2,4-Disubstituted-5-acetoxythiazoles: useful intermediates for the synthesis of thiazolones and 2,4,5-trisubstituted thiazoles

Article abstract of DOI:10.1016/j.tetlet.2008.03.140

A variety of 2,4-disubstituted-5-acetoxythiazoles were prepared from the substituted methyl benzoates in good to moderate yields using a three-step sequence: (1) ester to thionoester conversion, (2) coupling with an amino acid, and (3) acetic anhydride me

Full text of DOI:10.1016/j.tetlet.2008.03.140

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3682–3686
2,4-Disubstituted-5-acetoxythiazoles: useful intermediates for
the synthesis of thiazolones and 2,4,5-trisubstituted thiazoles
Q. Qiao, R. Dominique *, R. Goodnow Jr.
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110-1199, USA
Received 12 November 2007; revised 25 March 2008; accepted 26 March 2008
Available online 29 March 2008
Abstract
A variety of 2,4-disubstituted-5-acetoxythiazoles were prepared from the substituted methyl benzoates in good to moderate
yields using a three-step sequence: (1) ester to thionoester conversion, (2) coupling with an amino acid, and (3) acetic anhydride mediated
cyclization. In situ hydrolysis and alkylation of 2,4-disubstituted-5-acetoxythiazoles afforded the corresponding thiazolones and 2,4,5-
trisubstituted thiazoles. This methodology can be readily applied to the synthesis of thiazole-based chemical libraries.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Thiazole; Thiazolone; Thionation method; Microwave irradiation; Chemical libraries
1. Introduction
While a number of synthetic strategies have been devel-
oped for the synthesis of thiazoles, especially for 2,4-disub-
stituted thiazoles, which are generally assembled using the
Hantzsh reaction,6 fewer recent methods are available for
the preparation of 2,4-disubstituted-5-acetoxy thiazoles.7
Generally, these methods are impeded by the lack of com-
mercially available thionobenzoate derivatives and the pro-
longed heating conditions required for the conversion of
benzoate to thionobenzoate with traditional methods. To
circumvent these problems, we investigated for alternative
ways to prepare the desired thionobenzoate derivatives
required to have access to 2,4-disubstituted-5-acetoxythi-
azoles With the development of microwave heating tech-
nology,8 Polshettiwar et al.9 reported a milder microwave
assisted thionation method using phosphorous pentasulfide
and hexamethyldisiloxane (HMDO). Further, Varma and
Kumar10 reported an expeditious, solvent-free method
using Lawesson’s reagent11 under microwave irradiation.
Herein, we report a convenient three-step sequence
(Scheme 1) to provide access to a diverse array of
The thiazole ring system is commonly found in many
pharmaceutically important molecules. Numerous natural
products containing this heterocycle have been isolated
and exhibit significant biological activities such as cyto-
toxic, immunosuppressive, antifungal, and enzyme inhibi-
tory activity.1 Moreover, among the different aromatic
heterocycles, thiazoles occupy a prominent position in the
drug discovery process2 and this ring structure is found
in several marketed drugs. It can also be used in a scaffold
hopping strategy3 or as an amide isostere4 during the
course of probing structure activity relationships for lead
optimization. As a result, thiazoles are frequently included
in the design or are used as a core structure for the synthe-
sis of chemical libraries.5
In the course of a lead generation effort, we required a
flexible method, amenable to the high throughput chemical
synthesis of appropriately substituted 2,4,5-trisubstituted
thiazoles.
2,4-disubstituted-5-acetoxythiazoles
containing
aryl,
heteroaryl, and alkyl substitutions in moderate to good
yields. Alternatively, in situ hydrolysis and alkylation
of 2,4-disubstituted-5-acetoxythiazoles afforded the
*
Corresponding author. Tel.: +1 973 235 3231.
E-mail address: romyr.dominique@roche.com (R. Dominique).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.140

Q. Qiao et al. / Tetrahedron Letters 49 (2008) 3682–3686
3683
Table 1 (continued)
3a-e
S
O
O
N
Entry
Yield
(%)
Product
Yield
(%)
R
O
1-
O
S
O
P4S10
S
O
Ar
R
S
Ar
O
Ar
O
HMDO
MW
7
51
42
NaOH, rt
N
N
N
10
S
2g
R
150 oC, 1 h
2- Ac2O
100 oC, 1 h
S
S
1a-j
2a-j
4-21
AcO
AcO
NO2
Scheme 1. Synthesis of 2,4-disubstituted-5-acetoxythiazoles.
