Org. Synth. 1979, 59, 183
DOI: 10.15227/orgsyn.059.0183
THIAZOLES FROM ETHYL ISOCYANOACETATE AND THIONO ESTERS: ETHYL THIAZOLE-4-CARBOXYLATE
[4-Thiazolecarboxylic acid, ethyl ester]
Submitted by G. D. Hartman and L. M. Weinstock
1.
Checked by Louis E. Benjamin Sr, Norman W. Gilman, and Gabriel Saucy.
1. Procedure
A. N-Formylglycine ethyl ester. A 1-l., three-necked, round-bottomed flask fitted with a mechanical stirrer, a pressure-equalizing dropping funnel, and a reflux condenser bearing a calcium chloride drying tube is charged with 69.5 g. (0.495 mole) of glycine ethyl ester hydrochloride and 250 ml. of methyl formate (Note 1). The suspension is stirred and heated at reflux while 55.0 g. (0.544 mole) of triethylamine (Note 1) is added. The resulting mixture is stirred and heated under reflux for 20 hours, cooled to room temperature, and filtered through a Büchner funnel, removing triethylamine hydrochloride. The filtrate is concentrated on a rotary evaporator, and the remaining clear oil is distilled under reduced pressure, yielding 51.7–61.5 g. (79–94%) of N-formylglycine ethyl ester, b.p. 94–97° (0.05 mm., (Note 2)).
B. Ethyl isocyanoacetate. A 3-l., three-necked, round-bottomed flask equipped with a thermometer, a mechanical stirrer, and a pressure-equalizing dropping funnel bearing a nitrogen inlet is charged with 65.5 g. (0.500 mole) of N-formylglycine ethyl ester, 125.0 g. (1.234 moles) of triethylamine, and 500 ml. of dichloromethane, and the apparatus is flushed with nitrogen. The resulting solution is stirred and cooled to 0° to −2° in an ice–salt bath, and 76.5 g. (0.498 mole) of phosphorus oxychloride (Note 3) is added dropwise over 15–20 minutes while the temperature is kept at 0°. The mixture becomes reddish brown as it is stirred and cooled at 0° for an additional 1 hour. The ice–salt bath is removed and replaced by an ice-water bath. Stirring is continued as a solution of 100 g. of anhydrous sodium carbonate in 400 ml. of water is added dropwise at a rate such that the temperature of the mixture is maintained at 25–30° (Note 4). The two-phase mixture is stirred for another 30 minutes, after which water is added until the volume of the aqueous layer is brought to 1 l. The aqueous layer is separated and extracted with two 250-ml. portions of dichloromethane. The dichloromethane solutions are combined, washed with saturated sodium chloride solution, and dried over anhydrous potassium carbonate. Evaporation of the solvent under reduced pressure and distillation of the remaining brown oil afford 43–44 g. (76–78%) of ethyl isocyanoacetate, b.p. 89–91° (11 mm.) (Note 5).
C. O-Ethyl thioformate.
Caution! Hydrogen sulfide gas is highly toxic; this procedure should be conducted in a well-ventilated hood. A 1-l., three-necked, round-bottomed flask is equipped with a mechanical stirrer, a gas-inlet tube with a fritted-glass tip extending near to the bottom of the flask, and a gas-outlet connected to a scrubber flask containing 0.5–1.0 l. of aqueous 20% sodium hydroxide (Note 6). The flask is charged with 333 g. (2.25 moles) of triethyl orthoformate (Note 7), 330 ml. of glacial acetic acid, 3.2 g. of hydroquinone, and 0.4 ml. of concentrated sulfuric acid. The resulting solution is stirred and cooled in an ice bath as hydrogen sulfide gas is passed through the gas-inlet tube into the solution (Note 8). After the solution becomes saturated with hydrogen sulfide, the contents of the flask are poured into a 4-l. beaker containing a mechanically stirred mixture of 2.3 l. of ice and 340 ml. of diethyl ether. The mixture is poured into a separatory funnel, and the layers are separated. The organic layer is washed successively with two 100-ml. portions of aqueous saturated sodium hydrogen carbonate solution, two 100-ml. portions of water, three 80-ml. portions of aqueous saturated sodium hydrogen carbonate, and two 80-ml. portions of aqueous saturated sodium chloride. The solution is dried over anhydrous sodium sulfate and distilled at atmospheric pressure through a 45-cm. Vigreux column, affording 60–76.7 g. (30–38%) of O-ethyl thioformate as a yellow liquid, b.p. 87–89° (Note 9) and (Note 10).
