Efficient synthesis of novel polyfunctionalised 4,5′-bithiazol- 4′-ol derivatives

Article abstract of DOI:10.1055/s-2004-835629

2-Thiazolin-4-one derivatives, obtained by reaction of tert-butyl (3-methoxy-1-methyl-3-oxoprop-1-enyl)diazenecarboxylate with aryl thioamides, were transformed into 5-bromoacetyl-4-hydroxythiazole derivatives by polymer-supported reagents and simple work-up procedures. The compounds thus synthesised were coupled with thioamides bearing valuable functional groups affording novel polyfunctionalised 4,5′-bithiazol-4′-ol derivatives.

Full text of DOI:10.1055/s-2004-835629

LETTER
2681
Efficient Synthesis of Novel Polyfunctionalised 4,5¢-Bithiazol-4¢-ol Derivatives
Synthesisof
N
ove
n
l
Polyfunctio
t
nalised
o
4,5¢-Bithiaz
n
ol-4¢-ol
D
er
i
ivative
o
s
Arcadi,a Orazio A. Attanasi,b Paolino Filippone,*b Francesca R. Perrulli,b Elisabetta Rossi,c
Stefania Santeusanio*b
a
Dipartimento di Chimica, Ingegneria Chimica e dei Materiali della Facoltà di Scienze, Università de L’Aquila, Via Vetoio, Coppito Due,
67100 L’Aquila, Italy
b
Istituto di Chimica Organica della Facoltà di Scienze Matematiche, Fisiche e Naturali, Università di Urbino ‘Carlo Bo’, Via Sasso 75,
61029 Urbino, Italy
c
Istituto di Chimica Organica della Facoltà di Farmacia, Università di Milano, Via Venezian 21, 20139 Milano, Italy
Fax +39(0722)303441; E-mail: santeusanio@uniurb.it
Received 21 July 2004
number of reagents bearing the thioamide moiety which
Abstract: 2-Thiazolin-4-one derivatives, obtained by reaction of
could be used in the Hantzsch thiazole synthesis.
tert-butyl (3-methoxy-1-methyl-3-oxoprop-1-enyl)diazenecarbox-
ylate with aryl thioamides, were transformed into 5-bromoacetyl-4-
hydroxythiazole derivatives by polymer-supported reagents and
simple work-up procedures. The compounds thus synthesised were
coupled with thioamides bearing valuable functional groups afford-
ing novel polyfunctionalised 4,5¢-bithiazol-4¢-ol derivatives.
Thus, 5a–c easily react with thiobenzamide (6a), thio-
acetamide (6b), thiourea (6c), 2-cyanothioacetamide (6d),
N-acetylthiourea (6e), ethyl thiooxamate (6f) in EtOH
under reflux to afford by cyclocondensation reaction the
target 4,5¢-bithiazol-4¢-ol derivatives 7a–l (68–97%,
Scheme 1, Table 1);9 these compounds are difficult to
prepare by other methods.10
Key words: 1,2-diaza-1,3-butadienes, thioamides, nucleophilic ad-
dition, cyclizations, bithiazoles
NHBoc
HN
O
As a part of our research programme we have focused our
attention onto the preparation of thiazole derivatives by
reaction of 1,2-diaza-1,3-butadienes1 with bidentate S-nu-
cleophilic reagents2 according to the Hantzsch protocol.3
The reason of our interest is ascribable to the presence of
the thiazole ring in the structure of several bioactive com-
pounds (i. e. epothilone,4a althiomycin,4b sulfomycin4c).
Since natural products bearing bithiazole frameworks ex-
hibit antifungal,5 antitumor-antibiotic6 activities and have
attracted the attention of many researchers,7 we set out to
accomplish the synthesis of hitherto unknown polyfunc-
tionalised 4,5¢-bithiazol-4¢-ol derivatives with simple and
effective methodologies.
MeO2C
N
N
Boc
N
S
1
R1
MeOH
r.t.
