2-amino-4-dimethylamino-1-thia-3-azabutadienes as precursors of thiazoles

Article abstract of DOI:10.1080/10426500214568

The reaction of 2-amino-4-dimethylamino-1-thia-3-azabutadienes 1 with α-bromoketones gave rise to 2-aminothiazoles 2 together with 2-(N,N-dimethylaminomethylenamino)thiazoles 3. Competitive mechanisms are described. Furthermore, reaction of diene 1a with

Full text of DOI:10.1080/10426500214568

Phosphorus, Sulfur, and Silicon and the Related Elements
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2-Amino-4-dimethylamino-1-thia-3-azabutadienes
as Precursors of Thiazoles
C. Landreau , D. Deniaud , A. Reliquet & J. C. Meslin
To cite this article: C. Landreau , D. Deniaud , A. Reliquet & J. C. Meslin (2002) 2-Amino-4-
dimethylamino-1-thia-3-azabutadienes as Precursors of Thiazoles, Phosphorus, Sulfur, and
Silicon and the Related Elements, 177:11, 2651-2659, DOI: 10.1080/10426500214568
To link to this article: http://dx.doi.org/10.1080/10426500214568
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:2651–2659
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290110874
2-AMINO-4-DIMETHYLAMINO-1-THIA-
3-AZABUTADIENES AS PRECURSORS
OF THIAZOLES
C. Landreau, D. Deniaud, A. Reliquet, and J. C. Meslin
Laboratoire de Synthe`se Organique, Faculte´ des Sciences
et des Techniques, France
(Received December 14, 2001; accepted March 11, 2002)
The reaction of 2-amino-4-dimethylamino-1-thia-3-azabutadienes 1
with -bromoketones gave rise to 2-aminothiazoles 2 together with
2-( N,N-dimethylaminomethylenamino)thiazoles 3. Competitive mech-
anisms are described. Furthermore, reaction of diene 1a with methyl
-bromoacetate or hydroxylamine-O-sulfonic acid yielded respectively
2-( N,N-dimethylaminomethylenamino)thiazolin-4-one 4 and 5-amino-
1,2,4-thiadiazole 5.
Keywords: 2,4-Diamino-1-thia-3-azabutadienes; 1,2,4-thiadiazole;
thiazoles; thiazolin-4-one
INTRODUCTION
The use of 1-thia-3-azabutadienes in heterocyclic chemistry has been
widely developed, particularly in our laboratory, allowing the prepa-
4
ration of various compounds such as 6H-1,3-thiazines,1
2H-1,3-
thiazines,5,6 cephems,7
thiazolines11 and thiazoles.1,2,4 The lat-
10
ter are of great interest from a biological aspect. For instance,
2-guanidino-4-phenylthiazoles recently have been found to dis-
play bactericidal activities12 while 2-amino-4-(4-chlorophenyl)-5-
methylthiazole has been reported to inhibit secretion of IL-6 interleukin
in osteoblastic cells.13 Moreover such heterocyclic motifs are contained
in numerous natural compounds and may consequently be involved in
23,26
total syntheses.14,21
attention.15,24,25,27
Thus, their preparation still focuses chemists
The authors wish to express their gratitude to the French Ministry of Education and
the CNRS for financial support.
Address correspondence to D. Deniaud, Laboratoire de Synthe`se Organique, UMR
CNRS 66513, Nantes Cedex 44322, France. E-mail: deniaud@chimie.univ-nantes.fr
2651