D. Ethyl thiazole-4-carboxylate. A 250-ml., three-necked, round-bottomed flask fitted with a thermometer, a mechanical stirrer, and a pressure-equalizing dropping funnel bearing a calcium chloride drying tube is charged with 0.25 g. (0.0051 mole) of sodium cyanide and 10 ml. of absolute ethanol. The suspension is stirred vigorously at room temperature as a solution of 4.52 g. (0.0439 mole) of ethyl isocyanoacetate and 3.60 g. (0.0400 mole) of O-ethyl thioformate in 15 ml. of absolute ethanol is added slowly. Because the reaction is exothermic the temperature of the mixture should be kept below 45° by adjusting the addition rate and, if necessary, cooling the flask in an ice bath (Note 11). When the addition is completed, the contents of the flask are stirred and heated at 50° for another 30 minutes. The solvent is removed by rotary evaporation, and the resulting dark oil is extracted with three 60-ml. portions of hot hexane (Note 12). The combined hexane extracts are concentrated with a rotary evaporator until the product begins to separate, and the concentrate is cooled in an ice bath, yielding 5.1–5.5 g. (81–87%) of ethyl thiazole-4-carboxylate as off-white needles, m.p. 52–53° (Note 13).
2. Notes
1.
Glycine ethyl ester hydrochloride, methyl formate, and triethylamine were purchased from Aldrich Chemical Company, Inc., and were used without purification.
2.
The submitters obtained
63 g. (
96%), b.p.
104–106° (0.1 mm).
3.
The submitters recommend that
phosphorus oxychloride either be taken from a previously unopened bottle or distilled before use.
4.
Foaming generally occurs during the addition.
5.
Essentially no forerun need be taken prior to collection of the product. The last few milliliters of distillate were slightly yellow, and 2–3 g. of intractable material remained in the distillation flask. A boiling point of 76–78° (4 mm.) has been reported
2 for
ethyl isocyanoacetate. The submitters have found the distilled product to be stable for up to 6 months when stored under
nitrogen at −20°.
6.
The checkers used a gas-inlet tube without a fritted-glass tip and aqueous 30%
sodium hydroxide as scrubber solution.
7.
Triethyl orthoformate is available from Aldrich Chemical Company, Inc.8.
Hydrogen sulfide is admitted into the flask slowly at first, with bubble formation kept to a minimum. Initially the gas dissolves readily. As the solution becomes saturated, more bubbling action is apparent in the flask and the scrubber.
9.
The submitters reported a yield of
56.5 g. (
28%), b.p.
90–92°. The product is often contaminated with
ca. 5% of
ethyl formate; however, this impurity does not interfere with Part D. The submitters state that the product is stable when stored under
nitrogen at −20°.
10.
The checkers found that glassware in which the product was stored acquired a disagreeable odor that was difficult to remove with aqueous
sodium hydroxide.
11.
Controlling the temperature in this manner prevents discoloration of the final product and improves its yield.
12.
The product was obtained as tan needles when boiling
hexane was used by the checkers. Off-white needles were isolated when the temperature of the
hexane was 50–55°.
13.
The submitters reported a yield of
5.8 g. (
92%) of product as white needles, m.p.
53–54°. However, the checkers obtained colorless needles only after recrystallizing the product from
hexane. The melting points of the discolored needles obtained initially by the checkers and the recrystallized material were identical (lit.,
3,4 m.p.
57° and 52–54°). The spectral properties of the product are as follows: IR (CHCl
3) cm.
−1: 3130, 3030, 1724 (C=O), 1500, 1270;
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons, assignment): 1.39 (t,
J = 7, 3H, OCH
2C
H3), 4.43 (q,
J = 7, 2H, OC
H2CH
3), 8.33 (d,
J = 2.5, 1H,
H at C-5), 8.98 (d,
J = 2.5, 1H,
H at C-2).
