2,4,5-Trisubstituted thiazole building blocks by a novel multi-component reaction

Article abstract of DOI:10.1055/s-2004-836035

A novel multi-component reaction (MCR) of oxo-components, primary amines, thiocarboxylic acids and 3-bromo-2-isocyanoacrylates yielding 2,4,5-trisubstituted thiazole building blocks is described.

Full text of DOI:10.1055/s-2004-836035

LETTER
79
2
,4,5-Trisubstituted Thiazole Building Blocks by a Novel Multi-Component
Reaction
locks el Umkehrer,*a,b Jürgen Kolb, Christoph Burdack, Wolfgang Hiller
a
a
b
S
M
ynethesis of 2,4,5-Tri
i
substit
c
uted Thiazo
h
le Building
Ba
a
Priaton GmbH, Bahnhofstr. 9-15, 82327 Tutzing, Germany
Technical University Munich, Lichtenbergstr.4, 85747 Garching, Germany
Fax +49(8158)904022; E-mail: Umkehrer@priaton.de
b
Received 5 October 2004
ceutical potential of these thiazole-containing natural
products led to the development of several multi-step syn-
Abstract: A novel multi-component reaction (MCR) of oxo-com-
ponents, primary amines, thiocarboxylic acids and 3-bromo-2-iso-
cyanoacrylates yielding 2,4,5-trisubstituted thiazole building
blocks is described.
1
6–18
thetic protocols for their total synthesis
and to differ-
ent combinatorial modifications.1
9–26
Key words: combinatorial chemistry, multicomponent reaction, Dömling et al. developed the first true multicomponent
one-pot synthesis, 3-substituted 3-bromo-2-isocyanoacrylates, single step reaction towards 2,4-disubstituted thiazoles
2
,4,5-trisubstituted thiazoles
27
using b-dimethylamino-isocyanoacrylates. This isocya-
nide was first described by Schöllkopf et al. It contains a
dimethylamino leaving group in the b-position suitable
Thiazole containing peptides are a well known class of for one-pot, four-component thiazole synthesis.28
compounds with a high structural diversity and a high
For further progress in molecular diversity we developed
1
–7
pharmaceutical potential. Thiazole containing peptides,
especially those obtained from microbial and marine ori-
gins, exhibit important biological effects such as antitu-
mor, antifungal, antibiotic and antiviral activities.8
Examples of some prominent thiazole containing natural
a novel four-component reaction using 3-substituted 3-
29,30
bromo-2-isocyanoacrylates 4,
which allows general
access to the class of 2,4,5-trisubstituted thiazoles. In
comparison to the formerly used b-dimethylamino-isocy-
anoacrylates, it is now possible to introduce a new substit-
uent in 5-position of the thiazole system.
–11
1
2,13
products are the lissoclinum class of cyclic peptides,
1
1
14
such as bistratamide D (1), ascidiacylamide (2) and the
group of thiostrepton antibiotics (3). The high pharma-
1
5
O
O
O
NH2
O
NH
N
O
N
O
N
N
Bistratamide D (1)
S
N
N
N
O
NH
HN
N
O
N
S
S
N
OH
O
S
S
S
HN
O
N
O
O
H
N
N
O
HN
NH
HN
N
N
H
NH
O
O
N
N
N
H
N
O
S
S
O
NH
O
S
O
O
Ascidiacylamide (2)
Figure 1 Bioactive and natural products incorporating the thiazole motif
Thiostrepton Antibiotic GE2270 A (3)
SYNLETT 2005, No. 1, pp 0079–0082
0
5.
0
1.
2
0
0
5
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-836035; Art ID: G37904ST
©
Georg Thieme Verlag Stuttgart · New York

