An efficient synthesis of thiazolo[3,2-a]pyrimidinones

Article abstract of DOI:10.1016/j.tetlet.2010.04.052

A series of thiazolo[3,2-a]pyrimidinones was synthesised in a two-step procedure, using Eaton's reagent to effect cyclisation of 2-aminothiazoles. The use of relatively low temperatures, facile product isolation and short reaction times make this cyclisation procedure a particularly attractive option over more conventional methods.

Full text of DOI:10.1016/j.tetlet.2010.04.052

Tetrahedron Letters 51 (2010) 3263–3265
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An efficient synthesis of thiazolo[3,2-a]pyrimidinones
*
Nadia M. Ahmad, Keith Jones
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of thiazolo[3,2-a]pyrimidinones was synthesised in a two-step procedure, using Eaton’s reagent
to effect cyclisation of 2-aminothiazoles. The use of relatively low temperatures, facile product isolation
and short reaction times make this cyclisation procedure a particularly attractive option over more con-
ventional methods.
Received 19 January 2010
Revised 16 March 2010
Accepted 12 April 2010
Available online 18 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The thiazolo[3,2-a]pyrimidinone core is a popular motif in
medicinal chemistry and has been implicated in biological activity
in a variety of therapeutic areas. These include anticancer1,2 and
anti-ulcer activities,3 and more recently as kinase inhibitors. How-
ever, there are relatively few reported methods for accessing this
core structure.4–7 As part of a medicinal chemistry programme, a
series of thiazolo[3,2-a]pyrimidinone derivatives was required for
biological testing. A typical method for their synthesis involves
condensation of an aminothiazole with a malonate derivative fol-
lowed by intramolecular cycloacylation. This usually requires heat-
ing for prolonged periods at high temperatures.3,8
We were made aware of the use of commercially available
Eaton’s reagent, a mixture of 7.7 wt % phosphorus pentoxide solu-
tion in methanesulfonic acid, for such transformations by the re-
cent publication of Zewge and co-workers, who employed this
reagent in their synthesis of 4-quinolone derivatives.9 On applying
this protocol to our substrates, for example, 3, we were pleased to
observe the formation of the desired thiazolo[3,2-a]pyrimidinones
4 in excellent yield (Scheme 2).
Purification of the product consisted of a simple filtration of the
precipitate resulting from pouring the reaction mixture into a
sufficient quantity of saturated, aqueous sodium bicarbonate and
The synthesis of the desired thiazolo[3,2-a]pyrimidinones
began with 2-aminothiazole substrate 1 which was reacted with
dimethyl methoxymethylenemalonate 2; we were able to obtain
the condensation product 3 in excellent yield. However, the use
of conventional cyclisation methods such as heating in high boiling
solvents (e.g., Dowtherm, N-methylpyrrolidinone, sulfolane) failed
to give the desired thiazolo[3,2-a]pyrimidinones 4 (Scheme 1).3
The addition of organic base also did not aid cyclisation and usually
led to decomposition. Similarly, acidic conditions led to isolation of
the starting material only, with no product detected.
Several explanations can be put forth for the lack of reactivity in
this reaction. Mechanistically it is clear that the thiazole nitrogen
needs to attack the ester carbon (Fig. 1), thus both the nucleophi-
licity of the nitrogen and the electrophilic nature of the ester car-
bon need to be considered. It is well known that an ester
carbonyl is not particularly electrophilic in nature. Additionally,
aromaticity is lost in the first step. Similarly, the exocyclic nitrogen
is a part of a vinylogous amide leaving the thiazole nitrogen rela-
tively electron poor and unable to initiate cyclisation. Also, an
intramolecular hydrogen bond exists between the N–H and an
ester carbonyl oxygen, which holds the side chain in a conforma-
tion unsuitable for cyclisation (Fig. 1).
CO2Me
H
NH2
S
N
Δ
S
MeO2C
MeO2C
H
CO2Me
+
N
N
PhMe
OMe
But
But
100%
1
2
3
CO2Me
CO2Me
N
H
N
S
Dowtherm,
220 °C
S
N
CO2Me
N
But
O
But
4
3
Scheme 1. Synthesis of vinylogous amide 3 and cyclisation attempts.
H
N
O
O
S
N
OMe
OMe
3
* Corresponding author. Tel.: +44 208 722 4334; fax: +44 208 722 4126.
E-mail address: keith.jones@icr.ac.uk (K. Jones).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.052

