Facile generation of a library of 5-aryl-2-arylsulfonyl-1,3-thiazoles

Article abstract of DOI:10.1055/s-2006-926243

Treatment of N,N-diformylaminomethyl aryl ketones with phosphorus pentasulfide/triethylamine in chloroform gives 5-arylthiazoles directly in good yield. The 5-aryl-1,3-thiazole core has been successfully functionalised at the 2-position to yield, over two

Full text of DOI:10.1055/s-2006-926243

460
LETTER
Facile Generation of a Library of 5-Aryl-2-arylsulfonyl-1,3-thiazoles
Generation of
e
a
L
ibrary o
t
f
5-Ary
e
l-2-arylsulf
r
onyl-1,3-thiazo
W
le
s
. Sheldrake,* Mizio Matteucci, Edward McDonald*
Medicinal Chemistry Team, The Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research,
15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK
E-mail: peter.sheldrake@icr.ac.uk; E-mail: ted.mcdonald@icr.ac.uk.
Received 8 November 2005
Table 1 Conditions for the Preparation of 5-Phenyl-1,3-thiazole
Abstract: Treatment of N,N-diformylaminomethyl aryl ketones
with phosphorus pentasulfide/triethylamine in chloroform gives 5-
arylthiazoles directly in good yield. The 5-aryl-1,3-thiazole core has
been successfully functionalised at the 2-position to yield, over
two steps, a large array of 5-aryl-2-arylsulfonyl-1,3-thiazoles in a
parallel fashion.
Reagent
(equiv)
Et3N
(equiv)
Solvent Temp
(°C)
Time
(min)
Yield
(%)
Lawesson’s (1.2)
Lawesson’s (2.2)
Lawesson’s (2.0)
P2S5 (2.0)
–
PhMe
PhMe
PhMe
PhMe
CHCl3
90
90
90
90
60
70
110
90
14
37
55
62
82
–
Key words: heterocycles, 1,3-thiazole, lithiation, phosphorus
pentasulfide
2
2
120
45
The preparation of 4-aryl-1,3-thiazoles by the classical
Hantzsch synthesis of a-bromoacetophenones with thio-
formamide is one of the most widely used and reliable
reactions in heterocyclic synthesis.1 In contrast, the prep-
aration of the regioisomeric 5-arylthiazoles is problematic
as either a-aminoacetophenones or a-halo-a-arylacetalde-
hydes are required, neither of which is an easily handled
intermediate. Consequently, reactions have been devised
to attach an aryl group at the thiazole 5-position. Palladi-
um(0) and aryl bromides/iodides are used with 5-unsub-
stituted thiazoles2–5 and a cobalt catalyst has been
similarly employed.6 A 5-chlorothiazole has been used for
Suzuki coupling.7 When the thiazole 2-position is
blocked, deprotonation at the 5-position with n-butyl-
lithium, transmetallation and Negishi cross-coupling has
been exemplified.8
P2S5 (2.2)
2.2
Lawesson’s reagent in toluene gave a low yield of 5-phe-
nyl-1,3-thiazole (Table 1).
Increasing the amount of reagent and adding triethyl-
amine improved the yield, but impurities derived from the
Lawesson’s reagent were difficult to remove from the
product. Using phosphorus pentasulfide and changing the
solvent to chloroform brought further enhancement of the
yield.11,12 We did not observe any intermediate, which
would have helped us ascertain whether a formyl group is
lost before or after thiazole formation. Yields of other 5-
arylthiazoles 313,14 are shown in Table 2.
Ar1
Ar1
Ar1
CHO
a
Br
b
N
Within a project, we needed a range of 5-arylthiazoles for
conversion to 2-substituted-5-arylthiazoles. We thought
that such thiazoles should be prepared by thiazole ring
formation. The reaction of sodium diformylamide and a-
bromoketones to produce N,N-diformylaminoketones
such as 2 is reported,9 but surprisingly we found no
mention of these compounds being used directly for the
preparation of heterocycles. In contrast, the monoformyl-
aminoketones have been converted to thiazoles using
phosphorus pentasulfide.10
S
N
O
50–95%
O
CHO
1
2
3
Ar1
S
Ar1
c
d
N
S
N
16–100%
20–88%
SAr2
SO2Ar2
4
5
Scheme 1 Reagents and conditions: (a) NaN(CHO)2, MeCN, 70 °C;
(b) P2S5, Et3N, CHCl3, 60 °C, 45–60 min; (c) (i) LDA (1.3 equiv),
THF, –70 °C, 50 min, (ii) Ar2SSAr2 (1.3 equiv), –70 °C to r.t., 45 min;
(d) (i) MCPBA (5 or 10 equiv), CH2Cl2, r.t. or 40 °C, 3 h or 6 h, (ii)
MP-carbonate resin (4 peracid equiv), CH2Cl2, 2 h, r.t.
We reasoned that it might be unnecessary to remove a
formyl group from 2 in a separate step as this would likely
happen during or as a result of the cyclisation step. We
prepared bromomethylketones 1 either by Friedel–Crafts
reaction of the aromatic with bromoacetyl bromide or by
bromination of the methyl ketone, and displaced the bro-
mine using sodium diformylamide.9 Reaction of 2-di-
formylamino-1-phenylethanone with 1.2 equivalents of
As anticipated, we were able to functionalise the 2-posi-
tion of the thiazole by deprotonation with a modest excess
of LDA, followed by reaction with an electrophile. With
diaryldisulfides, we obtained thioethers 4 in yields of,
typically, greater than 70%.15,16 Surprisingly, we find little
precedent for the use of disulfides with 2-lithiothiazoles
and these examples used only dimethyldisulfide.17,18 The
thioethers were easily oxidised to the corresponding
SYNLETT 2006, No. 3, pp 0460–0462
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926243; Art ID: D33605ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Generation of a Library of 5-Aryl-2-arylsulfonyl-1,3-thiazoles