8
9
7
12
O2N
11
2h13c
corresponding thiazol-5-ones or 2,4,5-trisubstituted thia-
zoles as a major product depending on the type of electro-
phile used in the alkylation reaction.
N
N
13
4
N
S
12
AcO
2. Results and discussion
2i
a
4 equiv of 3a was used.
From the commercially available methyl benzoate deriv-
atives and with racemic phenylglycine, a variety of 2,4-
disubstituted-5-acetoxythiazoles were prepared in good to
moderate yields using the following protocol (Table 1).
The first step consisted in converting a methyl benzoate
into a thionoester. This type of conversion is generally
the most difficult thionation reaction due to the low reac-
tivity of the ester carbonyl group toward the usual thiona-
tion reagents such as Lawesson’s reagent, contrary to the
relatively short time for thionation of amides. As an alter-
native to Lawesson’s reagent, we considered the P4S10/
HMDO12 combination under microwave irradiation at
150 °C, which provided the desired thionoester in approx-
imately 1 h. The purified thionoester is then subjected to
the next step with phenylglycine to afford the desired 2,4-
disubstituted-5-acetoxythiazoles. The coupling is accom-
plished using a two-phase reaction mixture composed of
3 N NaOH and ether. Through acid–base liquid–liquid
extraction, the coupled product was obtained and treated
subsequently with acetic anhydride to give the desired thi-
azole derivatives.
As shown in Table 1, various substitutions could be
obtained at position 2 on the thiazole ring by simply substi-
tuting the initial methyl benzoate derivatives. The unsubsti-
tuted phenyl group (entry 1) afforded a reasonable 51%
yields of the thiazole. Various methyl benzoate derivates
bearing electron-withdrawing groups at the para position
were used to prepare the 2,4-disubstituted-5-acetoxythiaz-
oles. The best yields were obtained with 4-fluoro-methyl
benzoate (entry 2). In the case of the cyano derivative
(entry 9), the very low yield is explained by the fact that
the hydrolysis of the cyano group to the acid was observed.
Using methyl benzoate derivatives having an electron-
donating group at the para position such as methyl and
methoxy groups (entries 3 and 4) gave modest yields of
the 2,4-disubstituted-5-acetoxythiazoles. However, it was
observed that by using 4 equiv of phenylglycine resulted
in a slight increase in the yields. The same effect was
observed for entries 5 and 6. Interestingly, the 3-bromo-
methyl benzoate gave a satisfying 64% yield of the desired
thiazole bearing a bromo substituent, which could be used
Table 1
Yields obtained for the preparation of thionoesters and 2,4-disubstituted-
5-acetoxythiazoles using phenylglycine as amino acid
S
Entry
Yield Product
(%)
Yield
(%)
R
O
1
48
51
80
N
N
47b
2a12b
S
S
AcO
F
2
3
4
28
5
F
2b
AcO
N
51
6
14 (27)a
S
S
S
2c13a
AcO
O
N
N
66
7
18
O
AcO
2d13b
Br
5
6
55
64a
Br
8
2e
AcO
Cl
N
46
9
16a
S
Cl
AcO
2f

3684
Q. Qiao et al. / Tetrahedron Letters 49 (2008) 3682–3686
as a handle for further elaboration. Replacement of the
phenyl group by a thiophene ring did not affect the yields
for the formation of the desired thiazole (entry 7).
one rotatable bond to make the scaffold less rigid. The best
yields were obtained with the 4-fluoro-thionobenzoate,
which was also true with entry 2 shown in Table 1, suggest-
ing that the yields are not affected by changing a phenyl to
a benzyl group. Tyrosine was also used and as expected,
the free hydroxyl group was acetylated during the cycliza-
tion (entry 7). Encouraged by these results, we next inves-
tigated the use of an amino acid such as valine (entries 8
and 9) to prepare alkyl substituted thiazoles. Similar to
our previous results, the cyclization occurred smoothly
affording the desired thiazoles in modest yields.