2652
C. Landreau et al.
We recently have reported that 2-amino-4-dimethylamino-1-thia-3-
azabutadienes, when being alkylated by methyl iodide, were convenient
synthons for the preparation of various six-membered heterocycles.16
In a view to extend this work to the preparation of five-membered
ring systems, we decided to investigate the behaviour of these het-
eroatomic chains towards -bromoketones, methyl -bromoacetate and
hydroxylamine-O-sulfonic acid.
RESULTS AND DISCUSSION
A previous study conducted in our laboratory dealt with 1-thia-3-
azabutadienes bearing a monosubstituted amino group in position 2,
and a good-leaving group in position 4.4 Reaction with -bromoketones
afforded thiazoles in almost quantitative yields (Scheme 1).
SCHEME 1
As no trace of imidazole was observed, it was postulated that the re-
action began by alkylation of sulfur, the intermediary salt being depro-
tonated by triethylamine and cyclization occurring smoothly, followed
by deamination.
The extension of this procedure to similar 1-thia-3-azabutadienes
1 bearing an unsubstituted amino group in position 2 appeared more
complicated, since two competitive mechanisms could take place. In-
deed, the thioamide function might also be involved in a Hantzsch type
synthesis.17 This assertion was confirmed by experimental results. The
first step of these reactions was common to both pathways, consist-
ing in S-alkylation. The key step was the dehydrobromination of the
cationic intermediate, directing the course of the reaction toward path-
way a or b (Scheme 2). The expected 2-amino-5-aroylthiazoles 2 were
generally obtained in good yields, as listed in Table I. The reaction
proceeded by deprotonation of the N-alkyl amidinium bromides at the
methylene group (pathway a), the enolate undergoing intramolecular
cyclization with the iminium group, followed by loss of dimethylamine.
On the other hand, competitive nucleophilic attack on the carbonyl func-
tion by the generated imine (pathway b) gave rise after dehydration

2-Amino-4-dimethylamino-1-thia-3-azabutadienes
2653
SCHEME 2
to 4-aryl-2-(N,N-dimethylaminomethylenamino)thiazoles 3, in lower
yields.
The course of the reaction was found to depend on the nature of
the substituent of the bromomethyl reagent. Thus, the presence of a
weaker electron-withdrawing group inhibited reaction pathway a, so
that when thiazadiene 1a was alkylated by methyl -bromoacetate,
TABLE I Data for Compounds 2 and 3 Prepared
R
R0
Compounds
Yield (%)
Compounds Yield (%)
H
H
H
CH3
p-BrC6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
2aa
2ba
64
68
74
65
3a
3b
3c
3d
29
17
22
21
2ca
2d
aSee ref. 18.

2654
C. Landreau et al.
then treated with triethylamine, Hantzsch synthesis took place exclu-
sively to afford 2-(N,N-dimethylaminomethylenamino)thiazolin-4-one
4 (67%) (Scheme 3).
SCHEME 3
Furthermore, we continued our investigations by exposing thiazadi-
ene 1a to hydroxylamine-O-sulfonic acid. Amination, occurred on re-
flux, affording the expected 5-amino-1,2,4-thiadiazole 519 (Scheme 4).
This result corroborates the efficiency of this aminating agent which
was first used by Lin and coworkers20 for the synthesis of 5-aryl-1,2,4-
thiadiazoles from N0-(thioaroyl)-N,N-dimethylamidines.
SCHEME 4
CONCLUSION
Alkylation of 4-dimethylamino-1-thia-3-azabutadienes bearing an un-
substituted amino group in position 2 occurred unambiguously at sul-
fur. Conversely, intermediary salts might behave ambidently in the
presence of base allowing the synthesis of 2-amino-5-aroylthiazoles and

