Catalysis by zeolite leading to the construction of thiazole ring: An improved synthesis of 4-alkynyl substituted thiazoles

Article abstract of DOI:10.1016/j.tetlet.2012.05.062

Zeolite H-beta facilitated the reaction of α-chloro acetyl chloride with 1,2-bis-trimethyl silyl acetylene to give 1-chloro-4-(trimethylsilyl)but-3- yn-2-one which on treatment with thioacetamide afforded 2-methyl-4- [(trimethylsilyl)ethynyl]thiazole. l-P

Full text of DOI:10.1016/j.tetlet.2012.05.062

Tetrahedron Letters 53 (2012) 3885–3889
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalysis by zeolite leading to the construction of thiazole ring: an
improved synthesis of 4-alkynyl substituted thiazoles
K. Arunkumar a,b, D. Naresh Kumar Reddy a, K. B. Chandrasekhar b, P. Rajender Kumar a, K. Shiva Kumar c,
Manojit Pal c,
⇑
a Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500 049, India
b College of Engineering, Jawaharlal Nehru Technological University, Anantapur 533 003, Andhra Pradesh, India
c Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Zeolite H-beta facilitated the reaction of a-chloro acetyl chloride with 1,2-bis-trimethyl silyl acetylene to
give 1-chloro-4-(trimethylsilyl)but-3-yn-2-one which on treatment with thioacetamide afforded
Received 16 April 2012
Revised 11 May 2012
Accepted 13 May 2012
Available online 17 May 2012
2-methyl-4-[(trimethylsilyl)ethynyl]thiazole. -Proline on the other hand facilitated the coupling reac-
L
tion of 2-methyl-4-[(trimethylsilyl)ethynyl]thiazole with (hetero)aryl halides (modified Sonogashira
reaction) under Pd-Cu catalysis in the presence of aqueous K2CO3 affording an improved method for
the synthesis of corresponding 4-alkynyl substituted thiazole derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Zeolite H-beta
Thiazole
L
-Proline
Pd-Cu catalysis
Aryl halides
The thiazole framework has been found to be an integral part of
alkynes obtained via the Sonogashira type coupling at 70–80 °C
were not particularly high in all cases. This prompted us to develop
an improved method for the synthesis of 4-alkynyl substituted thi-
azole derivatives in good yields. Herein we report the first use of
zeolite H-beta followed by thioacetamide for the construction of
1,3-thiazole ring and subsequent Sonogashira type coupling in
many natural products as well as various pharmacologically active
substances.1 For example, thiazole derivatives have been used for
the treatment of various CNS related sufferings2–12 such as pain,2
depression,3–10 anxiety,12 etc. Several 4-alkynyl substituted thia-
zole derivatives such as 2-methyl-4-(pyridin-3-ylethynyl)thiazole
(A) and 2-methyl-4-(phenylethynyl)thiazole (B) (Fig. 1) have been
reported as potent and selective metabotropic glutamate subtype 5
receptor antagonists with anxiolytic activity12 whereas compound
C (or [18F]SP203, Fig. 1) was found to be effective as a positron
emission tomography (PET) radio ligand in rhesus monkeys.13
The strategy used for the synthesis of 4-alkynyl substituted thi-
azole derivatives generally involved a Sonogashira-type coupling
of appropriate aryl or heteroaryl halides with 4-(trimethylsilyle-
thynyl)-substituted-1,3-thiazole (Scheme 1)12,14 which in turn
the presence of L-proline under mild conditions (Scheme 1).
The use of solid supports such as zeolites15 has been explored in
various organic reactions because of several advantages such as
their acidic properties, shape-selectivities, environmental friendly
nature along with easy work-up, the high purity of products, and
recycling of the catalysts. Thus, zeolite H-beta has been reported
to be an efficient catalyst in a number of chemical transformations
including alkylation16 and acylation.17 Its activity owes to its large
pore size, high Si/Al ratio, high acid strength, and thermal stability.