To expand the scope of this methodology, several other
amino acids were investigated for the preparation of 2,4-
disubstituted-5-acetoxythiazoles. The results are summa-
rized in Table 2. D,L-a-aminothiophene-2-acetic acid gave
modest yields of the corresponding thiazole composed of
three heterocycles (entries 1 and 2). Phenylalanine (entries
3–6) was chosen as the coupling partner in order to intro-
duce a benzylic substituent on the thiazole ring and to add
Table 2
Yields obtained for the preparation of 2,4-disubstituted-5-acetoxythiazoles with various amino acids
Entry
Product
Yields
S
COOH
NH2
R
R
O
S
S
1
2g
57
N
N
S
13
3b
3b
S
S
AcO
S
2
3
4
5
6
7
2a
2a
2b
2h
14
15
16
30
41
81
23
55
33a
AcO
N
S
3c
3c
AcO
F
N
N
N
S
S
S
AcO
AcO
AcO
NO2
3c
3c
17
Cl
18
Cl
2j13a
2a
N
197b
HO
S
AcO
AcO
3d
N
S
8
2a
2b
20
21
26
56
3e
3e
AcO
AcO
F
N
S
9
a
4 equiv of 3d was used.

Q. Qiao et al. / Tetrahedron Letters 49 (2008) 3682–3686
3685
5-O-alkylation
4-C-alkylation
Benzyl bromide
OAc
S
O
S
N
O
S
F
K2CO3
F
F
N
N
+
Acetone
DMF
23
22
5
(1:6)
80%
Br
Br
Br
OAc
S
Allyl bromide
K2CO3
O
O
S
S
N
N
N
+
DMF
8
24
25
(1:6)
84%
OAc
S
Methyl iodide
K2CO3
O
O
S
S
N
N
N
+
DMF
4
4
26
26
27
(1:2)
60%
K2CO3
Single product observed in
yield
DMF
O
70%
MeO
S
OMe
O
Scheme 2. Synthesis of thiazol-5-ones and 2,4,5-trisubstituted thiazoles.
As shown in Tables 1 and 2, a wide range of 2,4-disub-
stituted-5-acetoxythiazoles can be synthesized using our
methodology. However, we were concerned about the sta-
bility of the 5-acetoxy group to basic conditions and we
envisioned that further derivatization would enlarge the
utility of this methodology.
by simply using hard electrophiles such as dimethyl sulfate.
Indeed, when 4 was treated with dimethylsulfate and potas-
sium carbonate in DMF, only the O-alkylation product
was observed giving a 70% yield of the 2,4,5-trisubstituted
thiazole.
In situ hydrolysis of the acetoxy group in thiazole 5 using
potassium carbonate as a base and an alkylating agent such
as benzyl bromide in a mixture of DMF and acetone affor-
ded an 80% yield of trisubstituted thiazole 22 and thiazol-5-
one 23 in a 1:6 molar ratio not separable by column
chromatography (Scheme 2). The ratio of the mixture was
3. Conclusion
In conclusion, we have developed a general and conve-
nient three-step sequence, which gives access to a variety
of 2,4-disubstituted-5-acetoxythiazoles containing aryl,
heteroaryl, and alkyl substitution in moderate to good
yields.14 We have also shown that we can convert the 2,4-
disubstituted-5-acetoxythiazoles into thiazol-5-ones and
2,4,5-trisubstituted thiazoles.15,16 This methodology is
highly flexible and amenable to the high throughput chem-
ical synthesis of thiazole-based libraries. With the use of
proper functional groups on methyl benzoate derivatives,
amino acids, and alkylating agent, various points of diver-
sification can be introduced to generate more complex mol-
ecules with interesting biological properties.
1
determined by the inspection of the H NMR spectra in
CDCl3, which revealed clearly a characteristic singlet for
the O–CH2–Ph moiety at 5.22 ppm for the 2,4,5-trisubsti-
tuted thiazole 22, whereas a doubled doublet was revealed
for the C–CH2–Ph moiety at 3.65 ppm for the 2,4,4-trisub-
stituted-thiazol-5-one 23. The use of other alkylating agents
such as methyl iodide and allyl bromide also gave a mixture
of the corresponding thiazol-5-ones and 2,4,5-trisubstituted
thiazoles. Similarly, the thiazol-5-one was found to be the
major product in both cases.Therefore, under these condi-
tions, the formation of the C-alkylation product is preferred
over the O-alkylation product.
