Synthesis of 2,4-diacetylthiazole and 2,5-diacetylthiazole

Article abstract of DOI:10.1016/j.tet.2008.02.064

Compounds 2,4-diacetylthiazole 5 and 2,5-diacetylthiazole 6, of interest for their flavour and aroma properties, have been prepared for the first time by tetrabromination and silver nitrate treatment of the corresponding diethylthiazoles.

Full text of DOI:10.1016/j.tet.2008.02.064

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Tetrahedron 64 (2008) 4384e4386
www.elsevier.com/locate/tet
Synthesis of 2,4-diacetylthiazole and 2,5-diacetylthiazole
*
Kati M. Aitken, R. Alan Aitken
EaStCHEM School of Chemistry, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK
Received 9 November 2007; received in revised form 4 February 2008; accepted 21 February 2008
Available online 26 February 2008
Abstract
Compounds 2,4-diacetylthiazole 5 and 2,5-diacetylthiazole 6, of interest for their flavour and aroma properties, have been prepared for the
first time by tetrabromination and silver nitrate treatment of the corresponding diethylthiazoles.
Ó 2008 Elsevier Ltd. All rights reserved.
1
. Introduction
O
O
S
S
O
S
Simple acetylated nitrogen and sulfur-containing heterocy-
N
N
N
cles occur in many cooked foodstuffs and are of current inter-
est to the food industry as flavour and aroma ingredients. For
example, 2-acetylthiazole 1 was detected in the 1970s in
1
2
3
O
S
O
O
S
O
1
,2
3
4
S
cooked and canned beef, cooked pork liver, cooked potato
5
N
O
and rice bran. More recently, the same compound has been
found to be formed from the garlic constituent alliin both by
NH
N
4
5
6
6
thermal degradation in acidic solution and upon interaction
7
8,9
with glucose, and to occur in sweet corn products cooked
1
clams, wines,
0
11,12
13
cooked mushrooms and frogs’ legs.
The partly saturated thiazoline analogue 2 was first detected
14
2
. Results and discussion
1
5
in beef broth and has since been found to occur in sweet
8
10
12
corn products, cooked clams
6
six-membered ring analogues 3 and 4 have also been pre-
and wine.
The
Since any approach based on acetylation of a thiazole
1
17
seemed unlikely to give the required selectivity, we decided
to construct thiazoles carrying substituents on the correct
positions that could be transformed into acetyl groups. The
convenient synthesis of 2-acetylthiazole by Jones and
co-workers in 1991 involving bromination of 2-ethylthiazole
to give the 2-(1,1-dibromoethyl) compound followed by its
hydrolysis in the presence of silver nitrate provided a good
model. These workers also prepared 2-formylthiazole from
the dibromomethyl compound, and more recently, 2-acetyl-
pared and all these compounds are found to have ‘roast’ or
‘popcorn-like’ aroma characteristics. We were therefore
surprised to discover that neither of the isomeric diacetylthi-
1
9
azoles 5 or 6 have apparently been described in the litera-
8
1
ture. In this paper, we report their preparation and full
characterisation.
4
-dibromomethylthiazole was reacted with silver acetate in
2
0
aqueous acetone to give 2-acetyl-4-formylthiazole. While
our work was in progress, a conceptually similar approach
*
Corresponding author.
E-mail address: raa@st-and.ac.uk (R.A. Aitken).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.064

K.M. Aitken, R.A. Aitken / Tetrahedron 64 (2008) 4384e4386
4385
to compounds 2 and 3 involving oxidation of the 2-ethyl
16
Compounds 12 and 13 were stable enough to be character-
ised and they could be stored in a freezer overnight, but
decomposed quickly at room temperature. They were thus
converted immediately to the final products by reaction with
silver nitrate in aqueous ethanol. While this reaction pro-
ceeded satisfactorily to give 5, the product in the case of 6
was accompanied by numerous byproducts, which had to be
separated by chromatography thus resulting in a poor yield.
Both products 5 and 6 possess a strong popcorn-like odour
similar to that of compounds 1e4.
t
analogues with SeO / BuOOH was also described.