In view of its role similar to AlCl3 in a Friedel–Crafts acylation of
anisole using acetyl chloride18 we anticipated that like AlCl3 the
had been prepared via the reaction of a-chloro acetyl chloride with
bis-trimethyl silyl acetylene in the presence of AlCl3 followed by
treating the resulting ynone with thioacetamide. While this strat-
egy has been used successfully for the preparation of a number
of compounds earlier, the requirement of a stoichiometric quantity
of environmentally harmful and non-recyclable AlCl3 during the
generation of the 1,3-thiazole ring precursor was one of the major
drawbacks of this procedure. Additionally, the yields of coupled
zeolite H-beta might facilitate the reaction of
a-chloro acetyl
CN
S
S
S
18F
N
N
N
N
F
C
B
A
⇑
Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
Figure 1. Pharmacologically active 4-alkynyl substituted thiazole derivatives.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.062

3886
K. Arunkumar et al. / Tetrahedron Letters 53 (2012) 3885–3889
Cl
N
thioacetamide (4)
O
Zeolite H-beta
Si
+
Si
S
Si
Cl
Si
S
Cl
DMF
CH2Cl2
45 - 50 °C
24 h
O
20-25 °C
17 h
1
2
5
3
RX (6)
L-Proline
N
R
PdCl2(PPh3)2,
CuI, K2CO3
7
(R = aryl
= heteroaryl)
(X = I, Br)
Scheme 1. Zeolite H-beta mediated construction of 1,3-thiazole ring and subsequent Sonogashira-type alkynylation in the presence of L-proline.
chloride (1) with 1,2-bis-trimethyl silyl acetylene (2). Initially, we
examined the zeolite H-beta mediated reaction of 1 with 2 in
dichloromethane (DCM) at room temperature when the formation
of desired product that is 1-chloro-4-(trimethylsilyl)but-3-yn-2-
one (3, Scheme 1) was not observed after 48 h. The increase of
reaction temperature to 40–45 °C however afforded the expected
product 3 (ꢀ70% yield) and the reaction was completed within
24 h. To test the recyclability of the catalyst the zeolite H-beta
was separated from the reaction mixture by filtration, washed with
DCM, dried, and reused. This process was repeated twice when the
product 3 was isolated in 65% and 60% yields. While a marginal
drop in product yield was observed in these cases the catalyst
however can potentially be recycled. Nevertheless, we were de-
lighted to develop an alternative but an environmentally safer
method for the synthesis of compound 3 which was then used
for the construction of the thiazole ring. The reaction of compound
3 with thioacetamide (4) in DMF provided the desired 2-methyl-4-
[(trimethylsilyl)ethynyl]thiazole
(Scheme 1).
5 in good yield (60% yield)
Having the key compound 5 in hand we then examined the one-
pot modified Sonogashira coupling of 5 which involved an in situ
desilylation in the presence of tetrabutylammonium fluoride
(TBAF) followed by Pd-Cu mediated cross-coupling of the resulting
terminal alkyne generated with an appropriate aryl halide. Accord-
ingly, the reaction of 5 with 1-(4-iodophenyl)ethanone (6a) was
carried out under the conditions (e.g., Pd(PPh3)4, CuI, NEt3, TBAF
in DMF at 80 °C or PdCl2(PPh3)2, PPh3, CuI, NEt3, TBAF, Bu4NI in
DMF at 80 °C) reported earlier.12,14b While the reaction proceeded
in these cases the desired product that is 1-{4-[(2-methylthiazol-4-
yl)ethynyl]phenyl}ethanone (7a) however was isolated only in
30–40% yield due to the formation of side product caused by the
oxidative homocoupling19 (Glaser coupling) of the terminal alkyne
generated in situ. The yield of 7a could not be improved in spite of
our several attempts. Since CuI in the presence of amine base plays
a significant role in such homocoupling reaction, in order to in-
crease the product yield we decided to examine the effect of a
range of ligands (L1–L6) on the present coupling reaction. The li-
gands were chosen based on their potential ability to chelate a cop-
per salt thereby modulating its reactivity. The results of this study
Table 1
Effect of ligands on modified Sonogashira coupling of 5 with 6aa
Ligand
N
O
N
O
PdCl2(PPh3)2
Si + I
S
S
CuI, Et3N
TBAF, DMF
40-50 °C
6a
5
7a
Yieldb (%)
Entry
1
Ligand
H2N
Time (h)
N
12
30
L1
O
N
OH
2
3
24
6
10
85
Table 2
L2
Effect of Cu salts, solvents, and bases for Sonogashira coupling reaction
H
N
O
OH
L-Proline
PdCl2(PPh3)2
L3
5
+
6a
7a
Cu-salt
Base, solvent
N
45-50 °C, 6 h
4
24
10
OH
Entry
Cu-salt
Base
Solvent
Yieldb (%)
L4
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Cu2O
Cu(OAc)2
CuI
K2CO3
Cs2CO3
DIPA
DMF
DMF
DMF
DMF
Toluene
i-PrOH
DMF
DMF
DMF
80
55
47
65
30
60
35
0
HO
O
N
5
6
24
24
15
10
Et3N
L5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
N
L6
15
85
10
DMF–H2O
a
All the reactions were carried out by using
5 (5.11 mmol, 1.0 equiv), 6a
a
(5.63 mmol, 1.1 equiv), PdCl2(PPh3)2 (0.042 mmol), ligand (0.51 mmol), CuI
(0.25 mmol), triethylamine (6.39 mmol, 1.25 equiv), and TBAF (5.63 mmol,
1.1 equiv) in DMF (2.5 mL).