461
(6) Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607.
Table 2 Yields of 5-Aryl-1,3-thiazoles 3 Prepared via Scheme 1.
(7) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 1363.
(8) Jensen, J.; Skjærbæk, N.; Vedso, P. Synthesis 2001, 128.
(9) Yinglin, H.; Hongwen, H. Synthesis 1990, 615.
(10) Bachstez, M. Chem. Ber. 1914, 47, 3163.
Ar1
Yield (%)
4-FC6H4
79
54
78
79
83
47
76
63
69
75
61
(11) General Procedure for the Preparation of Thiazoles 3.
The bisformamide derivative (1 mmol) was dissolved in
CHCl3 (5 mL). Then, Et3N (0.28 mL, 0.20 g, 2 equiv) was
added to the stirred mixture, followed by phosphorus
pentasulfide (0.44 g, 2 mmol, 2 equiv). The mixture was
stirred at 60 °C for the appropriate time (typically 45–60
min). After cooling to r.t., H2O (3 mL) was added and the
mixture stirred for 1 h. CH2Cl2 (15 mL) was then added and
layers separated. The organic layer was washed with H2O
and brine, dried (Na2SO4 or MgSO4) and the solvent
removed in vacuo. The crude product was purified by flash
chromatography [silica; Et2O–PE (60–80) mixtures as
eluant] or on silica preparative TLC plates.
2-MeOC6H4
4-MeOC6H4
2-MeC6H4
4-MeC6H4
3-NO2C6H4
4-ClC6H4
1-Naphthyl
2-Naphthyl
2-Furyl
(12) We were also able to convert 6 into the thiazole 7 by the
same method in 67% yield (Scheme 2).
MeO
2-Thienyl
MeO
Me
CHO
Me
N
sulfones 5, which were obtained in pure form by simple
treatment of the crude mixtures with MP-carbonate resin19
and subsequent filtration, with no need for aqueous work
up.20–23 We found the chemistry described here conve-
nient to carry out using a parallel reactor and we were able
to obtain a large array of compounds for project purposes
in a short time.
O
CHO
S
N
6
7
Scheme 2
(13) Spectroscopic data of 3 (Ar1 = 4-MeOC6H4): 1H NMR (250
MHz, CDCl3): d = 3.84 (s, 3 H), 7.50 (m, 2 H), 6.94 (m, 2 H),
7.98 (s, 1 H), 8.70 (s, 1 H). 13C NMR (62.5 MHz, CDCl3):
d = 55.53, 114.7, 123.8, 128.4, 138.2, 139.4, 151.4, 160.0.
(14) Spectroscopic data of 3 (Ar1 = 2-furyl): 1H NMR (250 MHz,
CDCl3): d = 6.46 (dd, J = 3.5, 1.8 Hz, 1 H), 6.57 (dd, J = 3.5,
0.6 Hz, 1 H), 7.45 (dd, J = 1.8, 0.6 Hz, 1 H), 8.05 (s, 1 H),
8.71 (s, 1 H). 13C NMR (62.5 MHz, CDCl3): d = 107.6,
111.94, 129.2, 138.7, 142.8, 146.4, 151.4.
In summary, a convenient preparation of 2,5-substituted-
1,3-thiazoles has been reported. This synthetic procedure
is amenable for parallel synthesis applications allowing
the rapid preparation of large arrays of compounds in a
short time from easily available starting materials and
reagents.
(15) Spectroscopic data of 4 (Ar1 = 3-NO2C6H4, Ar2 = 3-
BrC6H4): 1H NMR (250 MHz, CDCl3): d = 7.33 (m, 1 H),
7.52–7.68 (m, 3 H), 7.72–7.87 (m, 2 H), 7.97 (s, 1 H), 8.12–
8.22 (m, 1 H), 8.28 (m, 1 H). 13C NMR (62.5 MHz, CDCl3):
d = 121.3, 123.0, 123.6, 130.32, 130.36, 131.3, 132.3, 132.7,
133.1, 133.4, 136.3, 138.4, 140.4, 148.85, 148.86.
Acknowledgment
This work was supported by Cancer Research UK [CUK] pro-
gramme grant number C309/A2187. We thank Professor Keith
Jones for helpful comments during the preparation of this manus-
cript. We also thank Dr. Amin Mirza and Mr. Meirion Richards for
their assistance with NMR and mass spectromtry.
(16) Spectroscopic data of 4 (Ar1 = 4-MeC6H4, Ar2 = Ph): 1H
NMR (250 MHz, CDCl3): d = 2.35 (s, 3 H), 7.11–7.23 (m, 2
H), 7.29–7.51 (m, 5 H), 7.65 (m, 2 H), 7.82 (s, 1 H). 13
C
NMR (62.5 MHz, CDCl3): d = 21.3, 126.5, 128.2, 129.5,
129.8, 132.2, 133.6, 138.3, 138.5, 141.2, 164.2.
References and Notes
(17) Noyce, D. S.; Fike, S. A. J. Org. Chem. 1973, 38, 3321.
(18) Cronje, S.; Raubenheimer, H. G.; Spies, H. S. C.;
Esterhuysen, C.; Schmidbaur, H.; Schier, A.; Kruger, G. J. J.
Chem. Soc., Dalton Trans. 2003, 14, 2859.
(19) MP-carbonate resin (loading: 3.14 mmol/g) was purchased
from Argonaut Technologies.
(1) Wiley, R. H.; England, D. C.; Behr, L. C. Org. React. 1951,
6, 367.
(2) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
(3) Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2,
3111.
(4) Oscarsson, K.; Oscarsson, S.; Vrang, L.; Hamelink, E.;
Hallberg, A.; Samuelsson, B. Bioorg. Med. Chem. 2003, 11,
1235.
(5) Bold, G.; Fässler, A.; Capraro, H.-G.; Cozens, R.; Klimmait,
T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rösel, J.; Stover,
D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss,
E.; Eschbach, M.; Hürlimann, T.; Masso, E.; Roussel, S.;
Ucci-Stoll, K.; Wyss, D.; Lang, M. J. Med. Chem. 1998, 41,
3387.
(20) General Procedure for the Oxidation of Thioethers 4 to
Sulfones 5.
To a solution of the thioether (1 equiv, 0.2 M) in CH2Cl2, dry
MCPBA (5 or 10 equiv) was added. The resulting mixture
was stirred for 3 h at 40 °C (recommended for sterically
hindered thioethers) or 6 h at r.t. To the mixture diluted with
CH2Cl2 (35 mL/mmol of thioether), MP-carbonate resin was
added (4 equiv relative to the amount of peracid used) and
stirred for 2 h. The resin was filtered off and washed twice
Synlett 2006, No. 3, 460–462 © Thieme Stuttgart · New York