2-Amino-4-dimethylamino-1-thia-3-azabutadienes
2655
amidines derived from 4-aryl-2-aminothiazoles or 2-aminothiazolin-4-
one. The reactivity of such heterocyclic amidines is currently under
investigation.
EXPERIMENTAL
All reagents were purchased either from Acros Organics or Aldrich.
The CNRS Analysis Laboratory (Vernaison) performed the elemental
analyses. Column chromatography was conducted over silica gel 60 (40–
63 m), available from E. Merck. Thin layer chromatography was per-
formed on 0.5 mm 20 cm 20 cm E. Merck silica gel plates (60 F-254).
Melting points measured using a Reichert microscope are uncorrected.
The 13C and 1H NMR spectra were recorded at room temperature using
a Brucker AC 200 operating at 50 and 200 MHz respectively. Chem-
ical shifts ( ) are given in ppm downfield from tetramethylsilane as
internal standard. Mass spectra were determined with a Hewlett
Packard 5989 spectrometer. The IR spectra were obtained using a
Brucker Vector 22 spectrometer. All chemicals were reagent grade and
used without further purification. CH2Cl2 was distilled over CaH2. All
reactions were carried out under an atmosphere of nitrogen.
Preparation of Thiazadienes (1)16
N,N-dimethyl formamide dimethyl acetal (for 1a, 13 mmol) or N,N-
dimethyl acetamide dimethyl acetal (for 1b, 13 mmol) was added to a
suspension of thiourea (10 mmol) in methanol (for 1a, 10 mL) or CH2Cl2
(for 1b, 10 mL). The mixture was heated under reflux for 4 h then con-
centrated under vacuo. Compound 1a was crystallized from methanol.
Compound 1b was purified by filtration through a short pad of silica
gel using as eluant CH2Cl2/AcOEt 1/1, followed by crystallization from
diethyl ether.
Preparation of Thiazoles (2) and (3)
A solution of thiazadiene 1 (4 mmol) and -bromoketone (4 mmol)
(p-bromophenacyl bromide for 2a and 3a, p-chlorophenacyl bromide for
2b,d and 3b,d, p-toluoylacyl bromide for 2c and 3c) in CH2Cl2 (10 mL)
was stirred at room temperature for 15 min. Triethylamine (8 mmol)
was then added. After further stirring for 18 h, the solvent was re-
moved. The residue was diluted with CH2Cl2 and chromatographed,
furnishing first thiazoles 3 (elution CH2Cl2/AcOEt 1/1) then thiazoles
2 (elution AcOEt). Compounds 2 and 3 were crystallized from Et2O.

2656
C. Landreau et al.
2-Amino-5-p-bromobenzoylthiazole (2a)18
Yellow crystals, m.p. 187 C, yield 64%. 1H RMN (DMSO-d6) 7.65–
7.69 (m, 5H, ArH, NCH), 8.23 (s, 2H, NH ). 13C RMN (DMSO-d6)
2
125.4 (SCCO), 126.6 (ArC), 130.2, 131.6 (4
ArCH), 137.2 (ArC),
151.3 (NCH), 174.9 (SCN), 184.2 (CO). MS m/z (%): 284/282 (64/63,
1
M+), 185/183 (30/29), 157/155 (35/38), 127 (100). IR (KBr)
cm :
3349, 3114, 1589, 1496, 1233, 747. Anal. calcd. for C10H7BrN2OS
(283.1): C, 42.42; H, 2.49; N, 9.89. Found: C, 42.38; H, 2.56; N, 9.82.
2-Amino-5-p-chlorobenzoylthiazole (2b)18
Yellow crystals, m.p. 220 C, yield 68%. 1H RMN (DMSO-d6) 7.54–
7.77 (m, 4H, ArH), 7.66 (s, 1H, NCH ), 8.23 (s, 2H, NH2). 13C RMN
(DMSO-d6) 126.7 (SCCO), 128.7, 130.2 (4
ArCH), 136.5, 137.0
(2 ArC), 151.4 (NCH), 175.0 (SCN), 184.1 (CO). MS m/z (%): 240/238
(40/100, M+), 141/139 (14/42), 127 (100), 113/111 (16/56), 99 (39). IR
(KBr)
cm 1: 3443, 3081, 1604, 1478, 1255, 751. Anal. calcd. for
C10H7ClN2OS (238.7): C, 50.32; H, 2.96; N, 11.74. Found: C, 50.36; H,
2.91; N, 11.68.
2-Amino-5-p-toluoylthiazole (2c)18
1
Yellow crystals, m.p. 203 C, yield 74%. H RMN (DMSO-d6) 2.37
(CH3), 7.28–7.65 (m, 4H, ArH ), 7.61 (s, 1H, NCH), 8.12 (s, 2H, NH2).
13C RMN (DMSO-d6) 21.0 (CH3), 127.0 (SCCO), 128.3, 129.0 (4
ArCH), 135.5, 141.7 (2 ArC), 150.4 (NCH), 174.5 (SCN), 185.0 (CO).
MS m/z (%): 218 (100, M+), 203 (9), 176 (18), 119 (21), 91 (62). IR (KBr)
cm 1: 3337, 3084, 1587, 1470, 1231, 744. Anal. calcd. for C11H10N2OS
(218.3): C, 60.53; H, 4.62; N, 12.83. Found: C, 60.52; H, 4.68; N, 12.65.
2-Amino-5-p-chlorobenzoyl-4-methylthiazole (2d)
Yellow crystals, m.p. 215 C, yield 65%. 1H RMN (CDCl3) 2.35 (s, 3H,
CH3), 5.54 (br s, 2H, NH2), 7.40–7.70 (m, 4H, ArH). 13C RMN (DMSO-
d6) 18.8 (CCH3), 118.7 (SCCO), 128.6, 129.7 (4 ArCH), 136.1, 139.6
(2 ArC), 160.7 (CCH3), 171.9 (SCN), 185.4 (CO). MS m/z (%): 253/251
(37/86, M+), 216 (43), 141 (77), 113/111 (47/100). IR (KBr) cm 1: 3293,
3088, 1591, 1506, 1374, 1332, 1088, 753. Anal. calcd. for C11H9ClN2OS
(252.7): C, 52.28; H, 3.59; N, 11.08. Found: C, 52.03; H, 3.64; N, 11.31.
4-p-Bromophenyl-2-(N,N-dimethylaminomethylenamino)-
thiazole (3a)
Yellow crystals, m.p. 145 C, yield 29%. 1H RMN (CDCl3) 3.11, 3.13
(2s, 6H, N(CH3)2), 6.98 (s, 1H, SCH), 7.45–7.75 (m, 4H, ArH), 8.24
(s, 1H, NCH). 13C RMN (CDCl3) 34.9, 40.7 (N(CH3)2), 106.7 (SCH),