All the reactions were carried out by using
(5.63 mmol, 1.1 equiv), PdCl2(PPh3)2 (0.042 mmol),
(0.25 mmol), and a base (6.24 mmol, 1.25 equiv) in a solvent (2.5 mL) at 45–50 °C.
5
(5.11 mmol, 1.0 equiv), 6a
L-proline (0.51 mmol), Cu-salt
b
b
Isolated yields.
Isolated yields.

K. Arunkumar et al. / Tetrahedron Letters 53 (2012) 3885–3889
3887
Table 3
Pd-Cu mediated coupling reaction of 2-methyl-4-(trimethylsilylethynyl)-thiazole (5) with aryl and heteroaryl halides (6) in the presence of L-prolinea
Entry
Aryl/heteroaryl halide (6)
Productb (7)
Time (h)
Yieldc (%)
O
O
N
S
I
1
6
85
70
6a
7a
OH
OH
N
S
I
2
3
8
3
6b
7b
N
S
O
O
I
85
85
75
O
O
7c
6c
O
O
N
S
I
O
O
4
5
6
5
6d
7d
O
O
N
S
O
O
I
7e
H3CO
6e
H3CO
N
S
I
6
7
8
3
6
5
60
75
85
7f
6f
N
I
S
S
6g
7g
O
O
O
I
N
O
6h
7h
7i
O
O
S
N
S
Br
9
5
60
S
6i
HO
HO
S
N
N
S
S
Br
Br
10
11
5
3
55
70
S
S
6j
7j
S
6k
All the reactions were carried out by using 5 (5.11 mmol, 1.0 equiv), 6 (5.63 mmol, 1.1 equiv), PdCl2(PPh3)2 (0.042 mmol),
7k
a
L-proline (0.51 mmol), CuI (0.25 mmol), K2CO3
(6.24 mmol, 1.25 equiv) in DMF (2.5 mL), and water (0.15 mL) at 45–50 °C.
b
Identified by 1H NMR, IR, and MS.
Isolated yields.
c
are summarized in Table 1. The reaction was initially performed in
the presence of 10 mol % of N1,N1-dibenzyl-1,2-ethanediamine (L1)
in DMF for 12 h when no improvement of product yield was ob-
served (Table 1, entry 1). The use of 2-(dimethylamino)acetic acid
(L2) was also found to be ineffective (Table 1, entry 2). The yield of
considerably though not completely in this case leading to the for-
mation of a purer product. To suppress the homocoupling of alkyne
completely, we tried a few other ligands for example L4–6 but our
effort was not successful (Table 1, entries 4–6). Having identified
L-proline as the best among the ligands tested, we then examined
7a however was improved significantly when
used as a ligand and the reaction was completed within 6 h (Table
1, entry 3). The oxidative homocoupling of alkyne was suppressed
L
-proline (L3) was
the coupling reaction of 5 with 6a under various conditions for
example by changing several parameters such as solvent, copper
salt, and the desilylating agent (Table 2).

3888
K. Arunkumar et al. / Tetrahedron Letters 53 (2012) 3885–3889
L-proline
ated method, the present process represents a useful but relatively
safer alternative where the zeolite H-beta used can potentially be
recycled. -Proline on the other hand facilitated the coupling reac-
CuI aq K2CO3
O
L
tion of 2-methyl-4-[(trimethylsilyl)ethynyl]thiazole with (het-
ero)aryl halides (modified Sonogashira reaction) under Pd-Cu
catalysis in the presence of aqueous K2CO3 affording an improved
method for the synthesis of corresponding 4-alkynyl substituted
thiazole derivatives. A variety of (hetero)aryl iodides and bromides
possessing carbonyl, hydroxyalkyl, acyloxyalkyl, ester, or ether
substituents were employed to give the coupled products in good
yields. The overall process may find uses in the generation of li-
braries of small molecules of potential pharmacological interest
based on 4-alkynyl substituted thiazole.
