p. 255 2568 (EtOH/MeCN 1:1). UV/VIS: 363
(4.44). 1H-NMR (CDCl3): 1.20 (s, Me3C); 3.07( t, 4 H, CH2N); 3.56 (t, 4 H, CH2N); 3.80 (m, 8 H, CH2O); 7.54

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Helvetica Chimica Acta Vol. 86 (2003)
(d, 2 arom. H); 8.20 (d, 2 arom. H). Anal. calc. for C24H29N5O4S2 (515.65): C 55.90, H 5.67, N 13.58, S 12.44;
found: C 55.94, H 5.33, N 13.10, S 12.23.
2,4-Di(morpholin-4-yl)thiazole-5-carbonitrile (26). As described in the General Procedure for 24; with 18a
(0.01 mol, 4.0 g) and chloroacetonitrile (22d; 125 mmol, 1.0 g), MeCN (100 ml), and Et3N (0.01 mol, 1.4 ml).
Precipitation with H2O (50 ml) gave 26 (75%). Pale yellow crystals. M.p. 255 2568. IR (KBr): 2177. 1H-NMR
(CDCl3): 3.45 (t, 4 H, CH2N); 3.67( t, 4 H, CH2N); 3.73 (m, 8 H, CH2O). Anal. calc. for C12H16N4O2S (280.35):
C 51.41, H 5.75, N 19.98, S 11.44; found: C 51.60, H 6.12, N 19.52, S 11.49.
2,4-Di(morpholin-4-yl)-N5-[(morpholin-4-yl)methylene)]thiazole-5-carbothioamide (27). A mixture of
19a (6.3 g, 20 mmol), triethyl orthoformate (4.5 g, 30 mmol), and morpholine (2.6 g, 30 mmol) was heated at
1208 under removal of the formed EtOH. After cooling to r.t., the solid product was filtered off and
recrystallized from BuOH. Yield 6.0 g (73%). Orange crystals. M.p. 185 1878. 1H-NMR (CDCl3): 3.08
(t, CH2N); 3.52 (m, 6 H, CH2N); 3.66 3.74 (m, 16 H, CH2N, CH2O); 8.75 (s, CH). Anal. calc. for C17H25N5O3S2
(411.54): C 49.61, H 6.12, N 17.02, S 15.58; found: C 49.99, H 6.54, N 17.16, S 15.97.
Acceptor-Substituted 4,4'-([2,5'-Bithiazole]-2',4'-diyl]bis[morpholines] 29: General Procedures. Method A.
A mixture of 27 (4.1 g, 10 mmol) and an a-halomethyl compound 13 (10 mmol) in MeCN (50 ml) was refluxed
for 3 h. After cooling to r.t., Et3N (1.4 ml, 10 mmol) was added to the mixture, which was heated again for 1 h.
The product, crystallized after cooling, was filtered off, washed with EtOH, and purified by recrystallization:
29a d.
Method B: A mixture of 19a (3.15 g, 10 mmol) and an a-halomethyl compound 22 (10 mmol) in DMF
(25 ml) was heated at 1008 for 5 min. After cooling to r.t., POCl3 (3.1 g, 20 mmol), followed by Et3N (20 ml),
was added to the mixture. The formed product was precipitated by addition of H2O, filtered off, washed with
H2O, and recrystallized: 29e g.
1-[2',4'-Di(morpholin-4-yl)[2,5'-bithiazol]-5-yl]ethanone (29a). From 27 and 1-chloropropan-2-one (13a)
by Method A: 3.0 g (79%) of 29a. Yellow crystals. M.p. 218 2198. UV/VIS: 420 (4.31). 1H-NMR (CDCl3): 2.50
(s, Me); 3.13 (t, 4 H, CH2N); 3.52 (t, 4 H, CH2N); 3.77 (t, 4 H, CH2O); 3.87( t, 4 H, CH2O); 8.07( s, 1 hetero-
arom. H). Anal. calc. for C16H20N4O3S2 (380.49): C 50.51, H 5.30, N 14.73, S 16.86; found: C 50.49, H 5.56,
N 14.03, S 17.01.
