Facile synthesis of thiazoles via an intramolecular thia-Michael strategy

Article abstract of DOI:10.1016/j.tetlet.2006.09.157

A mild and efficient method for the synthesis of substituted thiazoles is reported via one-pot N-desilylation, thioacylation/oxythioacylation/thiothioacylation followed by thia-Michael cycloisomerisation. This method has a general applicability to introdu

Full text of DOI:10.1016/j.tetlet.2006.09.157

Tetrahedron Letters 47 (2006) 8661–8665
Facile synthesis of thiazoles via an intramolecular
thia-Michael strategyI
Pradip K. Sasmal,* S. Sridhar and Javed Iqbal
Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 049, AP, India
Received 2 August 2006; revised 20 September 2006; accepted 28 September 2006
Available online 20 October 2006
Abstract—A mild and efficient method for the synthesis of substituted thiazoles is reported via one-pot N-desilylation, thioacylation/
oxythioacylation/thiothioacylation followed by thia-Michael cycloisomerisation. This method has a general applicability to
introduce various oxo and thio functionalities including aliphatic and aromatic moieties, especially at the C2-position of thiazoles.
Ó 2006 Elsevier Ltd. All rights reserved.
Thiazoles play a prominent role in Nature. For example,
the thiazolium ring present in vitamin B1 serves as an
electron sink and its coenzyme form is important for
the decarboxylation of a-keto acids.1 Various pesticides
possessing a thiazole nucleus are well known in agricul-
ture. Large numbers of thiazole derivatives have
emerged as active pharmaceutical ingredients in several
drugs for their potential anti-inflammatory,2 anti-tu-
mour,3 anti-hyperlipidemic,4 anti-hypertensive5 and sev-
eral other biological properties.6 Besides, thiazoles are
also synthetic intermediates and common substructures
in numerous biologically active compounds. Thus, the
thiazole nucleus has been much studied in the field of or-
ganic and medicinal chemistry. Several methods7 for the
synthesis of thiazole derivatives were developed by
Hantzsch, Tcherniac, Cook–Heilbron, Gabriel and
several other groups, amongst which the most widely
used method is Hantzsch’s synthesis7,8 (reaction between
a-halocarbonyl compounds and thioamides, thioureas
or thiocarbamic acid derivatives or dithiocarbamic acid
derivatives). Relatively, newer methods involve cycload-
dition of TosMIC to thione derivatives,9 oxidation of
thiazoline/thiazolidine ring systems,10 Ugi reaction11
and others.12 Recently, palladium-mediated coupling
processes (Suzuki coupling,13 Stille reaction14 and Negi-
shi coupling15) have emerged as powerful tools to intro-
duce various aryl and olefinic moieties into the thiazole
ring systems. Nucleophilic reactions of lithiothiazole16
also afford substituted thiazoles. Despite these proce-
dures, novel methods for thiazole synthesis are still in
demand. We were interested in developing a general pro-
tocol to synthesise thiazoles which could accommodate
various C-, O-, S- and N- functionalities, especially at
the C2 position of the thiazole ring. Towards this pur-
pose, we envisioned an intramolecular thia-Michael
strategy (Scheme 1), where intermediate III will eventu-
ally give thiazole V with or without the help of any addi-
tives via the intermediacy of IV.
Initially we used the HCl salt of ethyl 3-aminoprop-
1-yn-1-carboxylate 1a17 and then ethyl 4-N,N-bis(tri-
methylsilyl)aminobut-2-ynoate 1b18 and N,N-dimethyl
4-N0,N0-bis(trimethylsilyl)aminobut-2-yne amide 1c18a
as amino compounds (Fig. 1).
For the thione counterparts, we used different benzo-
triazolylthione derivatives as the benzotriazole anion is
R3
O
P
S
P
N
O
+
R1
X
S
R2
R3
R1
N
H
R2
I
II
III
X = Leaving group
P = Protecting group
O
R3
O
S
S
R1
R1
R3
R2
N
R2
IV
N
Keywords: Thiazoles; Thia-Michael; Benzotriazoles; Desilylation.
q DRL Publication No. 570A.
