A practical preparation of 5-(ketoaryl)thiazoles

Article abstract of DOI:10.1016/S0040-4039(02)02230-X

This article describes a facile synthesis of 2-substituted-5-(ketoaryl)thiazoles, which are important intermediates for the synthesis of biologically active compounds. A variety of 2-substituted thiazole anions were added to aryl nitriles to provide the desired ketones after aqueous hydrolysis.

Full text of DOI:10.1016/S0040-4039(02)02230-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8845–8848
A practical preparation of 5-(ketoaryl)thiazoles
Karen M. Marcantonio,* Lisa F. Frey, Jerry A. Murry and Cheng-yi Chen
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 25 September 2002; accepted 4 October 2002
Abstract—This article describes a facile synthesis of 2-substituted-5-(ketoaryl)thiazoles, which are important intermediates for the
synthesis of biologically active compounds. A variety of 2-substituted thiazole anions were added to aryl nitriles to provide the
desired ketones after aqueous hydrolysis. © 2002 Elsevier Science Ltd. All rights reserved.
Thiazoles are important heterocycles in pharmaceutical
organic chemistry and are often used as amide isosteres
during the course of probing structure activity relation-
ships. In light of this, a useful intermediate for the
construction of biaryl thiazoles is the 5-
(ketoaryl)thiazole. These thiazoles are classically assem-
bled using the Hantzsch reaction,1 i.e. condensation of
a thiourea with an amide acetal to form a thiocar-
bamoylamidine, followed by base-promoted cyclization
Scheme 1. Thiazole anion addition to nitriles.
with a phenacyl halide. While the thiourea and for-
mamide can be appended with alkyl groups to produce
diversely substituted thiazoles, this method is limited in
that it only produces thiazoles with an alkylamino
group in the 2-position.2
overaddition, the imine intermediate is unlikely to react
with a second thiazole anion.
The reaction conditions were developed as follows.
Treatment of a low temperature THF solution of the
thiazole with n-BuLi effected clean deprotonation at
the 5-position, as demonstrated by deuterium quench-
ing experiments. Subsequent addition of the nitrile fol-
lowed by aging between −35 and −20°C resulted in
complete conversion to the lithio imine intermediate.5
After acidic hydrolysis, the ketones were obtained in
good to excellent yields.
The synthesis of 5-(ketoaryl)thiazoles lacking an amine
in the 2-position involves deprotonation of 2-substi-
tuted thiazoles in the 5-position, followed by addition
to acid chlorides,3a amides,3b ketenes,3a lactones,3c and
aldehydes3d (with subsequent oxidation) to afford the
desired ketone. However, these functional groups often
require synthetic manipulation to obtain and the reac-
tion intermediates may not be stable to some reaction
conditions. An appealing alternative would be addition
of the thiazole anion to a nitrile functionality,4 followed
by hydrolysis of the intermediate metallo imine species
to the ketone (Scheme 1). This would constitute a
convenient synthesis of 5-(ketoaryl)thiazoles, as many
substituted benzonitriles and 2-substituted thiazoles are
readily available, and the nitrile functionality is stable
to a range of reaction conditions. Furthermore, unlike
reactions with functional groups that are susceptible to
Scheme 2 illustrates one example (entry 1, Table 1):
4-Chlorobenzonitrile was added to lithiated 2-
(methylthio)thiazole, and the reaction was aged for 2 h
to give 90% HPLC assay yield of the ketone, after an
aq. HCl work-up to hydrolyze the imine.6,7
* Corresponding author. Tel.: 732-594-2075; fax: 732-594-5170;
e-mail: karen marcantonio@merck.com
–
Scheme 2. Example of thiazole addition chemistry.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02230-X