Methyl 2',4'-Di(morpholin-4-yl)[2,5'-bithiazole]-5-carboxylate (29b). From 27 and methyl bromoacetate
(13c) by Method A: 2.14 g (54%) of 29b. Colorless crystals. M.p. 179 1818. 1H-NMR (CDCl3): 3.12 (t, 4 H,
CH2N); 3.52 (t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 3.86 (s, MeO); 3.89 (t, 4 H, CH2O); 8.18 (s, 1 heteroarom. H).
Anal. calc. for C16H20N4O4S2 (396.49): C 48.47, H 5.08, N 14.13, S 16.18; found: C 48.80, H 5.23, N 13.96, S 16.32.
[2',4'-Di(morpholin-4-yl)[2,5'-bithiazol]-5-yl]phenylmethanone (29c). From 27 and phenacyl bromide
(13d) by Method A: 3.23 g (73%) 29c. Yellow crystals. M.p. 174 1758. UV/VIS: 439 (4.38). 1H-NMR (CDCl3):
3.17( t, 4 H, CH2N); 3.53 (t, 4 H, CH2N); 3.76 (t, 4 H, CH2O); 3.90 (t, 4 H, CH2O); 7.46 7.58 (m, 3 arom. H);
7.79 (d, 2 arom. H); 8.00 (s, 1 heteroarom. H). Anal. calc. for C21H22N4O3S2 (442.56): C 56.99, H 5.01, N 12.66,
S 14.49; found: C 57.52, H 4.85, N 12.41, S 14.49.
([1,1'-Biphenyl]-4-yl)[2',4'-di(morpholin-4-yl)[2,5'-bithiazol]-5-yl]methanone (29d). From 27 and 2-bro-
mo-1-([1,1'-biphenyl]-4-yl)ethanone (13g) by Method A: 3.37g (65%) 29d. Yellow crystals. M.p. 186 1888. UV/
VIS: 441 (4.45). 1H-NMR (CDCl3): 3.20 (t, 4 H, CH2N); 3.55 (t, 4 H, CH2N); 3.80 (t, 4 H, CH2O); 3.92 (t, 4 H,
CH2O); 7.36 7.49 (m, 3 arom. H); 7.62 (d, 2 arom. H); 7.69 (d, 2 arom. H); 7.90 (d, 2 arom. H); 8.08 (s, 1 het-
eroarom. H). Anal. calc. for C27H26N4O3S2 (518.65): C 62.53, H 5.05, N 10.80, S 12.37; found: C 62.49, H 4.67,
N 10.80, S 12.45.
4,4'-[5-(4-Nitrophenyl)[2,5'-bithiazole]-2,4-diyl]bis[morpholine] (29e). From 19a and 4-nitrobenzyl bro-
mide (22a) by Method B: 3.77 g (82%) of 29e. Red crystals. M.p. 284 2858. UV/VIS: 446 (4.40). 1H-NMR
(CDCl3): 3.22 (t, 4 H, CH2N); 3.57( t, 4 H, CH2N); 3.81 (t, 4 H, CH2O); 3.90 (t, 4 H, CH2O); 7.66 (d, 2 arom. H);
7.97 (s, 1 heteroarom. H); 8.22 (d, 2 arom. H). Anal. calc. for C20H21N5O4S2 (459.54): C 52.27, H 4.61, N 15.24,
S 13.96; found: C 52.14, H 4.62, N 14.61, S 13.94.
4-[2',4'-Di(morpholin-4-yl)[2,5'-bithiazol]-5-yl]benzonitrile (29f). From 19a and 4-(bromomethyl)benzo-
nitrile (22b) by Method B: 3.12 g (71%) of 29f. Yellow crystals. M.p. 254 2558. UV/VIS: 414 (4.41). 1H-NMR
(CDCl3): 3.14 (t, 4 H, CH2N); 3.52 (t, 4 H, CH2N); 3.80 (t, 4 H, CH2O); 3.92 (t, 4 H, CH2O); 7.59 (d, 2 arom. H);
7.64 (d, 2 arom. H); 7.88 (s, 1 heteroarom. H). Anal. calc. for C21H21N5O2S2 (439.56): C 57.38, H 4.82, N 15.93,
S 14.59; found: C 57.64, H 5.08, N 15.65, S 14.70.