V
*
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438; e-mail: sasmalpk@yahoo.co.in
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.157

8662
P. K. Sasmal et al. / Tetrahedron Letters 47 (2006) 8661–8665
Table 1. Concentration effect of MeOH on the rate of reaction
between 2 and 1b in THF (0.2 M with respect to 2) to synthesise
thiazole 14
O
R
CO2Et
H2N
(Me3Si)2N
1a
Entry
MeOH (equiv)
Reaction time
1b: R = OEt, 1c: R = NMe2
1
2
3
4
5
6
7
0
1
2
5
10
20
>2 d
4 h
2 h
1 h 20 min
1 h
Figure 1.
an excellent leaving group and its derivatives are non-
hazardous, easy to handle and are quite stable for long
periods of time. Thus, compounds 2–5 were prepared
(Scheme 2) following a standardised four-step protocol
viz., acylation of 2-nitroaniline, NiCl2–NaBH4-mediated
reduction19 of the nitro group, conversion of the amide
to a thioamide followed by benzotriazole formation
using Rapoport chemistry.20
30 min
10 min
Only MeOH as solvent
Table 2. Effect of different alcohols on the rate of reaction between 2
and 1b in THF (0.2 M with respect to 2) to synthesise thiazole 14
Entry
Alcohol (10 equiv)
Reaction time
Initially, compound 2 was reacted with amine 1a in THF
in the presence of triethylamine and according to our
expectation thiazole 14 (see Table 3) was obtained in
81% yield. While preparing 1a from 1b,17 we observed
N-desilylation of compound 1b in different solvents con-
taining traces of alcohol. In alcoholic solvent, this desi-
lylation was much faster. This observation suggested the
use of trimethylsilyl protected amines (1b and 1c) di-
rectly in our subsequent studies as it reduces by one step,
the overall synthesis.
1
2
3
4
5
MeOH
EtOH
n-PrOH
i-PrOH
t-BuOH
1 h
1 h 20 min
1 h 40 min
2 h
6 h
8) and thiazole 21 in 75% yield from amine 1c (entry
9). According to our knowledge, this is, so far, the fast-
est method available to synthesise compounds such as
20 and 21. Encouraged by these results, we then studied
related substrates like benzotriazole carbothioates, ben-
zotriazole carbodithioates and benzotriazolylaminome-
thanethione systems, most of which (compounds 8–13)
were prepared following Katritzky’s protocol23 (Scheme
3).
To understand better the effect of the alcohol solvent in
the desilylation process and in subsequent thiazole syn-
thesis, we studied the concentration effect of MeOH, as
well as the effect of different alcohols on the rate of reac-
tion between 2 and 1b in THF (Tables 1 and 2).
Once in hand, compound 724 and compounds 8–13 were
then reacted with amines 1b–c and the results are shown
in Table 3. We observed that in the case of the thio-
methyl derivative 7 (entry 10) and alkoxy derivatives 9
and 10 (entries 12 and 13), Bt (benzotriazolyl) acts as
a leaving group, whereas, in the case of the thiophenoxy
derivative 8 (entry 11), the Bt group was retained in the
thiazole product eliminating thiophenoxy as the leaving
group. In the case of phenoxy derivative 11 (entry 14),
there was leaving group competition between Bt and
OPh. As a result, 2-phenoxythiazole derivative 25 and
compound 20 were obtained in 26% and 60% yields,
respectively. As expected, p-methoxyphenoxy derivative
12 (entry 15) gave relatively more 2-aryloxythiazole 26
(40%) along with thiazole 20 (45%), as the methoxy
group reduces the leaving group capacity of the aryloxy
moiety. In the case of compound 13, inconclusive results
were obtained.25 The electronic effect of different substit-
uents on the final outcome of cycloisomerisation needs
special mention. In the case of both alkoxy and aryloxy
substituents, addition of Et3N facilitates the cyclisation
process from the initially formed intermediates whereas,
in all other cases, cyclisation was almost spontaneous
and the base was introduced to ensure that the cycloiso-
merisation–aromatisation process took place. Overall,
in all the cases, thiazole synthesis was very easy as indi-
cated in Table 3.26
We observed that higher concentrations of MeOH accel-
erated the rate of reaction and also, as expected, higher
homologues of MeOH slowed down the desilylation
process and hence the rate of reaction. Based on these
studies, we used a combination of 10 equiv of MeOH
in THF in our subsequent one-pot approach for thiazole
synthesis.
