Fluorous thiazolium salts for the intramolecular stetter reaction

Article abstract of DOI:10.3987/COM-08-S(N)77

The fluorous thiazolium salt 6 derived from 5-(2-hydroxyethyl)-4-methylthiazole was employed for an intramolecular Stetter reaction. The catalytic activity of the fluorous catalyst 6 was similar to that of the standard catalyst 1. The fluorous catalyst 6

Full text of DOI:10.3987/COM-08-S(N)77

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1027 - 1031. © The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2008, Accepted, 13th May, 2008, Published online, 19th May, 2008. COM-08-S(N)77
FLUOROUS THIAZOLIUM SALTS FOR THE INTRAMOLECULAR
STETTER REACTION
Osamu Hara,* Atsuko Kume, Michiharu Sugiura, and Isamu Maeba
Faculty of Pharmacy, Meijo University, 150 Yagotoyama Tempaku-ku, Nagoya,
Aichi, 468-8503 Japan e-mail : oshara@ccmfs.meijo-u.ac.jp
Abstract – The fluorous thiazolium salt 6 derived from 5-(2-hydroxy-
ethyl)-4-methylthiazole was employed for an intramolecular Stetter reaction.
The catalytic activity of the fluorous catalyst 6 was similar to that of the standard
catalyst 1. The fluorous catalyst 6 survived multiple reaction cycles.
1
Since the Stetter reaction was first described in 1973, a number of examples of this reaction using
cyanide ion, thiazolium salts, and triazolium salts as a catalyst have been reported including an
2
asymmetric reaction. One unique approach to the Stetter reaction was the use of polymer-supported
3
thiazolium salts catalysts. The polymer catalyst not only was easily separated by simple filtration but
also survived 4-6 cycles of the same reaction. Unfortunately, the synthetic utility of the polymer catalysts
HO
S
N+
Cl-
O
Ph
O
O
H
( 1 ) 20 mol%
CO Et
2
O
CO Et
2
DMF or t -BuOH
2
3
HO
Rf
O
Rf
O
N+
X-
S
N+
S
N+
S
Rf
Ph
X-
Rf
X-
I
II
III
Rf = perfluoro moiety
Figure 1. Intramolecular Stetter Reaction and Fluorous Thiazolium Salts
th
This manuscript is dedicated to Prof. Ryoji Noyori on the occasion of his 70 birthday.

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HETEROCYCLES, Vol. 76, No. 2, 2008
was less than that of a homogenous catalyst. Recently, Curran et al. introduced the concept of “fluorous
4
synthesis” as a fundamental strategic alternative to small molecules synthesis and solid phase synthesis.
The fluorous synthesis technique features facile purification of fluorous compounds by either extraction
5
with a fluorous solvent or fluorous solid phase extraction. We report herein the synthesis of fluorous
thiazolium salts I ~III and its application to an intramolecular Stetter reaction (Figure 1).
An intermediate in thiamine production, 5-(2-hydroxyethyl)-4-methylthiazole, is readily available, and
following quarternisation on the thiazole ring and protection of the hydroxyl group with alkyl halide,
gives a product that demonstrates catalytic activity in the presence of a base in the intramolecular Stetter
reaction. Using the above strategy we succeeded in preparing the corresponding fluorous thiazolium
salts (4 ~ 7) from 5-(2-hydroxyethyl)-4-methylthiazole. The fluorous catalysts 4 and 5 were readily
prepared by the treatment of 5-(2-hydroxyethyl)-4-methylthiazole with perfluorooctylethyl iodide or
6
p-(perfluorooctylethyl)benzyl bromide in CH CN, respectively. Protection of the hydroxyl group of
3
5
-(2-hydroxyethyl)-4-methylthiazole with p-(perfluorooctylethyl)benzyl bromide, followed by
quarternisation with benzyl bromide or p-(perfluorooctylethyl)benzyl bromide afforded the desired
7
fluorous catalyst 6 and 7, respectively(Figure 2).
HO
HO
C8F
17
S
N+
I-
S
N+
Br-
C8F
17
4
5
C8F
17
C8F17
O
O
C8F
17
S
N+
Br-
S
N+
Br-
Ph
6
7
Figure 2. Fluorous Thiazolium Salts
The intramolecular Stetter reaction of salicylaldehyde derivative 2 was investigated using the new
fluorous catalysts and the results are summarized in Table 1. The reaction using fluorous catalyst 4 in
the presence of Et N in DMF required a higher reaction temperature and longer reaction time than that of
3
catalyst 1 to afford the desired product 3 with an unsatisfactory chemical yield (entry 2). Changing the
fluorous moiety from an ethyl type to a benzyl type slightly improved reactivity of catalyst (entry 3).
Especially, the introduction of the fluorous benzyl moiety to the hydroxyl group, not on the thiazole ring,
affected chemical yield, which then further improved when the solvent was changed to t-BuOH (entry 4,
5
). The influence of the position of fluorous moiety on reactivity might be due to an electronic effect
around the active site of the catalyst. Use of catalyst 7 demanded a higher reaction temperature because