2
The required diethylthiazoles 10 and 11 are both known
compounds and were prepared by the published Hantzsch
method involving reaction of thiopropionamide 7, generated
in situ from propionamide and P S , with the appropriate
4
10
bromocarbonyl compounds in dioxane in the presence of mag-
nesium carbonate (Scheme 1). Reaction with 1-bromobutan-
2
-one 8 gave 2,4-diethylthiazole 10 (57%), while the
1
22
2
corresponding reaction with 2-bromobutanal 9 gave 2,5-
2
3
2
4
diethylthiazole (38%).
3. Experimental
Br
O
S
3.1. General
N
8
Infrared spectra were recorded for Nujol mulls on a Perkin
1
Elmer 1420 instrument. NMR spectra were obtained for H at
1
0
S
MgCO (0.5 eq)
3
dioxane, 75-80 °C
1
3
then 100 °C, 3 h
Br
300 MHz and for C at 75 MHz using a Bruker Avance 500
instrument. All spectra were run on solutions in CDCl with
internal Me Si as reference. Chemical shifts are reported in
NH
7
2
3
S
4
N
parts per million to high frequency of the reference and
coupling constants J are in hertz. Mass spectra were obtained
on a Micromass LCT mass spectrometer using Electrospray
O
11
9
Scheme 1. Synthesis of diethylthiazoles.
þ
Ionisation (ESI ). Melting points were determined in open
capillary tubes on a Gallenkamp apparatus and are uncor-
rected. Column chromatography was performed using silica
gel of 33e70 mm particle size with light petroleum (bp
The transformation of 10 and 11 to 5 and 6 was achieved in
two steps as shown in Scheme 2. Compound 10 could be
tetrabrominated to give 12 with 5 equiv of N-bromosuccin-
imide (NBS) in Arklone (1,1,2-trichloro-1,2,2-trifluoroethane),
ꢀ
4
3
3
0e60 C) as eluant.
which was used as a replacement for the toxic CCl . The mix-
4
.2. Synthesis of diethylthiazoles 10 and 11
ture was stirred under reflux for 7 h while being irradiated with
9
1
a 100 W light bulb to complete the reaction. Without irradi-
ation the bromination did not go to completion.
.2.1. 2,4-Diethylthiazole 10
Compound 10 was prepared in 57% yield from 1-bromobu-
2
tan-2-one 8 and thiopropionamide 7 according to the litera-
ture method. dH 1.29 (3H, t, J 7.5), 1.37 (3H, t, J 7.6), 2.78
1
AgNO3
O
22
NBS (5 eq)
h , Arklone
reflux, 7 h
Br Br
S
EtOH/H O
2
S
reflux, 20 min
49%
(2H, qd, J 7.5 and 0.9), 3.01 (2H, q, J 7.6) and 6.71 (1H, s); d
13.2 (CH ), 14.2 (CH ), 24.7 (CH ), 26.8 (CH ), 110.7 (CH),
C
10
N
~100%
N
3
3
2
2
Br
Br
O
158.4 (C-4) and 172.2 (C-2).
1
2
5
Br
Br
O
AgNO3
3
.2.2. 2,5-Diethylthiazole 11
Compound 11 was prepared analogously in 38% yield from
NBS (15 eq)
h , Arklone
reflux, 30 h
EtOH/H O
2
S
reflux, 20 min
15%
S
2
2-bromobutanal 9 and thiopropionamide 7 using the pub-
lished method. dH 1.29 (3H, t, J 7.5), 1.36 (3H, t, J 7.6),
2.81 (2H, qd, J 7.5 and 0.8), 2.97 (2H, q, J 7.6) and 7.31
(1H, s); d 14.1 (CH ), 16.0 (CH ), 20.5 (CH ), 26.9 (CH ),
3
11
Br
Br
N
N
9
0%
O
24
13
6
Scheme 2. Synthesis of diacetylthiazoles.
C
3
3
2
2
137.9 (CH), 140.3 (C-5) and 171.0 (C-2).
The tetrabromination of 11 proved more difficult. The
-ethyl side chain was brominated efficiently, but the 5-ethyl
2
3.2.3. 2,4-Bis(1,1-dibromoethyl)thiazole 12
group required a prolonged time and a large excess of NBS
for full conversion. With such a large amount of NBS required,
the use of the rather expensive but non-polar halogenated
solvent became a limiting factor and it proved more econom-
ical to perform the reaction once with 10 equiv of NBS for
A suspension of 2,4-diethylthiazole 10 (7.27 g, 51.5 mmol)
and NBS (45.8 g, 257 mmol) in Arklone (360 mL) was stirred
under reflux for 7 h under irradiation with a 100 W tungsten
bulb. The mixture was cooled with ice and filtered at 0 C.