2-Amino-4-dimethylamino-1-thia-3-azabutadienes
2657
121.2 (ArC), 127.5, 131.4 (4
ArCH), 133.9 (ArC), 150.5 (CC6H4),
155.8 (NCH), 174.2 (SCN). MS m/z (%): 311/309 (100/97, M+), 278/276
(83/80), 269/267 (11/14), 214 (13), 182/180 (19/18), 159 (16), 115 (47),
89 (54). IR (KBr) cm 1: 3120, 2911, 1608, 1333, 1098. Anal. calcd. for
C12H12BrN3S (310.2): C, 46.46; H, 3.90; N, 13.55. Found: C, 46.38; H,
3.99; N, 13.52.
4-p-Chlorophenyl-2-(N,N-dimethylaminomethylenamino)-
thiazole (3b)
Yellow crystals, m.p. 148 C, yield 17%. 1H RMN (CDCl3) 3.11, 3.13
(2s, 6H, N(CH3)2), 6.96 (s, 1H, SCH), 7.30–7.81 (m, 4H, ArH), 8.25
(s, 1H, NCH). 13C RMN (DMSO-d6) 34.4, 40.1 (N(CH3)2), 107.5 (SCH),
127.2, 128.4 (4 ArCH), 131.7, 133.6 (2 ArC), 149.2 (CC6H4), 156.1
(NCH), 173.9 (SCN). MS m/z (%): 267/265 (40/100, M+), 234/232 (24/74),
170/168 (11/29), 138/136 (10/27), 115 (9), 89 (32). IR (KBr) cm 1: 3120,
2911, 2364, 1610, 1335, 1100. Anal. calcd. for C12H12ClN3S (265.8): C,
54.23; H, 4.55; N, 15.81. Found: C, 54.29; H, 4.61; N, 15.73.
2-(N,N-Dimethylaminomethylenamino)-
4-p-tolylthiazole (3c)
1
Yellow crystals, m.p. 123 C, yield 22%. H RMN (DMSO-d6) 2.30
(s, 3H, CH3), 2.99, 3.12 (2s, 6H, N(CH3)2), 7.14–7.76 (m, 4H, ArH), 7.33
(s, 1H, SCH), 8.35 (s, 1H, NCH). 13C RMN (DMSO-d6) 20.8 (CH3), 34.5,
40.2 (N(CH3)2), 106.0 (SCH), 125.6, 129.0 (4 ArCH), 132.1, 136.7 (2
ArC), 150.4 (CC6H4), 156.1 (NCH), 173.5 (SCN). MS m/z (%): 245 (100,
M+), 212 (62), 148 (19), 147 (35), 91 (11). IR (KBr) cm 1: 3117, 2917,
1642, 1613, 1400, 1097. Anal. calcd. for C13H15N3S (245.3): C, 63.64; H,
6.16; N, 17.13. Found: C, 63.71; H, 6.12; N, 17.01.
4-p-Chlorophenyl-2-[1-(dimethylamino)ethylidenamino]-
thiazole (3d)
Yellow crystals, m.p. 90 C, yield 21%. 1H RMN (CDCl3) 2.27 (s, 3H,
CH3), 3.11 (s, 6H, N(CH3)2), 7.02 (s, 1H, SCH), 7.30–7.82 (m, 4H,
ArH). 13C RMN (DMSO-d6) 16.1 (CCH3), 38.4 (N(CH3)2), 107.9 (SCH),
127.4, 128.7 (4 ArCH), 133.1, 133.8 (2 ArC), 150.6 (CC6H4), 161.5
(CCH3), 173.3 (SCN). MS m/z (%):281/279 (36/98, M+), 248/246 (34/100),
168 (18), 136 (47). IR (KBr) cm 1: 1558, 1472, 1392, 1160, 1056, 738.
Anal. calcd. for C13H14ClN3S (279.8): C, 55.81; H, 5.04; N, 15.02. Found:
C, 55.73; H, 5.22; N, 14.94.
2-(N,N-Dimethylaminomethylenamino)thiazolin-
4-one (4)
A solution of thiazadiene 1 (4 mmol) and methyl bromoacetate
(4 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 15 min