O
N
H
N
Cu(I)
N
H
N
O
Cu
Si
S
O
S
aq K2CO3
5
L
E-1
R[PdII]X
RX
L
5
+
6
(X = I, Br)
L-proline
CuI
L
N
Pd0L2
PdCl2(PPh3)2
Pd R
L
E-2 (L = L-proline)
S
aq K2CO3
Acknowledgements
7
K.A. thanks Dr. V. Dahanukar and Mr. A. Mukherjee for encour-
agements and the analytical group of DRL for spectral support.
Scheme 2. Proposed reaction mechanism for the modified Sonogashira coupling of
5 with 6 in the presence of -proline.
L
Supplementary data
The use of K2CO3 in place of Et3N and TBAF was found to be
effective as the desired product 7a was isolated in 80% yield (Table
2, entry 1). The use of other bases, such as Cs2CO3, diisopropyl
ethyl amine (DIPA), or Et3N decreased the product yield (Table 2,
entries 2–4). Changing the solvent from DMF to toluene (Table 2,
entry 5) or i-PrOH (Table 2, entry 6) or the copper catalyst from
CuI to CuBr (Table 2, entry 7) or Cu2O (Table 2, entry 8) or
Cu(OAc)2 (Table 2, entry 9) did not provide good yield of 7a. Inter-
estingly, the use of water as a co-solvent though did not improve
the product yield, afforded a much purer product (Table 2, entry
10) perhaps due to the enhanced solubility of K2CO3 in the aque-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
062.
References and notes
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New York, NY, 1979. p 34; (f) Metzger, J. V. In Thiazoles and their Benzo
Derivatives; Potts, K. T., Ed.; Pergamon: New York, NY, 1984; Vol. 6, (g)
Rosowsky, A.; Mota, C. E.; Wright, J. E.; Ereisheim, J. H.; Mc Cormack, J. J.;
Queener, C. F. J. Med. Chem. 1993, 36, 3103; (h) Bousquet, E.; Romeo, G.;
Guererra, F.; Caruso, A.; Amico-Roxas, M. Farmaco Ed. Sci. 1985, 40, 869; (i)
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1989, 66, 48.
2. Varney, M. A.; Gereau, R. W. I. Curr. Drug Targets: CNS Neurol. Disord. 2002, 1,
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3. Brodkin, J.; Busse, C.; Sukoff, S. J.; Varney, M. A. Pharmacol. Biochem. Behav.
2002, 73, 359.
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R. D.; Gentsch, C. J. Pharmacol. Exp. Ther. 2000, 295, 1267.
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Pharmacol. 2002, 435, 161.
ous reaction medium. Thus, the combination of
L-proline,
(PPh3)2PdCl2, CuI, and K2CO3 in H2O–DMF was found to be the best
among all the conditions tested. A variety of aryl iodides (6) were
coupled with 5 under this condition to afford the corresponding 4-
alkynyl substituted thiazole derivatives (7) in good yields (Table
3).20 The presence of carbonyl, hydroxyalkyl, acyloxyalkyl, ester,
or ether substituents on the aromatic ring of 6 was well tolerated
and the reaction proceeded smoothly in all these cases. The reac-
tion also proceeded well when 2-bromothiophene derivatives
were employed.
The mechanism of the Pd-Cu mediated coupling of 5 with 6 can
be envisaged as shown in Scheme 2. The reaction seems to proceed
via desilylation21 of compound 5 in the presence of aqueous K2CO3
which subsequently forms the corresponding copper acetylide (E-
6. Tatarczynska, E.; Klodzinska, A.; Chojnacka-Wojcik, E.; Palucha, A.; Gasparini,
F.; Kuhn, R.; Pilc, A. Br. J. Pharmacol. 2001, 132, 1423.
7. Klodzinska, A.; Tatarczynska, E.; Chojnacka-Wojcik, E.; Pilc, A. Pol. J. Pharmacol.
2000, 52, 463.
8. Schulz, B.; Fendt, M.; Gasparini, F.; Lingenhohl, K.; Kuhn, R.; Koch, M.
Neuropharmacology 2001, 41, 1.