2-{{4-[2',4'-Di(morpholin-4-yl)[2,5'-bithiazol]-5-yl]phenyl}methylene}propanedinitrile (29g). From 19a and
2-{[4-(bromomethyl)phenyl]methylene}propanedinitrile (22c) by Method B: 3.34 g (68%) of 29g. Red crystals.
M.p. 253 255 8. UV/VIS: 487(4.46). 1H-NMR (CDCl3): 3.15 (t, 4 H, CH2N); 3.53 (t, 4 H, CH2N); 3.80 (t, 4 H,

Helvetica Chimica Acta Vol. 86 (2003)
1963
CH2O); 3.92 (t, 4 H, CH2O); 7.34 (s, CH); 7.67 (d, 2 arom. H); 7.89 (d, 2 arom. H); 7.96 (s, 1 heteroarom. H).
Anal. calc. for C24H22N6O2S2 (490.60): C 58.76, H 4.52, N 17.13, S 13.07; found: C 59.17, H 4.74, N 16.88, S 13.16.
2',4'-Bis(dialkylamino)[2,5'-bithiazol]-4(5H)-ones 30: General Procedure. A mixture of a 2,4-bis(dialkyl-
amino)thiazole-5-carbothioamide 19 (0.1 mol) and methyl bromoacetate (13c; 15.3 g, 0.1 mol) in EtOH
(200 ml) was refluxed for 2 h. After cooling to r.t., Et3N (14 ml, 0.1 mol) was added and the soln. refluxed for
30 min. The mixture was concentrated to half its volume, and the product, precipitated by cooling, was filtered
off: 30a and 30b.
2',4'-Di(morpholin-4-yl)[2,5'-bithiazol]-4(5H)-one (30a). From 19a. Yield 74%. Colorless crystals. M.p.
1
209 2118 (EtOH). H-NMR (CDCl3): 3.61 (m, 8 H, CH2N); 3.79 (m, 8 H, CH2O); 3.85 (s, 2 H, CH2). Anal.
calc. for C14H18N4O3S2 (354.45): C 47.44, H 5.12, N 15.81, S 18.09; found: C 47.33, H 5.13, N 15.24, S 18.28.
2',4'-Di(piperidin-1-yl)[2,5'-bithiazol]-4(5H)-one (30b). From 19b. Yield 67%. Pale brown crystals. M.p.
1
125 1268 (EtOH). H-NMR (CDCl3): 1.65 (m, 12 H, CH2); 3.54 (m, 8 H, CH2N); 3.82 (m, 2 H, CH2). Anal.
calc. for C16H22N4OS2 (350.50): C 54.83, H 6.33, N 15.98, S 18.30; found: C 54.73, H 6.53, N 15.74, S 18.68.
4-Substituted 2',4'-Bis(dialkylamino)-2,5'-bithiazoles 31: General Procedure. A mixture of a 2,4-bis(dialkyl-
amino)thiazole-5-carbothioamide 19 (0.1 mol) and an a-halomethyl ketone 13 (0.1 mol) in EtOH (250 ml) was
refluxed for 2 h. After cooling, Et3N (14 ml, 0.1 mol) was added and the mixture refluxed for 30 min. The
product, precipitated after cooling to r.t., was filtered off: 31a e.
4,4'-(4-Methyl[2,5'-bithiazole]-2',4'-diyl)bis[morpholine] (31a). From 19a and 1-chloropropan-2-one (13a).