2658
C. Landreau et al.
then triethylamine (8 mmol) was added. After further stirring for 18 h,
the solvent was removed. The residue, diluted with CH2Cl2, was chro-
matographed using acetone as eluant. Compound 4 was crystallized
from Et2O as yellow crystals (m.p. 131 C) in 67% yield. 1H RMN (CDCl3)
3.22, 3.23 (2s, 6H, N(CH3)2), 3.93 (s, 2H, CH2), 8.74 (s, 1H, NCH).
13C RMN (DMSO-d6) 35.0, 40.9 (N(CH3)2), 39.3 (CH2), 159.4 (NCH),
188.3 (CO), 193.4 (SCN). MS m/z (%): 171 (100, M+), 127 (14), 103 (83),
98 (92), 70 (40). IR (KBr) cm 1: 2968, 2928, 1688, 1621, 1492, 1242.
Anal. calcd. for C6H9N3OS (171.2): C, 42.09; H, 5.30; N, 24.54. Found:
C, 42.02; H, 5.24; N, 24.49.
5-Amino-1,2,4-thiadiazole (5)19
A solution of thiazadiene 1 (3 mmol) and hydroxylamine-O-sulfonic
acid (3.3 mmol) in EtOH (10 mL) was refluxed for 8 h. After cooling
to room temperature, triethylamine was added (8 mmol) and the re-
action mixture was further stirred for 18 h, then concentrated. The
residue, diluted with CH2Cl2, was chromatographed using as eluant
CH2Cl2/AcOEt 1/1. Compound 5 was crystallized from hexane as white
1
crystals (m.p. 115 C) in 46% yield. H RMN (DMSO-d6) 7.82 (s, 1H,
CH), 7.90 (br s, 2H, NH2). Anal. calcd. for C2H3N3S (101.1): C, 23.75;
H, 2.99; N, 41.55. Found: C, 23.87; H, 3.05; N, 41.59.
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