1) via reacting with L
-proline chelated Cu(I) species.22 The interme-
diate E-1 then undergoes trans-metallation with the organo palla-
dium complex RPd(II)X generated from RX and the Pd(0) species
produced in situ to give intermediate E-2. It is evident from entry
3 (vs other entries) of Table 1 and entry 10 (vs other entries) of Ta-
9. Busse, C. S.; Brodkin, J.; Tattersall, D.; Anderson, J. J.; Warren, N. A.; Tehrani, L.;
Bristow, L. J.; Varney, M. A.; Cosford, N. D. P. Neuropsychopharmacology 1971,
2004, 29.
10. Klodzinska, A.; Tatarczynska, E.; Chojnacka-Wojcik, E.; Nowak, G.; Cosford, N.
D. P.; Pilc, A. Neuropharmacology 2004, 47, 342.
ble 2 that
L
-proline in the presence of aqueous K2CO3 played a
11. Chiamulera, C.; Epping-Jordan, M. P.; Zocchi, A.; Marcon, C.; Cottiny, C.;
Tacconi, S.; Corsi, M.; Orzi, F.; Conquet, F. Nat. Neurosci. 2001, 4, 873.
12. Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N. D.; Anderson, J.;
Bristow, L.; Brodkin, J.; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney,
M. A. J. Med. Chem. 2003, 46, 204.
13. Shetty, H. U.; Zoghbi, S. S.; Siméon, F. G.; Liow, J. S.; Brown, A. K.; Kannan, P.;
Innis, R. B.; Pike, V. W. J. Pharmacol. Exp. Ther. 2008, 327, 727.
14. (a) Roppe, J. R.; Wang, B.; Huang, D.; Tehrani, L.; Kamenecka, T.; Schweiger, E.
J.; Anderson, J. J.; Brodkin, J.; Jiang, X.; Cramer, M.; Chung, J.; Reyes-Manalo, G.;
Munoz, B.; Cosford, N. D. Bioorg. Med. Chem. Lett. 2004, 14, 3993; (b) Iso, Y.;
Grajkowska, E.; Wroblewski, J.; Davis, J.; Goedders, N. E.; Johnson, K. M.;
Sankaer, S.; Roth, B. L.; Tuecckmantel, W.; Kozikowski, A. P. J. Med. Chem. 2006,
49, 1080.
favorable role in generating Pd(0) species in situ.23 The intermedi-
ate E-2 on reductive elimination of Pd(0) provided the expected
product 7 along with the Pd(0) species to complete the catalytic cy-
cle. The observed suppression of oxidative homocoupling reaction
could be explained by the chelating effect of L-proline which per-
haps prevented the copper acetylide to participate in the homo-
coupling reaction thereby diminishing the formation of undesired
side product.
In conclusion, zeolite H-beta facilitated the reaction of a-chloro
15. Sen, S. E.; Smith, S. M.; Sullivan, K. A. Tetrahedron 1999, 55, 12657.
16. Ferino, I.; Monaci, R.; Rombi, E.; Solinas, V.; Magnoux, P.; Guisnet, M. J. Appl.
Catal. A 1999, 183, 303.
17. Bhaskar, P. M.; Loganathan, D. Synlett 1999, 129.
18. Gaare, K.; Akporiaye, D. J. Mol. Catal. A: Chem. 1996, 109, 177.
acetyl chloride with 1,2-bis-trimethyl silyl acetylene to give
1-chloro-4-(trimethylsilyl)but-3-yn-2-one which on treatment
with thioacetamide afforded 2-methyl-4-[(trimethylsilyl)ethy-
nyl]thiazole. In comparison to the previously reported AlCl3 medi-

K. Arunkumar et al. / Tetrahedron Letters 53 (2012) 3885–3889
3889
19. (a) Rossi, R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26, 523; (b) Kundu, N.
G.; Pal, M.; Chowdhury, C. J. Chem. Res., Synop. 1993, 432; (c) Lei, A.; Srivastava,
M.; Zhang, X. J. Org. Chem. 1969, 2002, 67.
(0.51 mmol, 0.1 equiv), CuI (0.25 mmol, 0.05 equiv), K2CO3 (6.24 mmol,
1.25 equiv), and water (0.15 mL). The mixture was stirred at 45–50 °C for the
time mentioned in Table 3. After completion of the reaction the mixture was
cooled to room temp, partitioned between EtOAc (10 mL) and 0.1 N HCl
(3.0 mL). The organic layer was collected, washed with cold water (2 Â 10 mL),
dried over anhydrous MgSO4, filtered, and concentrated under low vacuum.