3264
N. M. Ahmad, K. Jones / Tetrahedron Letters 51 (2010) 3263–3265
CO2R
CO2R
employed in the two-step protocol. The results are summarised
in Table 1.
Mechanistically, the presence of acid is clearly central to the
H
N
S
Eaton's reagent
85 °C
N
S
N
CO2R
N
But
cyclisation (Scheme 3). In general, the formation of amides from
esters and amines is a base-catalysed process with formation of
the tetrahedral intermediate being the rate-determining step.10
Although the overall result of this cyclisation is formation of a lac-
tam from an ester, the functional groups involved are more com-
plex and the mechanism is not a simple aminolysis of an ester.
Protonation of starting thiazole A can take place on the thiazole
nitrogen leading to intermediate B which is unproductive, or on
the enamide oxygen leading to C. This removes the double bond
stereochemistry barrier to cyclisation and intermediate C can
But
O
3
4a (R = Me, 100%)
4b (R = Et, 99%)
Scheme 2. Synthesis of thiazolo[3,2-a]pyrimidinones 4 using Eaton’s reagent.
subsequent drying in air. The reaction could be scaled up to give
multigram quantities of the thiazolo[3,2-a]pyrimidinone esters 4.
In order to determine the limits of applicability of the cyclisa-
tion reaction using Eaton’s reagent, a range of substrates was
Table 1
Two-step synthesis of thiazolo[3,2-a]pyrimidinones from 2-aminothiazoles
Entry
Substrate
Condensation producta 311
Yieldb of 3 (%)
Cyclisation producta 412
Yieldc of 4 (%)
S
S
S
N
N
NH
NH2
NH2
CO2Me
CO2Me
N
But
But
Me
But
N
But
a
99
100
O
S
CO2Me
S
S
N
N
NH CO2Et
CO2Et
N
N
But
But
Me
b
c
d
e
f
96
81
34
72
32
60
73
99
74
57
35
92
53
24
O
S
CO2Et
S
S
N
NH2
NH CO2Me
CO2Me
N
N
N
O
N
Me
CO2Me
S
S
S
NH2
NH CO2Me
CO2Me
N
N
N
O
CO2Me
S
N
S
S
NH CO2Me
NH2
N
N
N
CO2Me
O
CO2Me
N
Cl
Cl
Cl
S
S
N
S
N
NH2
NH CO2Me
CO2Me
N
O
CO2Me
S
N
S
N
S
N
NH CO2Me
CO2Me
N
NH2
g
h
CO2Me
S
O
S
S
N
NH2
NH CO2Me
N
N
N
CO2Me
O
CO2Me
MeO
F3C
O
MeO
F3C
O
MeO
F3C
S
S
S
NH2
NH CO2Me
CO2Me
N
N
O
N
N
i
j
30
21
—
—
CO2Me
S
S
S
NH2
NH CO2Me
CO2Me
N
N
N
N
O
CO2Me
O
O
O
O
a
b
c
All compounds were characterised by 1H NMR, 13C NMR and LCMS.
Isolated yield after flash column chromatography.
Isolated yield after purification.