Acknowledgments
We were also interested in finding conditions that would
favor the O-alkylation product. We envisioned that the for-
mation of 2,4,5-trisubstituted thiazoles could be achieved
The authors are grateful to Theresa Burchfield for the
characterization of selected compounds and Paul Gillespie
for critical reading of this Letter.

3686
Q. Qiao et al. / Tetrahedron Letters 49 (2008) 3682–3686
irradiation (Emrys optimizer) for 60 min at 150 °C. The crude
References and notes
reaction mixture was then passed through a column of silica gel.
Thionoester 2e (1.1 g, 55%) was eluted using 0–20% ethyl acetate/
hexanes.
1. (a) Jin, Z. Nat. Prod. Rep. 2003, 20, 584–605; (b) Lewis, J. R. Nat.
Prod. Rep. 1999, 16, 389–416.
To thionoester 2e (300 mg, 1.3 mmol) in 5 mL of ether were added
10 mL of 3 N NaOH and D,L-a-phenylglycine (784 mg, 5.19 mmol).
The reaction mixture was stirred vigorously for 18 h at room
temperature. The aqueous layer was separated, acidified with 10%
HCl, and diluted with ethyl acetate. The organic layer was separated,
dried over anhydrous sodium sulfate and the solvent was removed
under reduced pressure. The oil obtained was then dissolved in acetic
anhydride (5 mL) and heated at 100 °C for 1 h. The reaction mixture
was evaporated to afford 310 mg (64%) of the desired thiazole 8: 1H
NMR (400 MHz, CDCl3): d 2.45 (s, 3H, CH3), 7.32 (t, J = 7.9 Hz,
1H, aromatic), 7.38 (m, 1H, aromatic), 7.49 (m, 2H, aromatic), 7.55
(ddd, J = 7.9 Hz, J = 1.8 Hz, J = 1.0 Hz, 1H, aromatic), 7.87 (ddd,
J = 7.9 Hz, J = 1.8 Hz, J = 1.0 Hz, 1H, aromatic), 8.04 (m, 2H,
aromatic), 8.18 (t, J = 1.8 Hz, 1H, aromatic). HRMS (ES+) m/z calcd
for C17H12NO2SBr [M+H]+ 373.9845, obsd 373.9844.
2. Sperry, J. B.; Wright, D. L. Curr. Opin. Drug. Discovery Dev. 2005, 8,
723–740.
3. (a) Zhao, H. Drug Discovery Today 2007, 12, 149–155; (b) Schneider,
G.; Schneider, P.; Renner, S. QSAR Comb. Sci. 2006, 25, 1162–1171;
(c) Bo¨hm, H.-J.; Flohr, A.; Stahl, M. Drug Discovery Today: Technol.
2004, 1, 217–224; (d) Wermuth, C. G. In The Practice of Medicinal
Chemistry, 2nd ed.; Academic Press: London, 2003; pp 193–196.
4. (a) Biron, E.; Chatterjee, J.; Kessler, H. Org. Lett. 2006, 8, 2417–2420;
(b) Deng, S.; Taunton, J. Org. Lett. 2005, 7, 299–301.
5. Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.;
Salvino, J. M. J. Comb. Chem. 2006, 8, 597–635.
6. (a) Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473–2476;
(b) Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 8004–8005; (c)
Qiao, Q.; So, S.-S.; Goodnow, R. A., Jr. Org. Lett. 2001, 3, 3655–
3658; (d) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 1363–
1365; (e) Marcantonio, K. M.; Frey, F. L.; Murry, J. A.; Chen, C.-Y.
Tetrahedron Lett. 2002, 43, 8845–8848; (f) Ochiai, M.; Nishi, Y.;
Hashimoto, S.; Tsuchimoto, Y.; Chen, D.-W. J. Org. Chem. 2003, 68,
7887–7888; (g) Boy, K. M.; Guernon, J. M. Tetrahedron Lett. 2005,
46, 2251–2252; (h) Thompson, M. J.; Heal, W.; Chen, B. Tetrahedron
Lett. 2006, 47, 2361–2364.