Yield 70%. Colorless crystals. M.p. 155 1568 (EtOH). 1H-NMR (CDCl3): 2.38 (s, Me); 3.07( t, 4 H, CH2N);
3.48 (t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 3.87( t, 4 H, CH2O); 6.68 (s, 1 heteroarom. H). Anal. calc. for
C15H20N4O2S2 (352.48): C 51.11, H 5.72, N 15.90, S 18.19; found: C 51.48, H 5.60, N 15.94, S 18.38.
1,1'-(4-Methyl[2,5'-bithiazole]-2',4'-diyl)bis[piperidine] (31b). From 19b and 1-chloropropan-2-one (13a).
Yield 59%. Colorless crystals. M.p. 142 1448 (EtOH). 1H-NMR (CDCl3): 1.57 1.76 ( m, 12 H, CH2); 2.38
(s, Me); 3.01 (t, 4 H, CH2N); 3.47( t, 4 H, CH2N); 6.63 (s, 1 heteroarom. H). Anal. calc. for C17H24N4S2 (348.53):
C 58.58, H 6.94, N 16.08, S 18.40; found: C 58.42, H 6.72, N 16.25, S 18.96.
4,4'-[4-(Chloromethyl)[2,5'-bithiazole]-2',4'-diyl]bis[morpholine] (31c). From 19a and 1,3-dichloropropan-
2-one (13b). Yield 62%. Colorless crystals. M.p. 154 1558 (EtOH). 1H-NMR (CDCl3): 3.09 (t, 4 H, CH2N);
3.49 (t, 4 H, CH2N); 3.77 (t, 4 H, CH2O); 3.86 (t, 4 H, CH2O); 4.63 (s, 2 H, CH2); 7.09 (s, 1 heteroarom. H).
Anal. calc. for C15H19ClN4O2S2 (386.92): C 46.56, H 4.95, N 14.48, S 16.57; found: C 46.72, H 4.90, N 14.30,
S 16.86.
4,4'-(4-Phenyl[2,5'-bithiazole]-2',4'-diyl)bis[morpholine] (31d). From 19a and phenacyl bromide (13d).
Yield 67%. Colorless crystals. M.p. 168 1708 (EtOH). 1H-NMR (CDCl3): 3.13 (t, 4 H, CH2N); 3.51 (t, 4 H,
CH2N); 3.80 (t, 4 H, CH2O); 3.90 (t, 4 H, CH2O); 7.28 (s, 1 heteroarom. H); 7.36 (m, 3 arom. H); 7.88
(d, 2 arom. H). Anal. calc. for C20H22N4O2S2 (414.55): C 57.95, H 5.35, N 13.52, S 15.47; found: C 58.00,
H 5.46, N 13.34, S 15.38.
1,1'-(4-Phenyl[2,5'-bithiazole]-2',4'-diyl)bis[piperidine] (31e). From 19b and phenacyl bromide (13d).
Yield 63%. Colorless crystals. M.p. 119 1218 (EtOH). 1H-NMR (CDCl3): 1.65 1.76 (m, 12 H, CH2); 3.05
(t, 4 H, CH2N); 3.50 (t, 4 H, CH2N); 7.28 7.40 (m, 4 arom. and heteroarom. H); 7.90 (d, 2 arom. H). Anal. calc.
for C22H26N4S2 (410.60): C 64.35, H 6.38, N 13.65, S 15.62; found: C 63.75, H 5.96, N 13.88, S 16.06.
2',4'-Di(morpholin-4-yl)[2,5'-bithiazole]-4,5-dione 5-[(4-Nitrophenyl)hydrazone] (33a). A freshly pre-
pared aq. 4-nitrobenzenediazonium hydrogen sulfate soln. (10 mm) was added under stirring to a mixture of 30a
(3.5 g, 0.01 mol) and DMF (35 ml). After standing for 1 h at r.t., the mixture was poured into H2O (200 ml) and
neutralized by addition of aq. NaOH soln. The crystallized product was filtered off and recrystallized from
BuOH: 3.4 g (68%) of 33a. M.p. 285 2878. UV/VIS: 514 (4.62). 1H-NMR (CDCl3): 3.62 3.85 (m, 12 H,
CH2N); 4.24 (t, 4 H, CH2O); 7.28 (s, NH); 7.31 (d, 2 arom. H); 8.10 (d, 2 arom. H). Anal. calc. for C20H21N7O5S2
(503.56): C 47.70, H 4.20, N 19.47, S 12.74; found: C 48.52, H 4.03, N 19.65, S 13.01.