Accordingly, benzotriazolylthione derivatives 2–5 were
treated with silyl protected amines 1b–c and the results
are summarised in Table 3. In all cases, cycloisomerisa-
tion was spontaneous and the corresponding thiazoles21
were obtained in good to excellent yields. Amines 1b and
1c both behaved in a similar fashion in these reactions.
We next investigated this methodology with di-ben-
zotriazolylmethanethione 6,22 and gratifyingly we ob-
tained thiazole 20 in 85% yield from amine 1b (entry
O
H2N
O2N
S
O
a
b-d
+
R1
N
R1
Bt
R1
Cl
H
NO2
2-5
N
R1 for 2:
4: -propyl, 5:
p
-chlorophenyl, 3: tolyl
N
BtH =
n
t-butyl
N
H
Scheme 2. Reagents and conditions: (a) pyridine, 0 °C to rt, 4 h; (b)
NiCl2Æ6H2O (2 equiv), NaBH4 (4 equiv), MeOH, 0 °C to rt, 2 h; (c)
P4S10 (0.5 equiv), Na2CO3 (0.5 equiv), THF, rt, 3 h; (d) NaNO2
(1.5 equiv), 70% aq HOAc, 0 °C to rt, 1 h.
Mechanistically, it can be postulated that initially inter-
mediate A is formed which after N-desilylation generates

P. K. Sasmal et al. / Tetrahedron Letters 47 (2006) 8661–8665
8663
Table 3.
Entry
Substratea
Amineb
Conditionsc
A
Timed (h)
1.5
Product
Yielde (%)
N
CO2Et
1
2
1a
81
S
Cl
14
15
2
3
2
2
1b
1c
B
B
1
4
14
80
74
N
CONMe2
S
Cl
N
CO2Et
4
5
6
7
8
9
3
4
5
5
6
6
1b
1b
1b
1c
1b
1c
B
B
B
B
B
B
1.5
5
78
93
74
78
85
75
S
16
CO2Et
N
nPr
S
17
18
19
20
21
N
CO2Et
3.5
6
tBu
tBu
S
N
CONMe2
S
N
CO2Et
0.5
1.5
Bt
S
N
CONMe2
Bt
S
N
CO2Et
10
11
12
7
8
9
1b
1b
1b
B
B
B
8
3
5
70
82
74
MeS
S
22
20
N
CO2Et
EtO
S
23
24
25
N
CO2Et
13
14
15
10
11
12
1b
1b
1b
B
B
B
3
2
3
93
26
40
BnO
S
N
CO2Et
N
PhO
MeO
S
CO2Et
O
S
26
a Concentration of substrate is 0.2 M in THF.
b Amine (1.5 equiv) was used.
c Reaction conditions: (A) THF, Et3N (1.5 equiv); (B) THF, MeOH (10 equiv), Et3N (1.0 equiv).
d Time required for the starting material to disappear before addition of Et3N.
e Pure isolated yield.
intermediate B (Scheme 4). Intermediate B subsequently
undergoes, spontaneously or in the presence of a base,
cycloisomerisation–aromatisation to give thiazoles via
the intermediacy of C. It should be noted that intermedi-
ates A and C were not observed by TLC, whereas inter-
mediate B was observed in TLC and in some cases could
be isolated by column chromatography.
As we obtained poor yields in the cases of aryloxy and
thio-aryloxy thiazoles (see entries 11, 14 and 15 in Table

8664
P. K. Sasmal et al. / Tetrahedron Letters 47 (2006) 8661–8665
S
S
References and notes
RX for 7: SMe, 8: SPh, 9: OEt, 10: OBn
11: OPh, 12: p-methoxyphenyl, 13: HN(allyl)
ref. 23
Bt
Bt
RX
Bt
1. Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
2. (a) Miwatashi, S.; Arikawa, Y.; Kotani, E.; Miyamoto,
M.; Naruo, K.-I.; Kimura, H.; Tanaka, T.; Asahi, S.;
Ohkawa, S. J. Med. Chem. 2005, 48, 5966; (b) Papado-
poulou, C.; Geronikaki, A.; Hadjipavlou-Litina, D.