N. M. Ahmad, K. Jones / Tetrahedron Letters 51 (2010) 3263–3265
3265
S
R
H
N
S
N
H
N
NH2
N
COOR
OR
S
S
CN
NC
R
H
N
MeCN, reflux
N
N
HO
COOR
OEt
But
But
O
A
OR
C
6
7
R = CO2Et, 45%
8 R = CN, 47%
1
H
N
S
Eaton's
reagent
COOR
OR
N
H
No cyclised product
O
Scheme 5. Reactions involving a cyano group.
B
S
S
N
N
N
N
O
O
In summary, we have reported a short, mild and effective proto-
col for the synthesis of thiazolo[3,2-a]pyrimidinones and related
bicycles which were unattainable by previously reported methods.
Further work will focus on determining which functional groups
can be manipulated to undergo such cyclisations under these
conditions.
H
COOR
COOR
OR
E
D
Scheme 3. Proposed mechanism of cyclisation.
S
N
S
LiI, pyridine
N
Acknowledgements
N
But
N
But
reflux, 24 h
This work was supported by Cancer Research UK [CUK] grant
numbers C309/A8274. We acknowledge NHS funding to the NIHR
Biomedical Research Centre. We also thank Dr. Amin Mirza and
Mr. Meirion Richards for their assistance with NMR and mass
spectrometry.
COOMe
O
O
COOH
93%
4a
5
Scheme 4. Ester cleavage.
References and notes
cyclise via an electrocyclic reaction to generate the tetrahedral
intermediate D. Breakdown of this by elimination of alcohol leads
to the desired product E. Clearly, base would lead to the deproto-
nation of the enamide leaving the ester carbonyl insufficiently
electrophilic. On the other hand, too much acid would lead to thi-
azole protonation reducing the nucleophilicity of the crucial nitro-
gen atom. Finally, insufficient acid would not allow the formation
of the key intermediate C. Table 1 shows that the electronic prop-
erties of the thiazole substituents affect the ease with which cycli-
sation takes place. Strongly electron-donating groups lead to
complete protonation whilst strongly electron-withdrawing
groups lead to insufficient protonation, both of which hinder the
cyclisation.
In this programme, our ultimate aim was to produce a library of
amides. Therefore, to further the synthesis, the carboxylic acid
functionality needed unmasking by removal of the ester. This
proved to be more difficult than anticipated as traditional methods
such as acid hydrolysis and saponification left the ester untouched.
Eventually, heating the methyl ester 4a with lithium iodide in pyr-
idine under reflux afforded the acid 5, thus clearing the way for the
synthesis of our library of amides (Scheme 4).
In an attempt to circumvent the ester hydrolysis step, we
decided to have in place alternative functional groups which could
be converted into the carboxylic acid after the key cyclisation step.
To this end, two alternative cyclisation precursors, 7 and 8, were
prepared (Scheme 5) containing one and two cyano groups, respec-
tively. Treatment with Eaton’s reagent under our optimised condi-
tions failed to give the desired cyclisation products. In these
examples, the lower electrophilicity of the nitrile group appears
to prevent cyclisation. The carboxylic acid, which could have re-
sulted from in situ hydrolysis of the nitrile or ester groups, was also
not detected.
1. Shridhar, D. R.; Jogibhukta, M.; Krishnan, V. S. H. Indian J. Chem. 1986, 25B, 345.
2. Shridhar, D. R.; Jogibhukta, M.; Joshi, P. P.; Rao, C.; Seshagiri, J. A. Y. Indian J.
Chem. 1984, 23B, 492.
3. Kadin, S. B. Fr. Demande 1981, 84.
4. Landreau, C.; Deniaud, D.; Reliquet, A.; Meslin, J.-C. Synthesis 2001, 2015.
5. Bonacorso, H. G.; Lourega, R. V.; Wastowski, A. D.; Flores, A. F. C.; Zanatta, N.;
Martins, M. A. P. Tetrahedron Lett. 2002, 43, 9315.
6. Zicane, D.; Ravinya, I.; Tetere, Z.; Rijkure, I.; Gudriniece, E.; Kelejs, U. Chem.
Heterocycl. Compd. 2000, 36, 754.
7. Trapani, G.; Franco, F.; Latrofa, A.; Genchi, G.; Liso, G. Eur. J. Med. Chem. 1992,
27, 30.
8. Ye, F.-C.; Chen, B.-C.; Huang, X. Synthesis 1989, 317.
9. Zewge, D.; Chen, C.-Y.; Deer, C.; Dormer, P.; Hughes, D. L. J. Org. Chem. 2007, 72,
4276.
10. Blackburn, G. M.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90, 2685.
11. Typical procedure for the synthesis of dimethyl 2-[(4-tert-buylthiazol-2-
ylamino)methylene]malonate (3a).
2-Amino-4-tert-butylthiazole (7.4 g, 48 mmol) was added to dimethyl 2-
(methoxymethylene)malonate (8.4 g, 48 mmol) in dry PhMe (100 mL). The
solution was heated under reflux for 16 h and then concentrated under vacuo.
Purification by column chromatography (1:4 EtOAc/PE) gave the title
compound as a cream-coloured solid (14.0 g, 99%); mp 92–95 °C; 1H NMR
(500 MHz, CDCl3) dH 1.31 (9H, s), 3.81 (3H, s), 3.87 (3H, s), 6.48 (1H, s), 8.70
(1H, d, J 12.9 Hz), 11.32 (1H, d, J 12.9 Hz); 13C NMR (125 MHz, CDCl3) dC 29.6
(CH3), 34.9 (C), 51.7 (CH3), 51.9 (CH3), 95.9 (C), 104.3 (CH), 150.9 (CH), 159.7
(C), 164.3 (C), 165.3 (C), 168.7 (C); mmax 1687, 1252, 1030 cmÀ1; MS (ESI)
[M+H]+ 299.4.
12. Typical procedure for the synthesis of methyl 3-tert-butyl-5-oxo-5H-thiazolo[3,2-
a]pyrimidine-6-carboxylate (4a).
Eaton’s reagent (120 mL) was added to malonate derivative 3a (14.0 g,
48 mmol) and the resulting solution was heated at 85 °C for 1.5 h. After this
period, the reaction was allowed to cool, then poured onto saturated NaHCO3
until pH >11. The resulting solid was filtered and dried in air to afford the title
compound as a pale-yellow solid (12.5 g, 100%); mp 157–159 °C; 1H NMR
(500 MHz, CDCl3) dH 1.59 (9H, s, C(CH3)3), 3.92 (3H, s, OCH3), 6.82 (1H, s,
C@CH), 8.66 (1H, s, C@CH); 13C NMR (125 MHz, CDCl3) dC 31.0 (CH3), 37.2 (C),
52.1 (CH3), 107.0 (CH), 109.0 (C), 151.8 (C), 156.8 (CH), 156.8 (C), 165.0 (C),
169.9 (C); mmax 1473, 1704, 1749, 3427 cmÀ1 HRMS (ESI) found [M+H]+
;
267.0798, C12H15N2O3S requires 267.0798.