6-[2,4-Di(morpholin-4-yl)thiazol-5-yl]-3-(4-nitrophenyl)thiazolo[5,4:e]-1,3,4,2-oxadiazaborine-2,2-diol
Diacetate (32a). A suspension of 33a (3.0 g, 6 mmol) and H3BO3 (0.04 g, 6 mmol) in Ac2O (15 ml) was refluxed
for 30 min. After cooling to r.t., the product precipitated from the deeply colored soln. It was filtered off and
washed with AcOEt and Et2O: 2.5 g (66%) of 32a. M.p. 297 300 8. UV/VIS: 572 (4.78). 1H-NMR (CDCl3): 1.99
(s, 6 H, Me); 3.51 (t, 2 H, CH2N); 3.63 (t, 2 H, CH2N); 3.85 (m, 8 H, CH2); 3.91 (t, 4 H, CH2O); 7.68
(d, 2 arom. H); 8.05 (d, 2 arom. H). Anal. calc. for C24H26BN7O9S2 (631.45): C 45.65, H 4.15, N 15.53, S 10.16;
found: C 46.02, H 4.40, N 15.67, S 9.98.
4,4'-(4-Chloro[2,5'-bithiazole]-2',4'-diyl)bis[morpholine] (34a). To a soln. of 30a (7.1 g, 0.02 mol) in DMF
(50 ml), POCl3 (61 g, 0.04 mol) was slowly added at r.t. After stirring for 2 h, the red mixture was poured into ice
water (300 ml). After neutralization of the mixture with aq. NaOH soln., the crystallized product was filtered

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Helvetica Chimica Acta Vol. 86 (2003)
1
off, washed with H2O, and recrystallized from EtOH: 5.3 g (71%) of 34a. M.p. 1508. H-NMR (CDCl3): 3.08
(t, 4 H, CH2N); 3.50 (t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 3.86 (t, 4 H, CH2O); 6.84 (s, 1 heteroarom. H). Anal.
calc. for C14H17ClN4O2S2 (372.90): C 45.09, H 4.60, N 15.02, S 17.20; found: C 45.43, H 4.71, N 14.59, S 17.55.
4-Chloro-2',4'-di(morpholin-4-yl)[2,5'-bithiazole]-5-carboxaldehyde (35a). To a mixture of N-methylform-
anilide (5.4 g, 0.04 mol) and POCl3 (9.2 g, 0.06 mol), 34a (0.02 mol) in DMF (20 ml) was added dropwise. After
stirring the mixture at r.t. overnight, it was heated at 65 708 for 7h and then, after cooling, poured into ice
water (400 ml). The mixture was neutralized by addition of aq. NaOH soln. and the precipitated product filtered
off, washed with H2O (50 ml), and recrystallized from EtOH: 2.8 g (35%) of 35a. M.p. 147 148 8. 1H-NMR
(CDCl3): 3.23 (t, 4 H, CH2N); 3.59 (t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 3.86 (t, 4 H, CH2O); 9.86 (s, CHO).
Anal. calc. for C15H17ClN4O3S2 (400.91): C 44.94, H 4.27, N 13.98, S 16.00; found: C 44.45, H 4.48, N 14.54,
S 16.09.
2',4'-Bis(dialkylamino)-5-{[4-(dimethylamino)phenyl]methylene}[2,5'-bithiazole]-4(5H)-ones 36: General
Procedure. A mixture of a 2',4'-bis(dialkylamino)[2,5'-bithiazol]-4(5H)-one 30 (0.01 mol), 4-(dimethylamino)-
benzaldehyde (1.5 g, 0.01 mol), and Et3N (5 drops) in DMF (100 ml) was refluxed for 2 h. The orange product
that precipitated after cooling was filtered off and recrystallized from DMF: 36a or 36b.