8
0
M. Umkehrer et al.
LETTER
Scheme 1 Proposed mechanism for the synthesis of 2,4,5-trisubstituted thiazoles 7
A possible mechanism is proposed in Scheme 1. During mined by separation of the major and minor diastereomer
the reaction, the isocyanide, the Schiff base and the thio- whereby the relative configuration was not assigned. In
carboxylic acid react regioselectively according to the this new four-component reaction the primary amines, the
2
9,30
mechanism of a Ugi reaction. The intermediate Ugi prod- oxo-components, the isocyanides
and the thiocarbox-
uct 5, which cannot be isolated, is in equilibrium with its ylic acids32 can be varied broadly, producing products
mercaptoimine tautomer 6. The following Michael addi- with four potential diversity points. The use of unsymmet-
tion and final hydrogen bromide abstraction lead to the rical ketones can even lead to molecules with five points
expected 2,4,5-trisubstituted thiazole 7.
of diversity.
In this communication we show an efficient synthesis of The reaction conditions of this novel thiazole MCR are
various types of 2,4,5-trisubstituted thiazoles 7 (Table 1) mild: stirring for 1 day at room temperature, basic and
using 3-substituted 3-bromo-2-iscyanoacrylates 4, which acid extraction, evaporation of the solvent and column
can be synthesized in 3 steps from commercially available chromatography on silica gel.33
methyl-isocyanoacetate 8 via 3-substituted 2-(formylami-
no)acrylates 9 (Scheme 2).
In summary, a novel one-pot solution-phase procedure for
3
1
the preparation of 2,4,5-trisubstituted thiazole building-
34
blocks has been reported. This reaction is suitable for the
total synthesis of certain naturally occurring thiazoles as
well as for the combinatorial chemistry. With final
products containing five points of potential diversity and
a facile and rapid production protocol, access to thousands
of diverse analogues with the aforementioned core
structure is now feasible.
Table 1 Synthesized 2,4,5-Trisubstituted Thiazoles
Product
Thiazole
Yield (%)
42
Scheme 2 Synthesis of 3-substituted 3-bromo-2-isocyanoacrylates
7
a
The main advantage of 3-substituted 3-bromo-2-isocy-
anoacrylates is the great variability of substitution at the
3
-position, which allows the easy addition of various sub-
stituents at the 5-position of the thiazole system. There-
fore, this novel four-component reaction represents a
powerful tool for the total synthesis of natural products
and for the combinatorial synthesis of interesting pharma-
cological templates incorporating the thiazole motif.
7
b
43
32
The reaction of 3-substituted 3-bromo-2-isocyanoacry-
lates together with Schiff bases and thiocarboxylic acids 7c
leads to the desired 2,4,5-trisubstituted thiazoles 7a–k in
a one-pot procedure (Table 1) with moderate yields. In re-
action 7j–k chiral amines were used and in the case of
compound 7j it was possible to determine a diastereomer-
ic excess of 71%. The diastereomeric ratio was deter-
Synlett 2005, No. 1, 79–82 © Thieme Stuttgart · New York

LETTER
Synethesis of 2,4,5-Trisubstituted Thiazole Building Blocks
81
Table 1 Synthesized 2,4,5-Trisubstituted Thiazoles (continued)
Current efforts are now focusing on the development of an
enantioselective one-pot synthesis of 2,4,5-trisubstituted
thiazoles.
Product
Thiazole
Yield (%)
41
7
d
References
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(
(
(
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h
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20) Martin, L. M.; Hu, B. H. Tetrahedron Lett. 1999, 40, 7951.
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897.
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28) Schöllkopf, U.; Porsch, H.; Lau, H. H. Liebigs Ann. Chem.
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k
31
(
32) Kolb, J. Doctoral Thesis; Technical University: Munich,
001.
2
(
33) Typical Procedure:
Aldehyde or ketone (1 mmol), amine and MgSO are stirred
4
under inert and water-free conditions in 2 mL dry MeOH at
0
°C. The imine is precondensed for 2 h and the solution is
cooled to –10 °C: 1 mmol of the thiocarboxylic acid and
Synlett 2005, No. 1, 79–82 © Thieme Stuttgart · New York