+
3a–c
S
NHBoc
N
R1
NH2
O
2a–c
N
S
R1
Our synthetic approach in assembly of the first thiazole
ring is based on the reaction of tert-butyl (3-methoxy-1-
methyl-3-oxoprop-1-enyl)diazenecarboxylate (1) with
arylthioamide derivatives 2a–c in MeOH at room temper-
ature to afford NH-Boc protected 2-thiazolin-4-one
derivatives 3a–c in hydrazino–hydrazono tautomeric
equilibrium.2a Subsequent hydrolytic removal of the NH-
Boc-hydrazo protecting group under heterogeneous catal-
ysis conditions,8 provides 5-acetyl-4-hydroxythiazole de-
rivatives 4a–c9 in a simpler way and with higher or
comparable yields then previously reported.2b The pres-
ence of the acetyl function at C5 represents a useful entry
to a-bromo ketone derivatives. In fact, the treatment of
4a–c in CHCl3 with polymer-supported tribromide fur-
nishes by simple work-up 5a–c in good yields (60–76%).9
This route is particularly attractive in light of the large
Amberlyst 15
(CH3)2CO, H2O
80 °C
O
O
OH
N
OH
- on Amberlyst A-26
CHCl3 r.t.
Br3
Br
N
S
S
4a–c
R1
5a–c
R1
S
S
OH
R2
NH2
R2
N
6a–f
N
S
EtOH
reflux
R1
7a–l
SYNLETT 2004, No. 15, pp 2681–2684
0
7
.1
2
.2
0
0
4
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835629; Art ID: D22104ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2682
A. Arcadi et al.
LETTER
Table 1 Results for the Synthesis of 4,5¢-Bithiazol-4¢-ol Derivatives 7a–m
Substrates 2–5
R1
Reagent 6
4,5¢-Bithiazol-4¢-ol (7)
Yield of 5 (%)a
R2
R1
R2
Yield (%)a
a
76
6a
6b
97
7a
7b
b
69
60
CH3
CH3
77
CH3
S
N
c
6c
6d
6e
6f
NH2
NH2
80
78
79
70
83
S
7c
7d
7e
7f
CH2CN
CH2CN
NHCOCH3
COOC2H5
NH2
NHCOCH3
COOC2H5
C(S)NH2
6g
CH3
S
7g
7h
7i
N
N
N
CH2CN
71
68
CH3
S
COOC2H5
CH3
S
NH2
82
73
70
73
S
7j
CH2CN
NHCOCH3
C(S)NH2
S
S
7k
7l
7m
a Yield of pure isolated products.
We have also studied the synthetic behavior of dithioox- transformations2e and useful for other heterocyclic ring
amide (6g). Depending upon the molar ratio used, 5a re- constructions. The polymer-supported reagents and the
acts with 6g to produce 4,5¢-bithiazol-4¢-ol derivative 7m simple reaction techniques employed represent a practical
(73%) or tetrathiazol-4,4¢¢¢-diol derivative 8 (68%, alternative method for polythiazole synthesis.11 More-
Scheme 2).
over, the presence of an amino or carboxylate function at
the 2-position of the thiazole ring in such compounds
promises potential utility as building blocks in medicinal
chemistry for DNA binding agents12 or bithiazole-type
antibiotics13 and will be further developed.
In conclusion, we report herein an efficient synthetic se-
quence for a number of new 4,5¢-bithiazol-4¢-ol deriva-
tives bearing different functionalities (i. e. hydroxy,
carbothioamide), which are suitable for further chemical
Synlett 2004, No. 15, 2681–2684 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of Novel Polyfunctionalised 4,5′-Bithiazol-4′-ol Derivatives
2683
Chem. Int. Ed. 2001, 40, 3184. (e) Boger, D. L.; Aquila, B.
M.; Tse, W. C.; Searcey, M. Tetrahedron Lett. 2000, 41,
9493. (f) Nussbaumer, T.; Neidlein, R. Heterocycles 2000,
52, 349.
S
HO
N
5a
1 equiv
S
N
EtOH
reflux
NH2
S
S
(8) Ballini, R.; Petrini, M. J. Chem. Soc., Perkin Trans. 1 1988,
2563.
H2N
R1
7m 73 %
NH2
(9) Representative Procedure for the Synthesis of 4, 5, 7 and
8.