HETEROCYCLES, Vol. 76, No. 2, 2008
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of its low solubility in DMF. Unfortunately, the attempted construction of a quaternary carbon with
8
catalyst 6 and substrate 2b under the same conditions resulted in no product (entry 8).
Table 1. Intramolecular Setter Reaction with Fluorous Thiazolium Salts
O
O
O
catalyst
(20 mol%)
R
H
CO Et
2
O
CO Et
2
Et N (20 mol%)
3
R
2
2
a : R = H
b : R = Me
3a : R = H
3b : R = Me
Entry
Substrate
Catalyst
Conditions
Yield (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2b
1
4
5
6
6
7
7
6
25 °C, 1.5 h, DMF
80 °C, 2 d, DMF
96
23
43
66
82
61
60
0*
80 °C, 23 h, DMF
40 °C, 24 h, DMF
60 °C, 24 h, t-BuOH
100 °C, 20 h, DMF
80 °C, 24 h, t-BuOH
70 °C, 23 h, t-BuOH
*
2b was recovered in 63% yield.
Table 2. Reuse of Fluorous Catalyst
Based on the above results, we investigated
the potential for the use of the fluorous
catalyst in multiple reaction cycles of the
intramolecular Stetter reaction (Table 2).
The recycling was examined as followed.
The salicylaldehyde derivative 2a (0.04
mmol) was treated with catalyst 6 (20 ~ 16
O
O
H
catalyst 6
CO Et
2
O
CO Et
2
Et N (20 mol%)
O
3
t- BuOH, 60 °C
2
a
3a
Catalyst 6
Recovered
catalyst (%)
Cycle
1
Yield (%)
82
(
mol%)
20
69
mol%) in the presence of Et N (20 mol%)
2
3
4
5
*
20
20
19
50 (58)**
49 (71)**
50 (86)**
48 (64)**
74
96
84
70
3
at 60 °C in t-BuOH. After stirring for
*
2
4h, the reaction mixture was purified on a
commercially available fluoro solid-phase
1
6
to separate the desired product and catalyst
*
*
A small amount of catalyst 6 was added to maintain reaction ratio.
* The value in the parentheses is the recovery yield of the starting
material.
9
6
.
The recovered fluorous catalyst was
used in the next reaction. As shown in