Il Farmaco 2005, 60, 969, and references cited therein.
3. (a) Kumar, Y.; Green, R.; Borysko, K. Z.; Wise, D. S.;
Wotring, L. L.; Townsend, L. B. J. Med. Chem. 1993, 36,
3843; (b) Ei-Subbagh, H. I.; Al-Obaid, A. M. Eur. J. Med.
Chem. 1996, 31, 1017.
7-13
6
Scheme 3.
EtO
O
S
CO2Et
- MeOSiMe3
- BtH
Me3Si
N
1b
R
Bt
S
SiMe3
4. Pereira, R.; Gaudon, C.; Iglesias, B.; Germain, P.;
Gronemeyer, H.; de Lera, A. R. Bioorg. Med. Chem.
Lett. 2006, 16, 49.
5. Tsuruni, Y.; Ueda, H.; Hayashi, K.; Takase, S.; Nishik-
awa, M.; Kiyoto, S.; Okuhara, M. J. Antibiot. 1995, 48,
1066.
:
R
N
A
MeOH
SiMe3
:
MeOH
- MeOSiMe3
EtO
O
6. (a) Millan, D. S.; Prager, R. H.; Brand, C.; Hart, P. H.
Tetrahedron 2000, 56, 811; (b) Wang, W.-L.; Yao, D.-Y.;
Gu, M.; Fan, M.-Z.; Li, J.-Y.; Xing, Y.-C.; Nan, F.-J.
Bioorg. Med. Chem. Lett. 2005, 15, 5284.
7. Metzger, J. V. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New
York, 1984; Vol. 6, pp 235–332.
S
N
S
N
CO2Et
CO2Et
Et3N
S
R
R
H
R
N
C
B
H
Scheme 4.
8. (a) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges.
1887, 20, 3118; (b) Aguilar, E.; Meyers, A. I. Tetrahedron
Lett. 1994, 35, 2473; (c) Varma, R. S. Pure Appl. Chem.
2001, 73, 193; (d) Ochiai, M.; Nishi, Y.; Hashimoto, S.;
Tsuchimoto, Y.; Chen, D.-W. J. Org. Chem. 2003, 68,
7887, and references cited therein.
9. Bergstrom, D. E.; Zhang, P.; Zhou, J. J. Chem. Soc.,
Perkin Trans. 1 1994, 3029.
10. (a) Martin, L. M.; Hu, B.-H. Tetrahedron Lett. 1999, 40,
7951; (b) You, S.-L.; Kelly, J. W. J. Org. Chem. 2003, 68,
9506.
(Me3Si)2N
1b
N
S
CO2Et
CO2Et
PhX
S
PhX
XPh
THF, MeOH
27: X = O
28: X = S
25: X = O, 10 h, 78%
29: X = S, 22 h, 60%
Scheme 5.
11. Kazmaier, U.; Ackermann, S. Org. Biomol. Chem. 2005, 3,
3184.
3), we decided to apply this method to di-aryloxy thione
and di-thioaryloxy thione systems. According to our
expectations, when compounds 27 and 28 were treated
with amine 1b (Scheme 5), the desired thiazoles 25 and
29 were obtained in good yields.
12. (a) Mustafa, S. M.; Nair, V. A.; Chittoor, J. P.; Krishna-
pillai, S. Mini-Rev. Org. Chem. 2004, 1, 375; (b) Walek,
W.; Pallas, M.; Augustin, M. Tetrahedron 1976, 32, 623;
(c) Golankiewicz, B.; Januszczyk, P.; Gdaniec, M.; Kos-
turkiewicz, Z. Tetrahedron 1985, 41, 5989; (d) Lin, Y.-I.;
Seifert, C. M.; Kang, S. M.; Dusza, J. P.; Lang, S. A., Jr.
J. Heterocycl. Chem. 1979, 16, 1377; (e) Short, K. M.;
Ziegler, C. B., Jr. Tetrahedron Lett. 1993, 34, 71; (f)
Wardakhan, W. W.; Elkholy, Y. M. Phosphorus, Sulfur,
Silicon Relat. Elem. 2002, 177, 2661; (g) Hermitage, S. A.;
Cardwell, K. S.; Chapman, T.; Cooke, J. W. B.; Newton,
R. Org. Proc. Res. Develop. 2001, 5, 37.
13. (a) Feuerstein, M.; Doucet, H.; Santelli, M. J. Organomet.