5-{[4-(Dimethylamino)phenyl]methylene}-2',4'-di(morpholin-4-yl)[2,5'-bithiazol]-4(5H)-one (36a). From
30a. Yield 76%. Orange crystals. M.p. 279 2818 (DMF). UV/VIS: 497(4.32). 1H-NMR (CDCl3): 2.97( s, 6 H,
MeN); 3.56 (m, 8 H, CH2N); 3.74 (t, 4 H, CH2O); 3.83 (t, 4 H, CH2O); 6.64 (d, 2 arom. H); 7.38 (d, 2 arom. H);
7.66 (s, CH). Anal. calc. for C23H27N5O3S2 (485.62): C 56.88, H 5.60, N 14.42, S 13.21; found: C 56.82, H 5.36,
N 14.56, S 13.57.
5-{[4-(Dimethylamino)phenyl]methylene}-2',4'-di(piperidin-1-yl)[2,5'-bithiazol]-4(5H)-one (36b). From
30b. Yield 68%. Orange crystals. M.p. 220 2228 (DMF). UV/VIS: 492 (4.40). 1H-NMR (CDCl3): 1.66
(m, 12 H, CH2); 2.99 (s, 6 H, MeN); 3.56 (m, 8 H, CH2N); 6.68 (d, 2 arom. H); 7.44 (d, 2 arom. H); 7.67 (s, CH).
Anal. calc. for C25H31N5OS2 (481.68): C 62.34, H 6.49, N 14.54, S 13.31; found: C 62.80, H 6.38, N 14.61, S 13.70.
2',4'-Bis(dialkylamino)-5-(1,3-dithiolan-2-ylidene)[2,5'-bithiazol]-4(5H)-ones 37: General Procedure. To a
suspension of a 2',4'-bis(dialkylamino)[2,5'-bithiazol]-4(5H)-one 30 (0.01 mol) in DMF (30 ml), KOH (1.1 g,
0.02 mol) in H2O (2 ml), followed by CS2 (0.8 g, 0.01 mol), was added. After stirring the red mixture at r.t. for
1 h, 1,2-dibromoethane (2.0 g, 0.01 mol) was added. The mixture was stirred for 1 h at r.t. and then diluted with
H2O (250 ml). The precipitated product was filtered off, washed with H2O, and recrystallized from DMF: 37a or
37b.
2',4'-Di(morpholin-4-yl)-5-(1,3-dithiolan-2-ylidene)[2,5'-bithiazol]-4(5H)-one (37a). From 30a. Yield 73%.
Orange crystals. M.p. 265 2678 (DMF). UV/VIS: 464 (4.69). 1H-NMR (CDCl3): 3.42 (t, 4 H, CH2N); 3.46
(t, 2 H, CH2); 3.51 (t, 2 H, CH2); 3.55 (t, 4 H, CH2N); 3.75 (t, 4 H, CH2O); 3.82 (t, 4 H, CH2O). Anal. calc. for
C16H20N4O3S4 (456.63): C 44.71, H 4.41, N 12.27, S 28.09; found: C 45.00, H 4.64, N 12.36, S 28.01.
2',4'-Di(piperidin-1-yl)-5-(1,3-dithiolan-2-ylidene)[2,5'-bithiazol]-4(5H)-one (37b). From 30b. Orange
crystals. Yield 64%. M.p. 221 2238 (DMF). UV/VIS: 469 (4.65). 1H-NMR (CDCl3): 1.67( m, 12 H, CH2);
3.39 (t, 4 H, CH2N); 3.43 (t, 2 H, CH2); 3.47( t, 2 H, CH2); 3.50 (t, 4 H, CH2N). Anal. calc. for C19H24N4OS4
(452.68): C 50.41, H 5.34, N 12.38, S 28.33; found: C 50.82, H 5.36, N 12.86, S 28.95.