3. Discussion
Ethyl thiazole-4-carboxylate has been prepared by hydrogenolysis of
ethyl 2-bromothiazole-4-carboxylate with
Raney nickel in
ethanol,
3 by desulfurization of
ethyl 2-mercaptothiazole-4-carboxylate with
hydrogen peroxide in concentrated
hydrochloric acid,
4 and by condensation of
ethyl bromopyruvate with
thioformamide in
ether.
5,6
The present procedure is illustrative of a mild and general method for preparing thiazoles substituted at the 4-position with electron-withdrawing substitutents such as ethoxycarbonyl,
7 cyano,
7 and
p-toluenesulfonyl.
8 Thus, condensation of
ethyl isocyanoacetate with various thiono esters affords the parent
ethyl thiazole-4-carboxylate as well as a series of analogs bearing substituents in the 5-position (Table I).
7 A similar reaction of
α-isocyanoacetonitrile with
O-ethyl thioformate gave the cyano analog in 23% yield. However, the instability of the latter isocyanide hampers the utility of this reaction.
TABLE I
THIAZOLES FROM CONDENSATION OF ETHYL ISOCYANOACETATE AND α-ISOCYANOACETAMIDE WITH THIONO ESTERS
|
|
Thiazole
|
M.p. or B.p. (°)
|
Yield(%)
|
|
|
|
89–90
|
82
|
|
|
85–87 (0.15 mm.)
|
68
|
|
|
183–185
|
22
|
|
|
49–50
|
75
|
|
|
55–56
|
23
|
|
The mechanism of the condensation in Part D probably involves thioformylation of the metallated
isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the
isonitrile. This
thiazole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides.
9,10 Interestingly,
ethyl formate does not react with
isocyanoacetate under the conditions of this procedure.
Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding
N-formylglycine esters with
phosgene2 and
trichloromethyl chloroformate,
11 respectively. The
phosphorus oxychloride method described here was provided to the submitters by Professor U. Schöllkopf
12 and is based on the procedure of Böhme and Fuchs.
13 The preparation of
O-ethyl thioformate was developed from a report by Ohno, Koizuma, and Tsuchihaski.
144-Substituted thiazoles are important intermediates, as in the synthesis of thiabendazole [
2-(4-thiazolyl)benzimidazole], a leading anthelminthic utilized for control of gastrointestinal nematodes in ruminants.
15 Other thiazoles have displayed significant pharmacologic activity as antiinflammatory
16 and antibacterial agents.
17 Recently, 4-substituted thiazoles were implicated as intermediates in the energy transfer mechanism of firefly bioluminescence.
18This preparation is referenced from:
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Glycine ethyl ester hydrochloride, methyl formate
Ethyl and methyl isocyanoacetate
ethanol (64-17-5)
potassium carbonate (584-08-7)
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ether,
diethyl ether (60-29-7)
sodium hydroxide (1310-73-2)
hydroquinone (123-31-9)
sodium hydrogen carbonate (144-55-8)
sodium cyanide (143-33-9)
sodium chloride (7647-14-5)
hydrogen sulfide (7783-06-4)
sodium carbonate (497-19-8)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
isonitrile (57-12-5)
Raney nickel (7440-02-0)
Phosphorus Oxychloride (21295-50-1)
phosgene (75-44-5)
hydrogen peroxide (7722-84-1)
triethyl orthoformate (122-51-0)
ethyl formate (109-94-4)
Triethylamine hydrochloride (554-68-7)
methyl formate (107-31-3)
dichloromethane (75-09-2)
Glycine ethyl ester hydrochloride (623-33-6)
thiazole (288-47-1)
hexane (110-54-3)
triethylamine (121-44-8)
Trichloromethyl chloroformate (503-38-8)
Ethyl isocyanoacetate (2999-46-4)
Ethyl thiazole-4-carboxylate,
4-Thiazolecarboxylic acid, ethyl ester (14527-43-6)
ethyl 2-bromothiazole-4-carboxylate
ethyl 2-mercaptothiazole-4-carboxylate
ethyl bromopyruvate (70-23-5)
thioformamide (115-08-2)
α-isocyanoacetonitrile
isocyanoacetate
2-(4-thiazolyl)benzimidazole (148-79-8)
N-Formylglycine ethyl ester (3154-51-6)
O-ethyl thioformate (21071-39-6)
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