8
2
M. Umkehrer et al.
LETTER
CO), 24.96 [(CH(CH ) ], 24.99 [CH(CH ) ], 27.89
isocyanide are added and the reaction volume is increased to
3
2
3 2
4
mL. The reaction mixture is allowed to warm up to r.t. and
[CH(CH ) ], 48.85 (CH -C H ), 51.56 (CH-CH ), 51.94
3 2 2 6 5 3
stirred for 24 h until the reaction is completed (indication by
TLC). Then the reaction mixture is diluted with 25 mL
CH Cl . The organic layer is washed with sat. NaHCO
(CH OOC-), 125.79, 127.17, 128.58, 137.30 (Cq), 138.60
(Cq), 159.71 (Cq), 162.71 (Cq), 166.35 (CON), 171.85
(COOMe).
3
2
2
3
solution, 3% HCl and sat. NaCl solution, dried over MgSO4
and concentrated in vacuo. The resulting oil is purified by
column chromatography on silica gel (hexane–EtOAc).
Compound 7d was isolated in 41% yield as a yellow oil.
HPLC-MS spectra (Varian 1200); RP OmniSpher C18
column, 3 mm × 150 mm, 5 mm; ProStar 320 (254 nm); 0.3
(
34) Compound 7b was isolated in 43% yield as a yellow oil.
HPLC-MS spectra (Varian 1200); RP OmniSpher C18
column, 3 mm × 150 mm, 5 mm; ProStar 320 (254 nm); 0.3
mL/min, 10 min, MeCN–H O = 80:20 coupled with a
2
Quadrupol MS/MS mass spectrometer using electrospray
ionisation (ESI): t (254 nm) = 5.08 min; m/z = 395.4 [M +
R
+
+ 1
mL/min, 10 min, MeCN–H O = 70:30 coupled with a
H] , 417.2 [M + Na] . H NMR (399.78 MHz, CDCl ):
2
3
Quadrupol MS/MS mass spectrometer using electrospray
d = 1.66 (d, 3 H, J = 7.26 Hz, H C-CH), 2.13 (s, 3 H, H C-
3
3
ionisation (ESI): t (254nm) = 5.37 min; m/z = 361.1 [M +
CO), 3.79 (s, 3 H, CH O-), 4.67 (s, 2 H, CH -C H ), 6.04 (q,
R
3 2 6 5
+
+
1
13
H] , 383.1 [M + Na] . H NMR (270.17 MHz, CDCl ):
1 H, J = 7.26 Hz, CH-CH ), 7.19–7.41 (m, 10 H, C H ). C
3 6 5
3
d = 1.30 [d, 6 H, J = 7.01 Hz, CH(CH ) ], 1.61 (d, 3 H,
NMR (100.53 MHz, CDCl ): d = 17.23 (H C-CH), 22.34
3
2
3
3
J = 7.01 Hz, H C-CH), 2.12 (s, 3 H, H C-CO), 3.91 (s, 3 H,
(H C-CO), 49.19 (CH -C H ), 51.85 (CH-CH ), 52.07
3 2 6 5 3
3
3
CH OOC), 4.07 [h, 1 H, J = 7.01 Hz, CH(CH ) ], 4.57 (s, 1
(CH OOC-), 125.94, 127.31, 128.11, 128.70, 129.09,
3
3
2
3
H, CH -C H ), 4.60 (s, 1 H, CH -C H ), 6.18 (q, 1 H,
129.73, 130.27, 137.34 (Cq), 139.27 (Cq), 147.29 (Cq),
162.53 (Cq), 168.86 (CON), 171.83 (COOMe).
2
6
5
2
6
5
J = 7.01 Hz, CH-CH ), 7.14–7.31 (m, 5 H, C H ). 13C NMR
3
6
5
(
100.53 MHz, CDCl ): d = 17.13 (H C-CH), 22.26 (H C-
3 3 3
Synlett 2005, No. 1, 79–82 © Thieme Stuttgart · New York