The filtrate was concentrated under reduced pressure to give
ꢀ
2
0 h, filter off the solid succinimide, and add another 5 equiv
the product (23.7 g, w100%), as an unstable pale yellow solid.
7
9
81
of fresh reagent and continue the reaction for a further 30 h.
This eventually gave the desired tetrabromo compound 13 in
excellent yield.
(Found: m/z, 457.7088. C H N Br Br S (MþH) requires
ꢁ
max
7
8
2
2
1
457.7070.) n /cm 3095, 2987, 2926, 1431, 1374, 1221
and 1179; d 2.94 (3H, s), 3.01 (3H, s) and 7.76 (1H, s); dC
H

4386
K.M. Aitken, R.A. Aitken / Tetrahedron 64 (2008) 4384e4386
þ
4
0.0 (CH ), 40.7 (CH ), 52.5 (C), 54.4 (C), 120.2 (CH), 158.2
3
(C-2), 190.1 (CO) and 191.7 (CO); m/z (CI ) 170 (MþH,
3
(
C-4) and 174.1 (C-2).
100%).
3
.2.4. 2,5-Bis(1,1-dibromoethyl)thiazole 13
A suspension of 2,4-diethylthiazole 11 (7.5 g, 53 mmol) and
Acknowledgements
NBS (94.3 g, 530 mmol) in Arklone (360 mL) was stirred under
reflux for 20 h under irradiation with a 100 W tungsten bulb. The
mixture was cooled with ice and filtered at 0 C, after which the
bromination procedure was repeated with additional NBS
We thank Dr. Kenny Tenza for helpful discussions.
ꢀ
References and notes
(
56.6 g, 318 mmol) during 30 h. The mixture was again cooled
1
. Wilson, R. A.; Mussinan, C. J.; Katz, I.; Sanderson, A. J. J. Agric. Food
Chem. 1973, 21, 873e876.
and filtered, and the filtrate concentrated under reduced pressure
to give the product (22 g, 90%), as an unstable pale yellow solid.
(
2. Peterson, R. J.; Izzo, H. J.; Jungermann, E.; Chang, S. S. J. Food Sci.
975, 40, 948e954.
3. Mussinan, C. J.; Walradt, J. P. J. Agric. Food Chem. 1974, 22, 827e831.
7
9
81
1
Found: m/z, 457.7086. C H N Br Br S (MþH) requires
7
8
2
2
ꢁ
1
57.7070.) n /cm 3095, 2978, 2926, 1717, 1508, 1438,
4
max
4
. Buttery, R. G.; Ling, L. C. J. Agric. Food Chem. 1974, 22, 912e914.
. Tsugita, T.; Kurata, T.; Fujimaki, M. J. Agric. Biol. Chem. 1978, 42,
643e651.
1
d 40.0 (CH ), 42.8 (CH ), 51.5 (CBr ), 52.0 (CBr ), 138.7 (4-
375, 1291, 1216 and 1163; d 2.97 (6H, s) and 7.84 (1H, s);
H
5
C
3
3
2
2
CH), 145.0 (C-5), 175.1 (C-2).
6. Yu, T.-H.; Wu, C.-M.; Rosen, R. T.; Hartman, T. G.; Ho, C.-T. J. Agric.
Food Chem. 1994, 42, 146e153.
7
. Yu, T.-H.; Wu, C.-M.; Ho, C.-T. J. Agric. Food Chem. 1994, 42,
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. Buttery, R. G.; Stern, D. J.; Ling, L. C. J. Agric. Food Chem. 1994, 42,
91e795.
9. Bredie, W. L. P.; Mottram, D. S.; Guy, R. C. E. J. Agric. Food Chem.
998, 46, 1479e1487.
0. Sekiwa, Y.; Kubiota, K.; Kobayashi, A. J. Agric. Food Chem. 1997, 45,
26e830.
3
.2.5. 2,4-Diacetylthiazole 5
A solution of AgNO (37.2 g, 219 mmol) in water (65 mL)
1
3
8
was added to a solution of 2,4-bis(1,1-dibromoethyl)thiazole
2 (23.7 g, 51.5 mmol) in EtOH (200 mL). The mixture was
heated under reflux for 20 min, after which the solution was
cooled and acidified with 12 M HCl (75 mL) and the silver
salt was filtered off. The solution was evaporated to about
50 mL and the residue was neutralised with satd aq NaHCO3.