S
S
N
S
N
5a
2 equiv
HO
6g
OH
N
Preparation of 4b: Compound 3b (354 mg, 1 mmol),
prepared as previously reported,2a was suspended in a
(CH3)2CO–H2O mixture (9:1, 10 mL) and heated under
reflux in the presence of Amberlyst 15 (500 mg) for 18 h.
The resin was filtered off, washed with THF (3 × 10 mL)
and, after evaporation of the solvents under reduced
pressure, the solid residue was treated with Et2O and filtered
in vacuo to obtain derivative 4b with a yield of 71%.2b
Preparation of 5b: To a magnetically stirred solution of 4b
(240 mg, 1 mmol) in CHCl3 (20 mL) was added tribromide
on Amberlyst A-26 (1.36 g) and the reaction was allowed to
stand at r.t. for 24 h (monitored by TLC). The fine solid
suspended in the reaction medium was filtered and furnished
the first crop of compound 5b. Then, the resin was washed
with THF (4 × 20 mL) and the combined filtrates were
evaporated under reduced pressure to afford an additional
amount of brominated product in overall yield of 69%. Data
for 2-bromo-1-(4-hydroxy-2¢-methyl-2,4¢-bi-1,3-thiazol-5-
yl)ethanone 5b: dark yellow powder from CHCl3, mp 194 °C
(dec.). IR (nujol): 3397, 3070, 1643, 1590, 1548, 1540 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.72 (s, 3 H, CH3), 4.58
(s, 2 H, CH2), 8.17 (s, 1 H, Ar), 11.78 (br s, 1 H, OH, D2O
exch.). 13C NMR (100 MHz, DMSO-d6): d = 18.77, 33.88,
108.55, 120.97, 146.59, 164.67, 165.09, 167.99, 183.34.
MS: m/z (%) = 320 (46) [ M+ – H], 318 (43), 238 (50), 225
(100). Anal. Calcd for C9H7BrN2O2S2: C, 33.86; H, 2.21; N,
8.78. Found: C, 33.68; H, 2.35; N, 8.61. Preparation of 7i:
a-Bromo ketone derivative 5b (319 mg, 1 mmol) was added
to a solution of ethyl thiooxamate (6f, 133 mg, 1 mmol) in
EtOH (40 mL). The mixture was heated under reflux for 10
h (monitored by TLC) during which time a yellowish
precipitate was formed. After partial removal of the solvent
the suspension was filtered yielding the desired product 7i.
Data for ethyl 4¢-hydroxy-2-methyl-4,2¢:5¢,4¢¢-ter-1,3-
thiazole-2¢¢-carboxylate (7i): yellow powder from EtOH, mp
224–234 °C (dec.). IR (nujol): 3395, 3118, 1717, 1587, 1510
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.33 (t, J = 7.4
Hz, 3 H, CH2 CH3), 2.71 (s, 3 H, CH3), 4.37 (q, J = 7.4 Hz,
2 H, CH2 CH3), 7.94 (s, 1 H, Ar), 8.07 (s, 1 H, Ar), 12.07 (s,
1 H, OH, D2O exch.). 13C NMR (100 MHz, DMSO-d6): d =
14.03, 18.80, 62.21, 103.26, 116.67, 118.84, 147.61, 148.48,
156.35, 156.98, 159.23, 159.87, 167.27. MS: m/z (%) = 353
(20) [M+], 229 (35), 201 (100). Anal. Calcd for
1 equiv
EtOH
reflux
N
S
S
R1
R1
8
68 %
Scheme 2
Acknowledgment
This work was supported by financial assistance from the M.I.U.R.-
Roma (COFIN 2002), and the Università di Urbino ‘Carlo Bo’.
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C13H11N3O3S3: C, 44.18; H, 3.14; N, 11.89. Found: C, 44.06;
H, 3.23; N, 11.76. Preparation of 7k: a-Bromo ketone
derivative 5c (304 mg, 1 mmol) was added to a solution of
2-cyanothioacetamide (6d, 100 mg, 1 mmol) in EtOH (20
mL). The mixture was heated under reflux for 8 h (monitored
by TLC) during which time brown needles precipitated.