8846
K. M. Marcantonio et al. / Tetrahedron Letters 43 (2002) 8845–8848
an HCl quench removed it completely.9 This lability
of the TBS group could be exploited as a temporary
protecting group for the 2-position to obtain ketones
capable of being further functionalized at that posi-
tion. Notably, when the commercially available 2-
(trimethylsilyl)thiazole was used, products were
detected that arose from reaction at the 2-position,
indicating that the TMS functionality was somewhat
labile under reaction conditions. This was not an
issue with the more robust TBS group.
In order to demonstrate this as a general method, a
range of thiazoles were added to commercially avail-
able nitriles. Inspection of Table 1 reveals that the
reaction was tolerant of electron withdrawing and
donating groups on both reacting partners.
Table 1. Effect of substitution on thiazole and benzonitrile
To probe the utility of this reaction further, 2-(t-
butyldimethylsilyl)thiazole was deprotonated and
added to a variety of electronically and structurally
different aryl nitriles (Table 2). The reaction was
found to be tolerant of substituents ortho to the
nitrile, although in a comparative study, reaction was
significantly slower with the more hindered 2-methyl-
versus 4-methylbenzonitrile (entries 1 and 2, Table 2).
However, when a bulky EWG was ortho to the
nitrile, the rate appeared unaffected, suggesting that
ring electronics may have a significant effect on the
rate of reaction (entry 3, Table 2). In line with these
findings, when an OMe was in the meta position of
the benzonitrile ring (entry 4, Table 2), the rate of
reaction was faster than when the same group was in
the para position (entry 6, Table 1).
Entry
X
R
Rxn time (h)
Yield (%)a
1
2
3
4
5
6
7
8
SMeb
SMe
SMe
Cl
H
OMe
Cl
H
OMe
H
OMe
2
3
4
1.5
1.5
8
3
5
90
90
94
98
98
88e
95
96
c
SitBuMe2
SitBuMe2
SitBuMe2
C(CF3)2OMOMd
C(CF3)2OMOM
a Assay yields determined by HPLC, compared with a standard.
b Prepared from 2-mercaptothiazole and MeI with K2CO3 in MeCN.
c Prepared from thiazole and TBSCl using n-BuLi.
To expand the scope of this reaction, other aryl
nitriles and substituted thiazoles were investigated.
Extension of this method into heteroaromatic nitriles
would lead to products of even greater structural
diversity, and it was found that 5-lithio-2-substituted
thiazoles added to 4-cyanopyridine and 2-furonitrile
to form biheteroaryl ketones in good and moderate
yields, respectively (entries 7–9, Table 2). In a similar
vein, thiazoles containing a masked ketone and a
masked amine (entries 10 and 11, Table 2) were
prepared and found to provide high yields of 5-
(ketoaryl)thiazoles capable of further functionali-
zation.
d Prepared by deprotonating thiazole with LiHMDS, quenching with
hexafluoroacetone, followed by addition of MOMCl.
e Yield of X=H, TBS was removed in work-up.
It is important to note that temperature control was
crucial in this reaction due to competitive decomposi-
tion of the iminium intermediate. Decomposition gen-
erally occurred at temperatures above −10°C, while
the addition reactions were sluggish at −50°C. As a
result, reactions were typically run between −35 and
−20°C to effect complete conversion within a few
hours, while minimizing decomposition.
In conclusion, a facile method for the preparation
of 5-(ketoaryl)thiazoles from 2-substituted thiazoles
and aryl nitriles has been developed. This method is
applicable to a broad range of substituted aryl and
heteroaryl nitriles as well as functionalized thiazoles
and affords the ketones in good to excellent yields.
These ketone intermediates can provide a base on
which to create pharmaceutically interesting com-
pounds.
The stability of the intermediate imine was notable.
The electronic parameters of the reacting partners
had an effect on the stability, and several of these
imines could be isolated and characterized. To isolate
the imine, the reaction was quenched into aq. NH4Cl,
while aq. AcOH or 2N HCl was used to effect
hydrolysis to the ketone. Electron poor imines
generally hydrolyzed instantly in acid, while electron
rich imines required a longer age to hydrolyze com-
pletely.8
Acknowledgements
The authors thank Drs. Richard D. Tillyer, Edward
J. J. Grabowski and Ulf-H. Dolling for helpful dis-
cussions and Drs. Robert A. Reamer, Peter G.
Dormer and Lisa M. DiMichele and for help in
NMR determinations.
The TBS group on the thiazole proved to be a ver-
satile appendage. It was discovered during hydrolysis
of the imine that an overnight age in aq. AcOH
retained the TBS group on the ketone product while