7. (a) Barrett, G. C.; Khokhar, A. R. J. Chem. Soc. 1969, 1117–1119; (b)
Sammour, A.; Selim, M.; Fahmy, A. F.; Nada, A. A.; Abd
Elmawgoud, I. A. Egypt. J. Chem. 1976, 19, 801–809; (c) Sammour,
A.; Abdallah, M. M.; Essawy, A.; Elmobayed, M. Egypt. J. Chem.
1976, 19, 911–926; (d) El-Kadi, M.; El-Hashash, M. A.; Sayed, M. A.
Rev. Roum. Chim. 1981, 26, 1161–1167.
8. Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Disc. 2006, 5, 51–63.
9. Polshettiwar, V.; Nivsarkar, M.; Paradashani, D.; Kaushik, M. P. J.
Chem. Res. 2004, 474–476.
10. Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697–700.
11. Jesberger, M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929–1958.
12. (a) Curphey, T. J. Tetrahedron Lett. 2002, 43, 371–373; (b) Curphey,
T. J. J. Org. Chem. 2002, 67, 6461–6473.
15. Representative procedure for the synthesis of thiazol-5-ones and 2,4,5-
trisubstituted thiazoles: To thiazole 4 (100 mg, 0.34 mmol), K2CO3
(234 mg, 1.69 mmol) in 2 mL of DMF was added dimethyl sulfate
(64 lL, 0.68 mmol). The reaction mixture was stirred and heated at
50 °C for 1 h, then cooled down. The reaction mixture was diluted
with ethyl acetate and washed with water and brine. The combined
organic phases were dried over anhydrous sodium sulfate and the
solvent was removed under reduced pressure. The crude material was
then purified by column chromatography using 10% ethyl acetate/
hexanes as eluent system to afford 65 mg (70%) of 2,4,5-trisubstituted
thiazole 26: 1H NMR (400 MHz, CDCl3): d 4.08 (s, 3H, CH3), 7.31
(m, 1H, aromatic), 7.37–7.48 (m, 5H, aromatic), 7.93 (m, 2H,
aromatic), 8.13 (m, 2H, aromatic); 13C (100 MHz, CDCl3): d 63.9,
125.5, 126.8, 126.9, 128.2, 128.7, 129.2, 133.8, 134.1, 135.6, 153.0,
157.4. HRMS (ES+) m/z calcd for C16H13NOS [M+H]+ 268.0791,
obsd 268.0790.
16. For 25: 1H NMR (400 MHz, CDCl3): d 3.10 (m, 2H, CH2), 5.11 (m,
1H, vinylic), 5.19 (m, 1H, vinylic), 5.71 (m, 1H, vinylic), 7.32–7.44 (m,
4H, aromatic), 7.55 (m, 2H, aromatic), 7.71 (ddd, J = 8.0 Hz, J = 2.0
Hz, J = 1.1 Hz, 1 H, aromatic), 7.82 (ddd, J = 7.8 Hz, J = 1.7 Hz,
J = 1.1 Hz, 1 H, aromatic), 8.1 (dd, J = 2.0 Hz, J = 1.7 Hz, 1H,
aromatic); 13C (100 MHz, CDCl3): 44.5, 91.3, 120.2, 123.1, 125.6,
127.1, 128.4, 128.6, 130.3, 130.6, 130.9, 135.0, 135.1, 137.4, 162.2,
207.9. HRMS (ES+) m/z calcd for C18H14NOSBr [M+H]+ 372.0052,
obsd 372.0052.
13. (a) Katada, T.; Kato, S.; Mizuta, M. Chem. Lett. 1975, 1037–1040; (b)
Latif, K. A.; Ali, M. Y. Tetrahedron 1970, 26, 4247–4249; (c) Voss, J.;
Wollny, B. Synthesis 1989, 684–685.
14. Representative procedure for the synthesis of 2,4-disubstituted-5-acet-
oxythiazoles:
A mixture of methyl 3-bromo-benzoate (2.0 g,
9.3 mmol), P4S10 (1.03 g, 2.32 mmol), HMDO (3.2 mL, 14.9 mmol)
was sealed in a tube. The sealed vial was heated by microwave