Chem. 2003, 687, 327; (b) Molander, G. A.; Biolatto, B. J.
Org. Chem. 2003, 68, 4302; (c) Hodgetts, K. J.; Kershaw,
M. T. Org. Lett. 2003, 5, 2911.
14. Nicolaou, K. C.; King, N. P.; Finlay, M. R. V.;
Roschangar, F.; Vourloumis, D.; Vallberg, H.; Sarabia,
F.; Ninkovic, S.; Hepworth, D. Bioorg. Med. Chem. 1999,
7, 665.
In conclusion, we have demonstrated a novel method
for the synthesis of thiazoles via one-pot N-desilylation,
thioacylation/oxythioacylation/thiothioacylation
fol-
lowed by cycloisomerisation in an intramolecular thia-
Michael fashion. The beauty of this method lies in the
fact that it is very mild, simple, highly efficient and
can introduce various oxo and thio functionalities
including aliphatic and aromatic moieties, especially at
the C2 position of thiazole derivatives. There is a huge
scope to expand this approach. Currently, we are
preparing different N-trimethylsilyl protected 1-alkyl/
aryl-substituted propargyl amines with various electron
withdrawing groups on the acetylenic moiety for the
synthesis of 2,4,5-trisubstituted thiazole libraries, details
of which will be published in due course.
15. (a) Sapountzis, I.; Dube, H.; Lewis, R.; Gommermann,
N.; Knochel, P. J. Org. Chem. 2005, 70, 2445; (b)
Lipshutz, B. H.; Frieman, B.; Birkedal, H. Org. Lett.
2004, 6, 2305.
16. Dondoni, A. Synthesis 1998, 1681.
17. Maclnnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2
1987, 1077.
Acknowledgements
18. (a) Corriu, R. J. P.; Bolin, G.; Iqbal, J.; Moreau, J. J. E.;
Vernhel, C. Tetrahedron 1993, 49, 4603; (b) Wipf, P.;
Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593.
19. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159.
We thank Dr. Reddy’s Laboratories Ltd. for the sup-
port and encouragement. Help from the analytical
department for spectral data is also appreciated.

P. K. Sasmal et al. / Tetrahedron Letters 47 (2006) 8661–8665
8665
20. Shalaby, M. A.; Grote, C. W.; Rapoport, H. J. Org.
Chem. 1996, 61, 9045.
tions for this class of compounds will be published in due
course.
21. All new compounds were characterised by spectral analysis.
22. Larsen, C.; Steliou, K.; Harpp, D. N. J. Org. Chem. 1978,
43, 337.
23. (a) Katritzky, A. R.; Ledoux, S.; Witek, R. M.; Nair, S. K.
J. Org. Chem. 2004, 69, 2976; (b) Katritzky, A. R.; Witek,
R. M.; Rodriguez-Garcia, V.; Mohapatra, P. P.; Rogers, J.
W.; Cusido, J.; Abdel-Fattah, A. A. A.; Steel, P. J. J. Org.
Chem. 2005, 70, 7866.
24. Wang, Y.-Q.; Ge, Z.-M.; Hou, X.-L.; Cheng, T.-M.; Li,
R.-T. Synthesis 2004, 675.
25. Even after a couple of days, more than half of the starting
material remained unreacted. Optimised reaction condi-
26. In a typical experiment, the thione (1.0 mmol) was
dissolved in THF (0.2 M) under an inert atmosphere. To
the solution at room temperature was added amine
(1.5 equiv) followed by MeOH (10 equiv). The reaction
mixture was stirred at the same temperature until the
disappearance of starting material, as checked by TLC.
Et3N (1.0 equiv) was added and the reaction mixture
stirred for 30 min. The reaction mixture was diluted with
ethyl acetate and the organic layer was successively
washed with 5% aq Na2CO3 solution, water and brine
and dried (MgSO4). Concentration and chromatographic
purification afforded the desired thiazole derivatives.