hantzsch-thiazole-synthesis-2010

296
Hantzsch Thiazole Synthesis
A. GENERAL DESCRIPTION OF THE REACTION
This reaction was first reported by Hantzsch and Weber in 1887.1 It is the formation
of thiazole derivatives by means of condensation of α-haloketones (or aldehydes) and
thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis.2 In addition,
other names, including the Hantzsch synthesis,2k,3 Hantzsch reaction,2m,3a,4 and Hantzsch
thiazole reaction5 are also used from time to time. Besides thioamides, other thio-ketone
derivatives such as thiourea,3b,4a,6 dithiocarbamates,2k and ketone thiosemicarbazone2k can
also condense with α-halo ketones (or aldehydes) to form thiazoles. This reaction occurs
because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas,6 and
normally gives excellent yields for simple thiazoles but low yields for some substituted
thiazoles, as of dehalogenation.7 This reaction has been proven to be a multistep reaction,
and the intermediates have been isolated at low temperatures,3c in which the dehydration of
cyclic intermediates seems to be the slow step.2k It is found that a variety of reaction condi-
tions might result in the racemized thiazoles that contain an enolizable proton at their chiral
center, and it is the intermediate not the final product that is involved in the racemization.2k
Therefore, some modifications have been made to reduce or even eliminate the epimeriza-
tion upon thiazole formation.8 In addition, this reaction has been modified using α-tosyloxy
ketones to replace α-haloketones.9
Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.
1330
CITED EXPERIMENTAL EXAMPLES 1331
B. GENERAL REACTION SCHEME
R2
O
S KHCO3 R1 = H, alkyl, aryl
X + S R1
R1 R2 = H, alkyl, aryl
R3 NH2 N R3 = alkyl, aryl, NH2, etc.
R2
R3
C. PROPOSED MECHANISMS
D. MODIFICATION
This reaction has been modified to reduce the epimerization upon the formation of
thiazole.8 In addition, α-tosyloxy ketones have been used to replace α-haloketones for such
reactions.9
E. APPLICATIONS
This reaction, the classic method for thiazoles, has wide application in the preparation
of thiazole derivatives.
F. RELATED REACTIONS
N/A
G. CITED EXPERIMENTAL EXAMPLES
O
Cl
H (42%)
S
p-Tol-O THF-EtOH (2:1) S N
O NH2 or p-Tol-O
O
OEt
p-Tol-O Br
OEt (70%) p-Tol-O
HCl/dioxane
Acetone
Reference 10.
1332 HANTZSCH THIAZOLE SYNTHESIS
Method A
2,5-Anhydro-3-deoxy-4,6-di-O-p-toluoyl-D-ribo-hexonthioamide (1.16 g, 3.0 mmol)
was dissolved in a mixture of 33 mL THF and 16 mL EtOH. Then 50% chloroacetalde-
hyde solution (3.18 mL, 25 mmol) was added, and the reaction mixture was refluxed
for 24 h. Another equivalent of chloroacetaldehyde solution (3.18 mL, 25 mmol) was
added, and the reaction mixture was refluxed for another 24 h. The solvents were
evaporated, and the residue was dissolved in EtOAc, washed with saturated NaHCO3
and brine, and dried over MgSO4 . Silica gel column chromotography (EtOAc/hexanes)
yielded 42% 2-(2 -deoxy-3 ,5 -di-O-p-toluoyl-β-d-ribofuranosyl)thiazole as a light yellow
solid.
Method B
2,5-Anhydro-3-deoxy-4,6-di-O-p-toluoyl-d-ribo-hexonthioamide (0.50 g, 1.21 mmol)
was dissolved in 7.1 mL dry acetone and 0.9 mL bromoacetaldehyde diethyl acetal (0.69 g,
3.5 mmol); then 13 mL of a 4 M HCl/dioxane solution was added. The resulting clear
solution was refluxed under argon for 24 h. The brown-colored solution was evaporated to
a dark oil, then dissolved in 100 mL EtOAc and washed with 100 mL saturated aqueous
NaHCO3 and 100 mL brine. The organic layer was dried over Na2 SO4 , filtered, and evap-
orated to a dark brown liquid. Purification by silica gel chromatography (EtOAc/hexanes)
provided 0.370 g 2-(2 -deoxy-3 ,5 -di-O-p-toluoyl-β-d-ribofuranosyl)thiazole as a light
brown gum, in a yield of 70%. Crystallization from ethanol converted the compound as a
solid.
Reference 4b.
A solution of Boc-d-alanine thioamide (1.17 g, 5.74 mmol) in 35 mL DME was cooled

to −13◦ C, followed by the addition of 4.97 g KHCO3 (49.7 mmol) under a nitrogen atmo-
sphere. The suspension was vigorously stirred for 15 min, followed by the addition of 2.4
mL ethyl bromopyruvate (19.1 mmol) under the inert atmosphere at −13◦ C. The reaction
mixture was further incubated at −13◦ C for 0.5 h, and then at room temperature for 0.5 h.
After the reactants were cooled to −13◦ C again, a solution of 3.6 mL trifluoroacetic anhy-
dride (25.5 mmol) and 6.2 mL lutidine (53.2 mmol) in 10 mL DME was added dropwise.
The reaction mixture was allowed to warm from 0◦ C to room temperature and incubated for
12 h. After removal of the volatile components in vacuo and the addition of 100 mL water, the
solution was extracted with CHCl3 (3 × 50 mL). The CHCl3 phase was dried over Na2 SO4 ,
and after the removal of the solvent, the residue was chromatographed on a silica gel
column (CHCl3 /EtOAc, 2:1) to afford 1.64 g ethyl (R)-2-(1-N-Boc-amino)ethylthiazole-
4-carboxylate as a yellow semisolid, in a yield of 95%, Rf = 0.53 (CHCl3 /EtOAc, 2:1).
Other references related to the Hantzsch thiazole synthesis are cited in the literature.11
REFERENCES 1333
H. REFERENCES
1. Hantzsch, A. and Weber, J. H., Ber., 1887, 20, 3118.

2. (a) Bagley, M. C.; Dale, J. W.; Jenkins, R. L. and Bower, J., Chem. Commun., 2004, 102.
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Sect. B, 1990, 29B, 533. (i) Singh, S. P.; Sehgal, S.; Singh, L. and Dhawan, S. N., Indian J. Chem.,
Sect. B, 1987, 26B, 154. (j) Bramley, S. E.; Dupplin, V.; Goberdhan, D. G. C. and Meakins, G. D.,
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296

Hantzsch Thiazole Synthesis

A. GENERAL DESCRIPTION OF THE REACTION

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

B. GENERAL REACTION SCHEME

G. CITED EXPERIMENTAL EXAMPLES

A solution of Boc-d-alanine thioamide (1.17 g, 5.74 mmol) in 35 mL DME was cooled

1. Hantzsch, A. and Weber, J. H., Ber., 1887, 20, 3118.

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