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P. W. Sheldrake et al.
LETTER
7.53 (m, 2 H), 7.91–8.10 (m, 3 H). 13C NMR (62.5 MHz,
CDCl3): d = 21.8, 55.6, 115.0, 122.2, 128.7, 130.2, 136.2,
139.5, 145.6, 146.9, 161.0, 164.2.
with CH2Cl2. The solvent was removed in vacuo to give the
expected sulfones in pure form. In a few cases, crude
sulfones required further purification by preparative TLC
(silica; Et2O–PE (60–80) 7:3 as eluant).
(23) Spectroscopic data of 5 (Ar1 = 2-thienyl, Ar2 = 2-MeC6H4):
1H NMR (250 MHz, CDCl3): d = 2.65 (s, 3 H), 7.01 (dd,
J = 5.0, 3.7 Hz, 1 H), 7.18–7.52 (m, 5 H), 7.84 (s, 1 H), 8.16
(m, 1 H). 13C NMR (62.5 MHz, CDCl3): d = 20.9, 127.0,
127.7, 127.9, 128.6, 130.6, 131.1, 133.1, 134.7, 137.2,
139.6, 139.9, 140.2, 164.7.
(21) Sulfones derived from 5-furylsubstituted thiazoles could not
be isolated, probably due to side reactions affecting the furan
ring under the acidic conditions used for the oxidation step.
(22) Spectroscopic data of 5 (Ar1 = 4-MeOC6H4, Ar2 = 4-
MeC6H4): 1H NMR (250 MHz, CDCl3): d = 2.43 (s, 3 H),
3.84 (s, 3 H), 6.89–7.01 (m, 2 H), 7.31–7.42 (m, 2 H), 7.43–
Synlett 2006, No. 3, 460–462 © Thieme Stuttgart · New York