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HETEROCYCLES, Vol. 76, No. 2, 2008
Table 2, this process was repeated 5 times and the catalyst still maintained the catalytic activity after the
fifth cycle. Although a significant decrease of the catalytic activity was observed at the second and
subsequent cycles, 70 % of the catalyst was recovered at the end of the last cycle.
In conclusion, we have demonstrated the preparation of fluorous catalysts and their application to the
intramolecular Stetter reaction. The fluorous catalyst represents a good catalytic activity and retains
catalytic activity on recovery.
ACKNOWLEDGEMENTS
This work was financially supported in part by a Grant-in-Aid for Scientific Research (C) (to OH) from
the Ministry of Education, Culture, Sports, Science and Technology, Japan.
REFERENCES AND NOTES
1
.
H. Stetter and H. Kuhlmann, Org. React., 1991, 40, 407; H. Stetter and M. Schreckenberg, Angew.
Chem., 1973, 85, 89; H. Stetter, Angew. Chem., Int. Ed. Engl., 1976, 15, 639.
2
.
E. M. Phillips, M. Wadamoto, A. Chan, and K. A. Scheidt, Angew. Chem. Int. Ed., 2007, 46, 3207;
Q. Jiu and T. Rovis, J. Am. Chem. Soc., 2006, 128, 2552; J. Read de Alaniz, and T. Rovis, J. Am.
Chem. Soc., 2005, 127, 6284; M. S. Kerr and T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876; M. S.
Kerr, J. Read de Alaniz, and T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298; D. Enders, K. Breuer, J.
Runskin, and J. Teles, Helv. Chim. Acta, 1996, 79, 1899.
3
.
B. -H. Chang and Y. L. Chang, J. Chinese Chem. Soc., 1983, 30, 55; C. S. Sell and L. A. Dorman, J.
Chem. Soc., Chem. Commun., 1982, 629; J. Castells, E. Dunach, F. Geijo, F. Pujol, and P. M. Segura,
Israel J. Chem., 1978, 17, 278.
4
5
.
.
A. Studer, S. Hadida, R. Ferritto, S. -Y. Kim, P. Jeger, P. Wipf, and D. P. Curran, Science, 1997, 275,
8
23; A. Studer and D. P. Curran, Tetrahedron, 1997, 53, 6681.
D. P. Curran, ‘Handbook of Fluorous Chemistry,’ ed. by J. Gladysz, I. Horvath, and D. P. Curran,
Wiley-VCH, Weinheim, Germany, 2004, pp. 101-127.
6
7
.
.
D. P. Curran and T. Furukawa, Org. Lett., 2002, 4, 2233.
1
Spectral data of compound 6: H NMR ( 500 MHz, CDCl ) δ11.37 (1H, s), 7.35-7.40 (6H, m),
3
7
.21-7.26 (4H, m), 6.01 (2H, s), 4.53 (2H, s), 3.72 (2H, t, J=6.2), 3.08 (2H, t, J=6.2), 2.92-2.95 (2H,
1
3
m), 2.40 (3H, s), 2.40 (2H, m); C NMR ( 125 MHz, CDCl ) δ158.48, 141.65, 139.19, 135.34,
3
1
9
1
35.28, 131.86, 129.50, 129.38, 128.64, 128.47, 128.3373.31, 67.63, 57.01, 27.76, 12.51; F NMR
(
470 MHz, CDCl ) δ -80.61, -114.49, -121.58, -121.81, -122.60, -123.31, -126.00; IR(KBr) 2942,
3
-
1
1
243, 1205, 1148, 750, 703, 657 cm ; Anal. Calcd for C H BrF NOS: C, 42.37; H, 2.96; N, 1. 65.
30 25 17
Found: C, 42.20; H, 2.97; N, 1.64.

HETEROCYCLES, Vol. 76, No. 2, 2008
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8
9
.
.
T. Nakamura, O. Hara, T. Tamura, K. Makino, and Y. Hamada, Synlett, 2005, 155.
The separation of catalyst was carried out with commercially available a fluorous SPE cartidge
®
(
FluoroFlash , 2 grams, 8 cc tube, Fluorous Technologies Incorporated). The reaction mixture was
loaded onto the column and eluted with MeOH (10 mL) to give a desired compound. After
treatment of 1N HCl (2 mL), the catalyst was eluted with MeOH ( 20 mL).