The mixture was extracted with dichloromethane and the
organic phase was dried (MgSO ) and concentrated, and the
4
7
1
1
1
1
8
1. Marchand, S.; de Revel, G.; Bertrand, A. J. Agric. Food Chem. 2000, 48,
4890e4895.
12. Keim, H.; de Revel, G.; Marchand, S.; Bertrand, A. J. Agric. Food Chem.
002, 50, 5803e5807.
3. Cho, I. H.; Kim, S. Y.; Choi, H.-K.; Kim, Y.-S. J. Agric. Food Chem. 2006,
4, 6332e6335.
2
1
1
crude product purified by distillation under reduced pressure
to give 2,4-diacetylthiazole (4.2 g, 49%) as colourless crystals,
5
4. N o´ brega, I. C. C.; Ata ´ı de, C. S.; Moura, O. M.; Livera, A. V.; Menezes,
ꢀ
mp 65e68 C. (Found: C, 49.6; H, 4.2; N, 8.4; m/z, 170.0274.
P. H. Food Chem. 2007, 102, 186e191.
C H NO S requires C, 49.7; H, 4.2; N, 8.3%; MþH,
15. Tonsbeek, C. H. T.; Copier, H.; Plancken, A. J. J. Agric. Food Chem.
971, 19, 1014e1016.
7
7
2
ꢁ
70.0276.) n /cm 1691; dH 2.72 (3H, s), 2.76 (3H, s)
max
1
1
1
16. Fuganti, C.; Gatti, F. G.; Serra, S. Tetrahedron 2007, 63, 4762e4767.
17. Hofmann, T.; Scieberle, P. J. Agric. Food Chem. 1995, 43, 2187e2194.
18. There is one brief mention of compound 5 as a minor byproduct in the
reaction of 2-trimethylsilyl-4-trimethylstannylthiazole with MeCOCl but
without any experimental details or characterisation: Dondoni, A.; Fantin,
G.; Fogagnolo, M.; Mastellari, A.; Medici, A.; Negrini, E.; Pedrini, P.
Gazz. Chim. Ital. 1988, 118, 211e231.
and 8.42 (1H, s); d 25.8 (CH ), 27.5 (CH ), 131.1 (5-CH),
C
3
3
1
56.0 (C-4), 166.6 (C-2), 191.4 (CO) and 192.8 (CO); m/z
þ
(
CI ) 170 (MþH, 100%).
3
.2.6. 2,5-Diacetylthiazole 6
The same procedure as for 2,4-diacetylthiazole was
1
9. Jones, G.; Ollivierre, H.; Fuller, L. S.; Young, J. H. Tetrahedron 1991, 47,
employed using the isomeric 2,5-bis(1,1-dibromoethyl)thi-
azole 13 (20.1 g, 43.6 mmol). The crude product was purified
by column chromatography to give 2,5-diacetylthiazole (1.1 g,
2
851e2860.
2
0. Figueira, V. B. C.; Praphakar, S.; Lobo, A. M. Arkivoc 2005, xiv, 14e19.
21. Catch, J. R.; Elliott, D. F.; Hey, D. H.; Jones, E. R. H. J. Chem. Soc. 1948,
72e275.
ꢀ
2
1
4
4
5%) as colourless crystals, mp 122.5e124.5 C. (Found: C,
9.6; H, 4.0; N, 8.4; m/z, 170.0277. C H NO S requires C,
2
2. Roussel, C.; Babadjamian, A.; Chanon, M.; Metzger, J. Bull. Soc. Chim.
Fr. 1971, 1087e1092.
7
7
2
ꢁ1
9.7; H, 4.2; N, 8.3%; MþH, 170.0276.) nmax/cm 1686
2
3. Yanovskaya, L. A.; Terent’ev, A. P. Zh. Obshch. Khim. 1952, 22,
1598e1602.
and 1661; d 2.65 (3H, s), 2.73 (3H, s) and 8.43 (1H, s); d
H
C
2
5.9 (CH ), 27.9 (CH ), 144.7 (C-5), 147.6 (CH), 171.1
3
24. Poite, M.; Metzger, J. Bull. Soc. Chim. Fr. 1962, 2078e2085.
3