2',4'-Bis(dialkylamino)[2,5'-bithiazole]-5-carboxaldehyde 38: General Procedure. A mixture of DMF
(35 ml), POCl3 (9.2 g, 0.06 mol), and a 4-substituted 2',4'-bis(dialkylamino)-2,5'-bithiazole 31 (0.02 mol) was
stirred at r.t. for 24 h and then heated at 758 for 7h. The mixture was diluted with H 2O (50 ml) and neutralized
by addition of aq. NaOH soln. The crystallized product was filtered off: 38a or 38b.
4-Methyl-2',4'-di(morpholin-4-yl)[2,5'-bithiazole]-5-carboxaldehyde (38a). From 31a. Yield 42%. Yellow
crystals. M.p. 215 2168 (DMF). IR (KBr): 1647. 1H-NMR (CDCl3): 2.61 (s, Me); 3.16 (t, 4 H, CH2N); 3.53
(t, 4 H, CH2N); 3.78 (t, 4 H, CH2O); 3.89 (t, 4 H, CH2O); 9.94 (s, CHO). Anal. calc. for C16H20N4O3S2 (380.49):
C 50.51, H 5.30, N 14.73, S 16.86; found: C 50.61, H 5.69, N 14.88, S 16.90.
2',4'-Di(morpholin-4-yl)-4-phenyl[2,5'-bithiazole]-5-carboxaldehyde (38d). From 31d. Yellow crystals.
1
Yield 33%. M.p. 246 2488 (DMF). IR (KBr): 1637. H-NMR (CDCl3): 3.22 (t, 4 H, CH2N); 3.56 (t, 4 H,
CH2N); 3.80 (t, 4 H, CH2O); 3.91 (t, 4 H, CH2O); 7.46 (m, 3 arom. H); 7.69 (d, 2 arom. H); 9.88 (s, CHO). Anal.
calc. for C21H22N4O3S2 (442.56): C 56.99, H 5.01, N 12.66, S 14.49; found: C 57.09, H 5.04, N 12.68, S 14.45.
2-{[2',4'-Bis(dialkylamino)[2,5'-bithiazol]-5-yl]methylene}propanedinitrile 39: General Procedure. A mix-
ture of
a 2',4'-bis(dialkylamino)[2,5'-bithiazole]-5-carboxaldehyde 38 (0.01 mol), malononitrile (0.8 g,
0.012 mol), Ac2O (10 ml), and 3 drops of Et3N was refluxed for 1 h. The product, precipitated after cooling
of the mixture, was filtered off and recrystallized: 39a or 39b.
2-{[4-Methyl-2',4'-di(morpholin-4-yl)[2,5'-bithiazol]-5-yl]methylene}propanedinitrile (39a). From 38a. Red
crystals. Yield 60%. M.p. 233 2358 (DMF). UV/VIS: 536 (4.58). 1H-NMR (CDCl3): 2.49 (s, Me); 3.24 (t, 4 H,

Helvetica Chimica Acta Vol. 86 (2003)
1965
CH2N); 3.59 (t, 4 H, CH2N); 3.79 (t, 4 H, CH2O); 3.90 (t, 4 H, CH2O); 7.69 (s, CH). Anal. calc. for C19H20N6O2S2
(428.53): C 53.25, H 4.70, N 19.61, S 14.97; found: C 53.16, H 4.79, N 19.49, S 15.09.
2-{[2',4'-Di(morpholin-4-yl)-4-phenyl[2,5'-bithiazol]-5-yl]methylene}propanedinitrile (39d). From 38d.
Yield 53%. Red crystals. M.p. 170 1718 (DMF). UV/VIS: 538 (4.46). 1H-NMR (CDCl3): 3.34 (t, 4 H,
CH2N); 3.61 (t, 4 H, CH2N); 7.39 (t, 4 H, CH2O); 3.93 (t, 4 H, CH2O); 7.55 (m, 5 arom. H); 7.70 (s, CH). Anal.
calc. for C24H22N6O2S2 (490.60): C 58.76, H 4.52, N 17.13, S 13.07; found: C 58.61, H 4.51, N 17.19, S 13.09.
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Received August 21, 2002