After cooling to r.t. the solid was filtered off yielding the
bithiazole derivative 7k. Data for (4¢-hydroxy-2¢-thien-2-yl-
4,5¢-bi-1,3-thiazol-2-yl)acetonitrile (7k): brown crystals
from EtOH, mp 220–223 °C. IR (nujol): 3140, 3088, 2255,
1580, 1554, 1511 cm–1. 1H NMR (400 MHz, DMSO-d6): d =
4.60 (s, 2 H, CH2), 7.17 (dd, J = 3.9 Hz, J = 4.9 Hz, 1 H Ar),
7.69 (dd, J = 1.6 Hz, J = 3.9 Hz, 1 H Ar), 7.70 (s, 1 H Ar),
7.72 (dd, J = 1.6 Hz, J = 4.9 Hz, 1 H Ar), 12.00 (s, 1 H, OH,
D2O exch.). 13C NMR (100 MHz, DMSO-d6): d = 21.39,
102.74, 113.57, 117.05, 126.83, 128.85, 129.09, 136.77,
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Synlett 2004, No. 15, 2681–2684 © Thieme Stuttgart · New York

2684
A. Arcadi et al.
LETTER
disappearance of 7m before each addition of 6g. After
146.08, 155.26, 158.49, 159.03. MS: m/z (%) = 305 (27)
[M+], 196 (41), 168 (100). Anal. Calcd for C12H7N3OS3: C,
47.19; H, 2.31; N, 13.76. Found: C, 47.03; H, 2.47; N, 13.84.
Preparation of 7m: a-Bromo ketone derivative 5a (298 mg,
1 mmol) was added portionwise to a stirred and heated
solution of dithiooxamide (6g, 120 mg, 1 mmol) in EtOH (20
mL) monitoring, by TLC analysis, the disappearance of 5a
before further addition. After reaction was complete (16 h)
the solid formed was filtered off to furnish the bithiazole
derivative 7m. Data for 4¢-hydroxy-2¢-phenyl-4,5¢-bi-1,3-
thiazole-2-carbothioamide (7m): brown powder from EtOH,
mp >350 °C. IR (nujol): 3444, 3322, 3121, 1584, 1574, 1504
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 7.47–7.53 (m, 3
H, Ar), 7.86–7.88 (m, 2 H, Ar), 7.99 (s, 1 H, Ar), 9.70 and
10.17 (2 s, 2 H, NH2, D2O exch.), 11.90 (s, 1 H, OH, D2O
exch.). 13C NMR (100 MHz, DMSO-d6): d = 103.20, 121.46,
125.24, 129.42, 130.41, 132.95, 147.72, 159.78, 161.29,
167.89, 186.34. Anal. Calcd for C13H9N3OS3: C, 48.88; H,
2.84; N, 13.15. Found: C, 48.96; H, 2.76; N, 13.09.
reaction was complete (24 h) the solid precipitate was
collected by filtration furnishing tetrathiazol-4,4¢¢¢-diol
derivative 8. Data of 2,2¢¢¢-diphenyl-5,4¢:2¢,2¢¢:4¢¢,5¢¢¢-quater-
1,3-thiazole-4,4¢¢¢-diol(8): brown powder from EtOH, mp
>350 °C. IR (nujol): 3124, 2926, 1667, 1584, 1570, 1504
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 7.46–7.55 (m, 6
H, Ar), 7.94–7.98 (m, 3 H, Ar), 12.01 (s, 2 H, OH, D2O
exch.). Anal. Calcd for C24H14N4O2S4: C, 55.58; H, 2.72; N,
10.80. Found: C, 55.46; H, 2.85; N, 10.69.
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Preparation of 8: Dithiooxamide (6g, 120 mg, 1 mmol) was
added portionwise to a heated and stirred solution of a-
bromo ketone derivative 5a (596 mg, 2 mmol) in EtOH (40
mL). The reaction was monitored by TLC checking for
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Synlett 2004, No. 15, 2681–2684 © Thieme Stuttgart · New York