The residue was purified by column chromatography on silica gel using
hexane–EtOAc as solvent system to give the desired product; compound 7a:
Pale yellow solid; mp 126–127 °C; 1H NMR (400 MHz, CDCl3) d 2.61 (s, 3H),
2.75 (s, 3H), 7.43 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) d 19.2, 26.6, 86.5, 87.9, 123.1, 127.3, 128.2 (2C), 131.8
(2C), 136.4, 142.0, 165.9, 197.2; IR (cmÀ1, KBr) 2210, 1678; m/z (CI) 242 (M+1,
100%); HRMS (ESI) calcd for C14H12NOS (M+H)+ 242.0640, found 242.0645.
compound 7b: 1H NMR (CDCl3, 400 MHz) d 1.49 (d, 3H) 2.74 (s, 3H), 4.94 (q,
J = 6.4 Hz, 1H), 7.35 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) d 13.6, 25.1, 65.4, 70.0, 71.3, 121.5, 122.1, 125.4 (2C),
131.9 (2C), 138.3, 146.3, 166.6; IR (cmÀ1, KBr) 3383, 2216, 1735; m/z (CI) 244
20. (a) Preparation of compound 5; Step 1: To
a
solution of bis
(trimethylsilyl)acetylene (15.7 mL, 70.0 mmol) and chloroacetyl chloride
(5.6 mL, 70.0 mmol) in CH2Cl2 (120 mL), was added Zeolite H-beta (9.00 g).
The mixture was stirred at 45–50 °C for 24 h. After completion of the reaction
(monitored by TLC) the mixture was cooled to room temp and filtered to
separate the catalyst. The filtrate was collected and concentrated. The residue
was treated with ethyl acetate (75 mL) and washed with cold water
(2 Â 25 mL). The organic layers were collected, combined, dried over
anhydrous MgSO4, filtered, and evaporated in vacuo to give the desired 1-
chloro-4-(trimethylsilyl)but-3-yn-2-one (3) (8.10 g, 70% yield) which was used
directly in the next step. Step 2: To a solution of compound 3 in DMF (120 mL)
was added thioacetamide (6.31 g, 84.0 mmol) and the mixture was allowed to
stir at 20–25 °C for 17 h. After completion of the reaction (indicated by TLC) the
mixture was diluted with EtOAc (100 mL), washed with 0.1 N HCl (300 mL) and
H2O (2 Â 50 mL), dried over anhydrous MgSO4, filtered, and evaporated under
low vacuum. The residue was purified by column chromatography on silica gel
using hexanes–EtOAc to give the desired product 5 (7.11 g, 60% yield); 1H NMR
(CDCl3, 400 MHz) d 0.27 (s, 9H), 2.70 (s, 3H), 7.31 (s, 1H); 13C NMR (CDCl3,
100 MHz) 10.34 19.16, 83.36, 94.43, 98.28, 122.91, 122.89, 136.84, 165.46; MS
(M+1, 100%); HRMS (ESI) calcd for
244.0814.
C
14H14NOS (M+H)+ 244.0796, found
21. Rao, R. M.; Reddy CH, U.; Nakhi, A.; Mulakayala, N.; Alvala, M.; Arunasree, M.
K.; Poondra, R. R.; Iqbal, J.; Pal, M. Org. Biomol. Chem. 2011, 9, 3808.
22. The Cu complexes of
Wagner, C. C.; Torre, M. H.; Baran, E. J. Lat. Am. J. Pharm. 2008, 27, 197.
23. For a Pd( -proline)2 catalyzed reaction, see: (a) Allam, B. K.; Singh, K. N.
L-proline are known in the literature, see for example:
(ESI) m/z 196.10 (M+H)+; IR (cmÀ1
C9H14NS (M+H)+ 196.0616, found 196.0611. (b) General procedure for the
preparation of compound 7: To solution of 2-methyl-4-
, KBr) 2163.20.; HRMS (ESI) calcd for
L
a
Synthesis 2011, 1125; For a similar observation using (S)-prolinol, see (b) Pal,
M.; Subramanian, V.; Parasuraman, K.; Yeleswarapu, K. R. Tetrahedron 2003, 59,
9563.
(trimethylsilylethynyl)-thiazole (5, 5.11 mmol) in DMF (2.5 mL) was added
an appropriate (hetero)aryl halide (6, 5.63 mmol, 1.1 equiv) under nitrogen. To
this mixture were added PdCl2(PPh3)2 (0.042 mmol, 0.01 equiv), L-proline