K. M. Marcantonio et al. / Tetrahedron Letters 43 (2002) 8845–8848
Table 2. Addition of 2-substituted thiazoles to a variety of aryl nitriles
8847
a
See Ref. 6 for a representative procedure; using HCl work-up, except entries 4 and 8 where AcOH was used. Alternatively, the TBS in those
cases could be removed using HCl work-up.
Assay yield by HPLC, as compared to chromatographed standard.
b

8848
K. M. Marcantonio et al. / Tetrahedron Letters 43 (2002) 8845–8848
temperature below −40°C, forming a deep red solution,
References
which became a slurry. 4-Cyanopyridine (500 mg, 4.80
mmol) was dissolved in THF (3 mL) and added to the
reaction, and the temperature was held between −35 and
−20°C for 20 min. Aqueous AcOH (1 M, 28.8 mmol) was
added, and the hydrolysis was aged overnight. The solu-
tion was diluted with EtOAc and H2O, and the organic
was washed with a 50% aq. K2CO3 solution (2×20 mL).
After drying over Na2SO4, the solution was filtered and
concentrated to an orange oil. The ketone was purified by
column chromatography using 20% EtOAc in hexanes and
isolated as a yellow oil. 1H NMR (DMSO): l 8.83 (dd,
2H, J=4.42, 1.61 Hz), 8.67 (s, 1H), 7.77 (dd, 2H, J=4.42,
1.61 Hz), 0.95 (s, 9H), 0.40 (s, 6H) ppm; 13C NMR
(DMSO): l 186.4, 182.2, 152.4, 151.0, 144.4, 140.4, 122.6,
26.5, 17.0, −5.2 ppm. To remove TBS, the reaction was
poured into 2N HCl and THF, aged for 1 h, and worked-
up in a similar manner.
1. Hantzch, A.; Traumann, V. Ber. Dtsch. Chem. Ges. 1888,
21, 938.
2. For recent variations, see: (a) Lin, Y.; Seifert, C. M.;
Kang, S. M.; Dusza, J. P.; Lang, S. A., Jr. J. Heterocyclic
Chem. 1979, 16, 1377; (b) Knoll, A.; Liebscher, J.; Rade-
glia, R. J. Prakt. Chem. 1985, 3, 463; (c) Romero-Ortega,
M.; Aviles, A.; Cruz, R.; Fuentes, A.; Gomez, R. M.;
Plata, A. J. Org. Chem. 2000, 65, 7244; (d) Rajappa, S.;
Sudarsanam, V.; Advani, B. G.; Rane, A. V. Proc. Indian
Acad. Sci. 1982, 91, 445.
3. (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1988, 53, 1748; (b) Sawhney, I.;
Wilson, J. R. H. J. Chem. Soc., Perkin Trans. 1 1990, 329;
(c) Pyne, S. G.; Ung, A. T. Synlett 1998, 280; (d) South,
M. S.; Van Sant, K. A. J. Heterocyclic Chem. 1991, 28,
1017.
7. Analysis of reaction mixtures revealed that none of the
tertiary alcohol product expected from overaddition had
formed.
8. The imine stability was problematic when R=OMe, X=
SMe because the HCl salt of the imine precipitated before
hydrolysis was complete
9. In some cases (entries 1–3 and 9, Table 2) a slow imine
hydrolysis with aq. AcOH led to some cleavage of the TBS
group before imine hydrolysis was complete.
4. For precedence with thiophene, see: Graham, S. L.;
Scholz, T. H. J. Org. Chem. 1991, 56, 4260.
5. An excess of thiazole was used to ensure complete conver-
sion of nitrile, though a slight excess of either substrate has
been shown to effect complete reaction.
6. Representative procedure: 2-(t-Butyldimethylsilyl)thiazole
(1.27 g, 9.60 mmol) was dissolved in THF (15 mL) and
cooled to −60°C. n-BuLi (6.0 mL, 9.60 mmol, 1.6 M in
hexanes) was added at such a rate as to keep the reaction